Article

Current Concepts for Genital Herpes Simplex Virus Infection: Diagnostics and Pathogenesis of Genital Tract Shedding

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Abstract

Herpes simplex virus 2 (HSV-2) is a DNA virus that is efficiently transmitted through intimate genital tract contact and causes persistent infection that cannot be eliminated. HSV-2 may cause frequent, symptomatic self-limited genital ulcers, but in most persons infection is subclinical. However, recent studies have demonstrated that the virus is frequently shed from genital surfaces even in the absence of signs or symptoms of clinical disease and that the virus can be transmitted during these periods of shedding. Furthermore, HSV-2 shedding is detected throughout the genital tract and may be associated with genital tract inflammation, which likely contributes to increased risk of HIV acquisition. This review focuses on HSV diagnostics, as well as whatwehave learned about the importance of frequent genital HSV shedding for (i) HSV transmission and (ii) genital tract inflammation, as well as (iii) the impact of HSV-2 infection on HIV acquisition and transmission.Weconclude with discussion of future areas of research to push the field forward. © 2015, American Society for Microbiology. All Rights Reserved.

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... Additionally, HSV-1 is increasingly investigated as an etiological factor in Alzheimer's Disease [4][5][6]. Moreover, a close cousin of HSV-1, HSV-2 is a serious human pathogen as well as a risk factor for acquiring human immunodeficiency virus-1 (HIV-1) infection [7,8]. ...
... Cell-free virions shed from the epithelium during reactivation are the agents responsible for human-human transmission. The interaction of HSV-2 with humans is quite similar to that of HSV-1, although for this virus the genital tract is the usual site of infection [8]. ...
... However, it also suggests that HSV-1 has evolved an efficient mechanism to shed progeny virions in the tissues associated with transmission. Although HSV-1 shedding has not been well studied, clues to this process can be gleaned from work on HSV-2 shedding that has been carried for more than 20 years by investigators at the University of Washington (UW) [8,13,[96][97][98][99][100][101]. A groundbreaking initial study enlisted HSV-2-positive individuals to swab their genitalia over the course of many weeks and provide the samples to the clinic for PCR-detection of virus [101]. ...
Article
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Herpes simplex virus type 1, or HSV-1, is a widespread human pathogen that replicates in epithelial cells of the body surface and then establishes latent infection in peripheral neurons. When HSV-1 replicates, viral progeny must be efficiently released to spread infection to new target cells. Viral spread occurs via two major routes. In cell-cell spread, progeny virions are delivered directly to cellular junctions, where they infect adjacent cells. In cell-free release, progeny virions are released into the extracellular milieu, potentially allowing the infection of distant cells. Cell-cell spread of HSV-1 has been well studied and is known to be important for in vivo infection and pathogenesis. In contrast, HSV-1 cell-free release has received less attention, and its significance to viral biology is unclear. Here, I review the mechanisms and regulation of HSV-1 cell-free virion release. Based on knowledge accrued in other herpesviral systems, I argue that HSV-1 cell-free release is likely to be tightly regulated in vivo. Specifically, I hypothesize that this process is generally suppressed as the virus replicates within the body, but activated to high levels at sites of viral reactivation, such as the oral mucosa and skin, in order to promote efficient transmission of HSV-1 to new human hosts.
... HSV-2 remains the leading cause of genital herpes and is associated with 60% of genital ulcers in the United States, Asia, Africa, and parts of Europe [1]. The epidemiology of genital herpes is changing, however, as first-time genital herpes infections in industrialized, high income countries are increasingly associated with HSV-1, especially among individuals under 25 years of age, college students, females, and men who have sex with men. ...
... The epidemiology of genital herpes is changing, however, as first-time genital herpes infections in industrialized, high income countries are increasingly associated with HSV-1, especially among individuals under 25 years of age, college students, females, and men who have sex with men. This is likely driven by reduced prevalence of early childhood HSV-1 infection, leaving adolescents and young-adults susceptible to genital infection when they become sexually active [1][2][3][4]. Genital herpes caused by HSV-2, however, has a markedly different clinical progression than that caused by HSV-1, characterized by greater frequencies of clinical recurrences and episodes of asymptomatic viral shedding [1,3,5,6]. ...
... This is likely driven by reduced prevalence of early childhood HSV-1 infection, leaving adolescents and young-adults susceptible to genital infection when they become sexually active [1][2][3][4]. Genital herpes caused by HSV-2, however, has a markedly different clinical progression than that caused by HSV-1, characterized by greater frequencies of clinical recurrences and episodes of asymptomatic viral shedding [1,3,5,6]. HSV-2 infects an estimated 13% of the global population and the World Health Organization estimates that nearly half a billion people 15-49 years of age are infected with HSV-2 [7]. The infection disproportionately impacts women worldwide [8]. ...
Article
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Treatment to ameliorate the symptoms of infection with herpes simplex virus 2 (HSV-2) and to suppress reactivation has been available for decades. However, a safe and effective preventative or therapeutic vaccine has eluded development. Two novel live-attenuated HSV-2 vaccine candidates (RVx201 and RVx202) have been tested preclinically for safety. Hartley guinea pigs were inoculated vaginally (n = 3) or intradermally (n = 16) with either vaccine candidate (2 × 107 PFU) and observed for disease for 28 days. All animals survived to study end without developing HSV-2-associated disease. Neither vaccine candidate established latency in dorsal root or sacral sympathetic ganglia, as determined by viral DNA quantification, LAT expression, or explant reactivation. Infectious virus was shed in vaginal secretions for three days following vaginal inoculation with RVx202, but not RVx201, although active or latent HSV-2 was not detected at study end. In contrast, guinea pigs inoculated with wild-type HSV-2 MS (2 × 105 PFU) vaginally (n = 5) or intradermally (n = 16) developed acute disease, neurological signs, shed virus in vaginal secretions, experienced periodic recurrences throughout the study period, and had latent HSV-2 in their dorsal root and sacral sympathetic ganglia at study end. Both vaccine candidates generated neutralizing antibody. Taken together, these findings suggest that these novel vaccine candidates are safe in guinea pigs and should be tested for efficacy as preventative and/or therapeutic anti-HSV-2 vaccines.
... Los beneficios de esta estrategia consisten en disminuir el número de recurrencias y la liberación de partículas de HSV-2 en un 70%-80%, por lo que resulta útil también para parejas serodiscordantes. 5,129 Esta terapia no ha mostrado reducir la adquisición o transmisión del HIV. 129 Pacientes con infección por HSV y HIV. ...
... 5,129 Esta terapia no ha mostrado reducir la adquisición o transmisión del HIV. 129 Pacientes con infección por HSV y HIV. La liberación de HSV es mayor en personas con HIV. ...
Article
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Dedicamos este relato a todos aquellos que día a día luchan por ser visibilizados: a las mujeres en general y a las cirujanas en particular; a los hispano parlantes, principalmente de lugares que no pertenecen al denominado primer mundo; a los que producen conocimiento en países no hegemónicos; a los que tienen un acceso dificultoso al sistema de salud y, en especial, a los que padecen infecciones sexualmente transmisibles y no encuentran a un profesional integralmente preparado para atenderlos.
... Infection occurred in infants delivered vaginally to asymptomatic mothers who were shown to be shedding HSV by the viral culture at delivery. 46 Symptoms include ulcers on the genital and oral mucosa. Systemic symptoms such as headache, fever, and myalgia may accompany primary infection in women. ...
... Preventive strategies such as frequent prenatal examinations, encouraging a healthy lifestyle, and avoiding numerous sex relations should be prioritized in our daily lives. 46 Reduced disease-related risks will come from a detailed sexual history, increased early detection of HSV infections, screenings, as well as appropriate disease counseling and education. Genital herpes occurs late in pregnancy, the easiest way to avoid prenatal herpes illnesses is to minimize viral exposure to a neonate, while the incidence of serious neonatal infection is low in repeated episodes. ...
Article
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TORCH-S is a medical acronym for a set of perinatal infections with known adverse impact on fetal developmental and pregnancy outcome. This includes infections with , Rubella virus, Cytomegalovirus, Herpes simplex virus (1 and 2) and (Syphilis). TORCH-S infections group of prenatal illnesses that have been linked to adverse outcomes in fetal development and pregnancy. Infections caused by TORCH-S can affect anybody, including children, men, and non-pregnant women. However, because they may be passed to the embryo while it is still in the womb, major fetal problems can arise if a mother is exposed during the first 5 months of pregnancy. The cornerstone of congenital infection prevention is the primary prevention of maternal infections during pregnancy. Early identification of TORCH-S infection will help in appropriate treatment and management of these infections.
... Herpes Simplex Virus (HSV) is a well-known pathogen which accounts for lifelong infections in humans. Globally, millions of people are infected with either one or both serotypes of the virus with 19.2 million new infections occurring yearly [1,2]. Two types of viruses most commonly cause all clinical manifestations: HSV type 1 and HSV type 2. HSV type 1 typically causes orofacial infections, whereas HSV type 2 is better known for causing genital herpes and is the leading cause of genital ulcer disease worldwide [3,4]. ...
... The virus is capable of causing recurrent infections in the host due to its ability to go into a latency state [4,6,7,8]. HSV also responsible for neonatal herpes infections, genital ulcer disease and increases the acquisition of other sexually transmitted infections such as Human Immunode ciency Virus (HIV) and Human Papillomavirus (HPV) [1,3]. Modern lifestyles such as oral sex and multiple sexual relationships contribute to the spread of the virus. ...
Preprint
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Herpes simplex virus infections account for a large burden of disease worldwide. HSV-1 is traditionally considered to cause orofacial infections, whereas HSV-2 is known for genital infections. A number of studies have suggested an increase of genital herpes infections caused by HSV-1. As reporting of diseases caused by herpes simplex virus is not mandatory in Ghana, reliable statistics on the epidemiology of infections are not available. We took advantage of the Cervicare program in Ghana to screen for the presence of HSV variants 1 and 2 among a convenient subset of asymptomatic women presenting for cervical screening in Accra, Ghana (n = 94). Genetic markers for both HSV 1 and 2 were detected in cervical swabs. There was a preponderance of HSV-1 (12.8%) genital infections in our study sample: compared to HSV-2 (4.8%). HSV-1 and 2 co-infection was detected in 4.3% of study population. Among positive cases for HSV-1 DNA, 92% had con rmed seropositive HSV-1 status and 8% were borderline result. All positive HSV-2 DNA were con rmed seropositive HSV-2 status. We have successfully demonstrated the presence of herpes simplex virus type 1 and type 2 gene variants in genital swabs. Owing to the lack of epidemiological data on genital HSV-1 infection in Ghana, the role of sexual transmission for HSV-1 is unclear: the ndings of our pilot study have important public health implications. A bigger surveillance study is recommended in Ghana to identify the etiology of genital herpes and estimate the true burden of asymptomatic herpes infection in the population.
... While seroprevalence indicates that HSV-1 is widespread-e.g., 50% of adults in the Americas (Looker et al., 2015)-not all infected individuals experience symptomatic outbreaks. Because HSV infections are lifelong and incurable, the primary clinical goal for infected individuals is to manage symptoms, and to reduce the likelihood of transmission to uninfected partners (e.g., through antiviral suppression therapy, and/or avoidance of contact during symptomatic outbreaks) ( Johnston and Corey, 2015). There is a social stigma associated with genital herpes, and to a lesser extent with orolabial herpes, which can present a barrier to identification and clinical study enrollment of infected individuals. ...
... However, even for individuals willing to contribute samples for clinical studies, there is the added challenge that HSV reactivation occurs spontaneously and unpredictably in each individual. There is no way to predict the timing of viral shedding (i.e., viral release from the skin), nor to intentionally trigger a reactivation to allow precise sample collection on a clinicallycontrolled timeline ( Johnston and Corey, 2015). Thus most studies on the natural ecology of HSV shedding have utilized repeated sample collections, spanning days or weeks, in order to document the rate and frequency of viral shedding and lesions ( Johnston et al., 2014;Ramchandani et al., 2016;Schiffer et al., 2011;van Velzen et al., 2013). ...
Chapter
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Over the last two decades, the viromes of our closest relatives, the African great apes (AGA), have been intensively studied. Comparative approaches have unveiled diverse evolutionary patterns, highlighting both stable host-virus associations over extended evolutionary timescales and much more recent viral emergence events. In this chapter, we summarize these findings and outline how they have shed a new light on the origins and evolution of many human-infecting viruses. We also show how this knowledge can be used to better understand the evolution of human health in relation to viral infections.
... While seroprevalence indicates that HSV-1 is widespread -e.g., 50% of adults in the Americas ( Looker et al., 2015) -not all infected individuals experience symptomatic outbreaks. Because HSV infections are lifelong and incurable, the primary clinical goal for infected individuals is to manage symptoms, and to reduce the likelihood of transmission to uninfected partners (e.g., through antiviral suppression therapy, and/or avoidance of contact during symptomatic outbreaks) (Johnston and Corey, 2015). There is a social stigma associated with genital herpes, and to a lesser extent with orolabial herpes, which can present a barrier to identification and clinical study enrollment of infected individuals. ...
... However, even for individuals willing to contribute samples for clinical studies, there is the added challenge that HSV reactivation occurs spontaneously and unpredictably in each individual. There is no way to predict the timing of viral shedding (i.e., viral release from the skin), nor to intentionally trigger a reactivation to allow precise sample collection on a clinically-controlled timeline (Johnston and Corey, 2015). Thus most studies on the natural ecology of HSV shedding have utilized repeated sample collections, spanning days or weeks, in order to document the rate and frequency of viral shedding and lesions (Johnston et al., 2014;Ramchandani et al., 2016;Schiffer et al., 2011;van Velzen et al., 2013). ...
Chapter
Herpes simplex viruses (HSV) cause chronic infection in humans that are characterized by periodic episodes of mucosal shedding and ulcerative disease. HSV causes millions of infections world-wide, with lifelong bouts of viral reactivation from latency in neuronal ganglia. Infected individuals experience different levels of disease severity and frequency of reactivation. There are two distantly related HSV species, with HSV-1 infections historically found most often in the oral niche and HSV-2 infections in the genital niche. Over the last two decades, HSV-1 has emerged as the leading cause of first-episode genital herpes in multiple countries. While HSV-1 has the highest level of genetic diversity among human alpha-herpesviruses, it is not yet known how quickly the HSV-1 viral population in a human host adapts over time, or if there are population bottlenecks associated with viral reactivation and/or transmission. It is also unknown how the ecological environments in which HSV infections occur influence their evolutionary trajectory, or that of co-occurring viruses and microbes. In this review, we explore how HSV accrues genetic diversity within each new infection, and yet maintains its ability to successfully infect most of the human population. A holistic examination of the ecological context of natural human infections can expand our awareness of how HSV adapts as it moves within and between human hosts, and reveal the complexity of these lifelong human-virus interactions. These insights may in turn suggest new areas of exploration for other chronic pathogens that successfully evolve and persist among their hosts.
... Herpes simplex virus (HSV) is a DNA virus widespread in the human population due to its effective transmission. Among the different herpesvirus types, HSV-1 and HSV-2 are responsible for many important diseases such as orolabial herpes, encephalitis, and genital herpes [1][2][3]. After primary infection, latency occurs in specific neurons and the latent virus can be periodically reactivated [2,4,5]. ...
Article
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Herpes viruses are widespread in the human population and can cause many different diseases. Genital herpes is common and can increase the risk of HIV infection and neonatal herpes. Acyclovir is the most used drug for herpes treatment; however, it presents some disadvantages due to its poor oral bioavailability. In this study, some ethylene vinyl acetate devices with different acyclovir amounts (0, 10, and 20 wt.%) were manufactured by fused filament fabrication in two different geometries, an intrauterine device, and an intravaginal ring. Thermal analyses suggested that the crystallinity of EVA decreased up to 8% for the sample loaded with 20 wt.% of acyclovir. DSC, SEM, and FTIR analyses confirmed that the drug was successfully incorporated into the EVA matrix. Moreover, the drug release tests suggested a burst release during the first 24 h followed by a slower release rate sustained up to 80 days. Biological assays showed the biocompatibility of the EVA/ACV device, as well as a 99% reduction in vitro replication of HSV-1. Finally, the EVA presented a suitable performance for 3D printing manufacturing that can contribute to developing personalized solutions for long-term herpes treatment.
... HSV-2 is transmitted through genital contact, causing persistent infection, which may cause frequent, symptomatic, and self-limited genital ulcers, but in most cases, the infection is subclinical. [6] CNS infections caused due to HSV-2 are less frequently diagnosed than HSV-1 infections, and meningitis caused could be due to primary infection or reactivation of latent infection. In previous studies, a prior history of genital herpes has been reported in up to 40% of HSV-2 meningitis cases and concurrent outbreaks in 86%, but more recent data have shown genital outbreaks at the time of meningitis in less than 10% of the cases. ...
... The severe, atypical presentation of HSV in our patient was most consistent with IRIS due to viral shedding after the initiation of cART [13][14][15][16]. IRIS develops in approximately 16% of persons living with HIV who start antiretroviral therapy, which is called "unmasking" when occurring in the context of a previously unrecognized opportunistic infection and "paradoxical" when the opportunistic infection was previously recognized and being treated [17][18][19][20]. ...
... The herpes simplex virus type 1 (HSV-1) infection is transmitted usually via saliva and occurs most commonly in the head and neck region, while HSV-2 infects mostly the genital region and is sexually transmitted [1]. However, HSV-2 can also cause oral infections and HSV-1 genital infections [2,3]. ...
Article
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The aim was to evaluate the herpes simplex virus (HSV) seroprevalence and seroconversion among 285 pregnant women and their 120 male spouses in Finland during a six-year follow-up (FU) between 1998–2008. We also studied the effect of sexual habits, pregnancy, and other demographic factors on the acquisition of HSV infection. Combined HSV-1 and HSV-2-IgG antibodies were assessed in the first baseline serum samples with an indirect enzyme immunoassay method. The individuals with seronegative or borderline HSV serology at baseline were additionally tested using their latest FU serum sample available. The overall HSV seroprevalence during the FU was 58.9% (168/285) among the women and 53.3% (64/120) among their spouses. The seroconversion rate was 11.4% (15/132) and 12.5% (8/64) among women and their spouses, respectively. Both spouses were HSV seropositive in 39.2% (47/120). To determine the HSV-2 seroprevalence, we also tested all HSV-seropositive participants using HSV-2-specific antigen. HSV-2 seropositivity was detected in 10.9% (44/405) of the participants. The age (p = 0.006) and history of genital warts (p = 0.006) of the women were associated with combined HSV-1 and/or HSV-2 seropositivity, while a younger age was related to HSV seroconversion (p = 0.023). Among the male spouses, HSV seropositivity was associated with the practice of oral sex (p = 0.033). To conclude, women of childbearing age acquire primary HSV infections and the presence of HSV in oral epithelium is common among HSV-seropositive individuals.
... Most HSV infections are asymptomatic and when they show cyclical manifestations, they do so in the same anatomi- cal region, alternating with periods of latency of variable duration. 32 These episodes are commonly associated with periods of physical or emotional stress, fever, medication use, solar radiation, menstruation, or even sexual activity. Some patients have a more severe initial condition, usually called primary infection. ...
Article
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Genital ulcers (GUs) represent a diagnostic challenge and can be secondary to neoplastic and inflammatory processes of different causes. Among those of infectious etiology, there are sexually transmitted infections (STIs), a very frequent reason for seeking the health service. The most common agents are herpes simplex virus and Treponema pallidum and, more rarely, Haemophilus ducreyi, Klebsiella granulomatis and Chlamydia trachomatis. A careful dermatological examination offers important diagnostic elements; however, atypical manifestations are very common. Distinctive characteristics of ulcers to look out for include their margin, edge, bottom, and base. Regional lymph node chain alterations should be evaluated regarding their number, size, mobility, consistency, inflammation, and pain on palpation. Diagnostic tests have variable sensitivity and specificity, and molecular tests are currently considered the reference exams. The rapid immunochromatographic tests represented a significant advance, as they can be performed with blood obtained from the digital pulp, offer results in up to 30 minutes, and do not require a laboratory structure. The treatment of persons affected by GU/STIs must be immediate, as it aims to prevent complications, as well as reduce transmission. It is not always considered that people with GUs/STIs have varying degrees of depression, anxiety, and self-reproach, with an impact on relationships. Establishing a bond and trusting the professional is essential for adherence to treatment and preventive measures that must be discussed individually.
... HSV-2 can cause rare but serious diseases such as encephalitis and newborn infections [6]. In these highly contagious viruses, transmission occurs through unprotected oral or genital sexual intercourse with an infected person [7][8][9][10]. Improvements in type-specific HSV serological tests have ensured the increase in the information about HSV-2 epidemiology. ...
Article
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Aim: Herpes simplex virus type 2 (HSV-2) is one of the most common causes of sexually transmitted genital infections and remains latent in neuronal cells for the lifetime of humans. This retrospective study aimed to determine the seroprevalence of HSV-2 and evaluate its relationship with age and gender. Materials and Methods: In this study, 976 serum samples sent to Virology Laboratory between October 2016 and December 2018 were evaluated. HSV-2 IgM and IgG antibodies were tested with VirClia EIA/CLIA device by using a commercial kit. Results: The median age of 976 patients included in the study was 31 (0−88). Fortythree point three percent (423) of the patients were male. HSV-2 IgM was found in 0.3% (3/976) of the patients and HSV-2 IgG was found in 3.7% (36/976). HSV-2 IgG was detected in 2.8% of male patients (12/423) and 4.3% (24/553) of female patients (p = 0.120). The highest HSV-2 IgG seropositivity rate was between the ages of 40 and 59 in both genders (8.3% in males and 8.3% in females) (p = 0.010 and p = 0.250 respectively). Conclusion: The HSV-2 IgG seropositivity rates we detected in this study were consistent with other study data in our country and in the world. Studies on HSV-2 IgG seroprevalence and determination of the age groups at risk will be guides for public health studies aimed for protection against HSV-2 infection.
... In addition to the above referred confounding effects [36], another phenomenon that can blur the high co-factor effect of genital ulcers is that, after they heal, inflammation may persist in the area for weeks, as was demonstrated for HSV-2 [38]. This inflammation also likely increases the odds of HIV acquisition and transmission and may explain part of the diluted RRs found in studies (Table 1). ...
Article
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In the early 1990s, several observational studies determined that genital ulcer disease (GUD), in either the index or the exposed person, facilitates HIV transmission. Several meta-analyses have since presented associated risk ratios (RR) over the baseline per-act transmission probability (PATP) usually in the range of 2–5. Here we review all relevant observational studies and meta-analyses, and show that the estimation of RRs was, in most cases, biased by assuming the presence of GUD at any time during long follow-up periods, while active genital ulcers were present in a small proportion of the time. Only two studies measured the GUD co-factor effect in PATPs focusing on acts in which ulcers were present, and both found much higher RRs (in the range 11–112). We demonstrate that these high RRs can be reconciled with the studies on which currently accepted low RRs were based, if the calculations are restricted to the actual GUD episodes. Our results indicate that the effect of genital ulcers on the PATP of HIV might be much greater than currently accepted. We conclude that the medical community should work on the assumption that HIV risk is very high during active genital ulcers.
... Дослідження показали, що вакуум-терапія робить позитивний вплив на перебіг всіх стадій раневого процесу. Це проявляється зменшенням місцевого набряку, зниженням продукції ранового виділення, поліпшенням мікроциркуляції [9,16,20]. ...
Article
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The purpose of the study. is to give a clinical evaluation of the effectiveness of vacuum therapy in combination with autodermoplasty in the complex treatment of patients with necrotic erysipelas. Materials and methods of research. 114 case histories of patients who were hospitalized in the center of purulentseptic surgery in the Non profit municipal enterprise «City Hospital № 3» in Zaporizhzhia for the period 2019–2020 were analyzed retrospectively and prospectively. Results. Patients on admission to the clinic underwent surgical treatment, which consisted in opening a purulent lesion, necrectomy. After installation of the vacuum aspirator the general condition and the general state of health of patients considerably improved, already by the 5th day cleaning of a wound and emergence of granulation had been noted. The use of a vacuum device contributed to the dosed pressing of the skin flap to the wound surface, reliable fixation of the skin flap and to some extent – the improvement of local microcirculation. Conclusions. The use of vacuum therapy helps to clean the purulent wound, reduces the first phase of the wound process and potentiates the filling of the wound surface with mature granulation tissue. The use of vacuum therapy provides reliable fixation of skin grafts on the wound surface, eliminates the risk of their displacement in the near future after autodermoplasty
... These viruses are transmitted by direct contact with mucosa, secretions and oral or genital lesions of an infected person 139,[142][143][144][145][146] ; therefore, HSV-1 can cause genital herpes through oral sex 151 . HSV infections are the leading cause of sexually transmitted genital ulcers in the world 152 . Women are more likely to acquire genital herpes than men, either by HSV-1 or by HSV-2, owing to a woman's anatomy, as the lining of the vagina is thinner and more delicate than the skin on a penis, genital ulcers at the vagina are not easily visible, women have fewer or non-specific symptoms and because genital herpes is more easily transmitted from men to women than from women to men during penilevaginal sex 153,154 . ...
Article
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Every day, more than one million people worldwide acquire a sexually transmitted infection (STI). This public health problem has a direct effect on women's reproductive and sexual health as STIs can cause irreversible damage to fertility and can have negative consequences associated with discrimination and social exclusion. Infection with one sexually transmitted pathogen predisposes to co-infection with others, suggesting the existence of shared pathways that serve as molecular links between these diseases. Galectins, a family of β-galactoside-binding proteins, have emerged as endogenous mediators that facilitate cell-surface binding, internalization and cell invasion of many sexually transmitted pathogens, including Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, Candida albicans, HIV and herpes simplex virus. The ability of certain galectins to dimerize or form multimeric complexes confers the capacity to interact simultaneously with glycosylated ligands on both the pathogen and the cervico-vaginal tissue on these proteins. Galectins can act as a bridge by engaging glycans from the pathogen surface and glycosylated receptors from host cells, which is a mechanism that has been shown to be shared by several sexually transmitted pathogens. In the case of viruses and obligate intracellular bacteria, binding to the cell surface promotes pathogen internalization and cell invasion. Inflammatory responses that occur in cervico-vaginal tissue might trigger secretion of galectins, which in turn control the establishment, evolution and severity of STIs. Thus, galectin-targeted therapies could potentially prevent or decrease STIs caused by a diverse array of pathogenic microorganisms; furthermore, anti-galectin agents might reduce treatment costs of STIs and reach the most vulnerable populations.
... However, either cell entry or expression of immediate-early HSV-2 genes was required, since UV-treated virus did not enhance ZIKV binding and a short exposure (4 h) of cells to HSV-2 was insufficient to evidence an enhancement in ZIKV binding. Even though the enhancement of in vitro binding of ZIKV to target cells was, on average, only 2.5-fold after a single exposure of epithelial cells to HSV-2, it is plausible that in vivo the effect can be amplified because of intermittent HSV-2 reactivations with concomitant viral shedding, which happens in the absence of symptoms and even when antiviral drugs are taken (Wald et al., 1997;Johnston and Corey, 2016). Therefore, the repeated inflammatory stimulation of the mucosal epithelium with each HSV reactivation event could increase the susceptibility to ZIKV infection to a higher extent than observable by single-point in vitro experiments. ...
Article
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Zika virus (ZIKV) is transmitted to people by bite of an infected mosquito and by sexual contact. ZIKV infects primary genital epithelial cells, the same cells targeted by herpes simplex virus 2 (HSV-2). HSV-2 seroprevalence is high in areas where ZIKV is endemic, but it is unknown whether HSV-2 increases the risk for ZIKV infection. Here, we found that pre-infecting female genital tract epithelial cells with HSV-2 leads to enhanced binding of ZIKV virions. This effect did not require active replication by HSV-2, implying that the effect results from the immune response to HSV-2 exposure or to viral genes expressed early in the HSV-2 lifecycle. Treating cells with toll-like receptor-3 ligand poly-I:C also lead to enhanced binding by ZIKV, which was inhibited by the JAK-STAT pathway inhibitor ruxolitinib. Blocking or knocking down the well-studied ZIKV receptor AXL did not prevent binding of ZIKV to epithelial cells, nor prevent enhanced binding in the presence of HSV-2 infection. Blocking the α5 integrin receptor did not prevent ZIKV binding to cells either. Overall, our results indicate that ZIKV binding to genital epithelial cells is not mediated entirely by a canonical receptor, but likely occurs through redundant pathways that may involve lectin receptors and glycosaminoglycans. Our studies may pave the way to new interventions that interrupt the synergism between herpes and Zika viruses.
... Specific IgM antibodies have a low sensitivity and giving false positive results at low index values (1.1-3.5). In the present case, anti-IgM value of HSV-2 is 1.30 which can provide false positive results; and specific IgM antibody can occur in recurrent infection (Biškup et al., 2015;Johnston & Corey, 2016). Therefore, laboratory results alone cannot be used as single consideration of diagnosis. ...
Article
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The symptoms of recurrent oral herpes infection may vary, from mild discomfort to life threatening. Dentists are more likely to be consulted in this oral infection, hence the ability to diagnose and treat this disease is mandatory. This article described manifestation and therapy of recurrent oral herpes infection. In the first case, a 41-year-old woman came with a complaint of painful sore mouth in her lower gingiva. She experienced canker sores for two to three times a year on the tongue, lips and palate. Laboratory results showed positive IgM anti HSV-2, which matched with the primary herpes infection. However, based on the history and clinical manifestations, she was diagnosed with recurrent intra oral herpes infection. In the second case, a 70-year-old man came with a very painful canker sores in his entire mouth. The patient had to be hospitalised for three days and received analgesic, antibiotic and gel containing triamcinolone. After hospitalisation, canker sores did not heal. Extraorally, we found a crust in the vermillion border of the upper lip and intraorally, we found multiple ulceration of keratinised and non-keratinised mucosa. The use of topical steroid in this patient may aggravated ulceration due to its ability to cause rapid spreading of the virus. The first patient was given chlorhexidine gluconate 0.2% and the second patient was prescribed with doxycycline rinse. Both patients received multivitamin containing zinc. Complete history taking, objective and adjunctive examination played a role in establishing the diagnosis and treatment of recurrent oral herpes infections.
... The rate of asymptomatic viral shedding is more with HSV-2 than HSV-1. The median duration of asymptomatic viral shedding following the clinical lesions for primary infection and the recurrent episode is about 12 days and four days, respectively, and accounts for at least 70 % of viral transmission [45]. PCR-based studies (which are more sensitive than culture-based studies) suggest that asymptomatic viral shedding occurs 12-25 % of days [46,47]. ...
... It is therefore advisable that the clinical diagnosis of genital herpes is confirmed by type-specific laboratory tests and that positive subjects also be diagnosed for HIV, considering that genital HSV infection has long been identified as a risk factor in HIV acquisition, with a 2-to 3-fold higher risk, also due to multiple sex partners. The biological basis of increased susceptibility is due to both increased ulceration and increased inflammation (with higher CD4+ cells) present in the skin and mucosa of HSV-2 infected individuals [43]. ...
Article
Some maternal infections, contracted before or during pregnancy, can be transmitted to the fetus, during gestation (congenital infection), during labor and childbirth (perinatal infection) and through breastfeeding (postnatal infection). The agents responsible for these infections can be viruses, bacteria, protozoa, fungi. Among the viruses most frequently responsible for congenital infections are Cytomegalovirus (CMV), Herpes simplex 1-2, Herpes virus 6, Varicella zoster. Moreover Hepatitis B and C virus, HIV, Parvovirus B19 and non-polio Enteroviruses when contracted during pregnancy may involve the fetus or newborn at birth. Recently, new viruses have emerged, SARS-Cov-2 and Zika virus, of which we do not yet fully know the characteristics and pathogenic power when contracted during pregnancy. Viral infections in pregnancy can damage the fetus (spontaneous abortion, fetal death, intrauterine growth retardation) or the newborn (congenital anomalies, organ diseases with sequelae of different severity). Some risk factors specifically influence the incidence of transmission to the fetus: the timing of the infection in pregnancy, the order of the infection, primary or reinfection or chronic, the duration of membrane rupture, type of delivery, socio-economic conditions and breastfeeding. Frequently infected neonates, symptomatic at birth, have worse outcomes than asymptomatic. Many asymptomatic babies develop long term neurosensory outcomes. The way in which the virus interacts with the maternal immune system, the maternal-fetal interface and the placenta explain these results and also the differences that are observed from time to time in the fetal-neonatal outcomes of maternal infections. The maternal immune system undergoes functional adaptation during pregnancy, once thought as physiological immunosuppression. This adaptation, crucial for generating a balance between maternal immunity and fetus, is necessary to promote and support the pregnancy itself and the growth of the fetus. When this adaptation is upset by the viral infection, the balance is broken, and the infection can spread and lead to the adverse outcomes previously described. In this review we will describe the main viral harmful infections in pregnancy and the potential mechanisms of the damages on the fetus and newborn.
... While controlling HSV-2 infection is a main pillar of the global effort to address the population's sexual and reproductive health needs, 18 19 current prevention modalities are inadequate to control transmission and there are no specific programmes for HSV-2 prevention and control even in highincome countries. [20][21][22] This highlights the critical need for HSV-2 vaccination as a strategic approach to control transmission and to reduce if not eliminate the clinical, psychosexual and economic burden of this infection. 18 [23][24][25][26] Against this context, the WHO is spearheading a multisectorial effort to establish the business case and return on investment for HSV-2 vaccines. ...
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Objective To characterise epidemiology of herpes simplex virus type 2 (HSV-2) in Latin America and the Caribbean. Methods HSV-2 reports were systematically reviewed and synthesised, and findings were reported following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Meta-analyses and metaregressions were conducted. Finding 102 relevant reports were identified including 13 overall incidence measures, 163 overall (and 402 stratified) seroprevalence measures, and 7 and 10 proportions of virus detection in genital ulcer disease and in genital herpes, respectively. Pooled mean seroprevalence was 20.6% (95% CI 18.7% to 22.5%) in general populations, 33.3% (95% CI 26.0% to 41.0%) in intermediate-risk populations, 74.8% (95% CI 70.6% to 78.8%) in female sex workers, and 54.6% (95% CI 47.4% to 61.7%) in male sex workers, men who have sex with men and transgender people. In general populations, seroprevalence increased from 9.6% (95% CI 7.1% to 12.4%) in those aged <20 years to 17.9% (95% CI 13.6% to 22.5%) in those aged 20–30, 27.6% (95% CI 21.4% to 34.2%) in those aged 30–40 and 38.4% (95% CI 32.8% to 44.2%) in those aged >40. Compared with women, men had lower seroprevalence with an adjusted risk ratio (ARR) of 0.68 (95% CI 0.60 to 0.76). Seroprevalence declined by 2% per year over the last three decades (ARR of 0.98, 95% CI 0.97 to 0.99). Pooled mean proportions of HSV-2 detection in GUD and genital herpes were 41.4% (95% CI 18.9% to 67.0%) and 91.1% (95% CI 82.7% to 97.2%), respectively. Conclusions One in five adults is HSV-2 infected, a higher level than other world regions, but seroprevalence is declining. Despite this decline, HSV-2 persists as the aetiological cause of nearly half of GUD cases and almost all of genital herpes cases.
... Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) are DNA-based viruses from the Herpesviridae family, responsible for causing herpes (genital or oral) and fulminate encephalitis in humans [1][2][3][4][5]. It has been estimated that more than 500 million people globally, including 50 million in the US, have been infected with HSV [6][7][8][9]. ...
Article
Full-text available
Herpes is a widespread viral infection caused by the herpes simplex virus (HSV) that has no permanent cure to date. There are two subtypes, HSV-1 and HSV-2, that are known to cause a variety of symptoms, ranging from acute to chronic. HSV is highly contagious and can be transmitted via any type of physical contact. Additionally, viral shedding can also happen from asymptomatic infections. Thus, early and accurate detection of HSV is needed to prevent the transmission of this infection. Herpes can be diagnosed in two ways, by either detecting the presence of the virus in lesions or the antibodies in the blood. Different detection techniques are available based on both laboratory and point of care (POC) devices. Laboratory techniques include different biochemical assays, microscopy, and nucleic acid amplification. In contrast, POC techniques include microfluidics-based tests that enable on-spot testing. Here, we aim to review the different diagnostic techniques, both laboratory-based and POC, their limits of detection, sensitivity, and specificity, as well as their advantages and disadvantages.
... This has been observed during the replication process of EBV and HCMV, where both viruses can trigger proinflammatory cytokine production and consequently could influence systemic inflammation [109,110]. Similarly, inflammation associated with post-infection complications of oral and genital herpes was reported in diverse medical observations [111][112][113]. Besides, KSHV inflammatory cytokine syndrome (KICS) caused by KSHV has recently been described [114,115]. ...
Article
Full-text available
Human herpesviruses are known to induce a broad spectrum of diseases, ranging from common cold sores to cancer, and infections with some types of these viruses, known as human oncogenic herpesviruses (HOHVs), can cause cancer. Challenges with viral latency, recurrent infections, and drug resistance have generated the need for finding new drugs with the ability to overcome these barriers. Berberine (BBR), a naturally occurring alkaloid, is known for its multiple biological activities, including antiviral and anticancer effects. This paper comprehensively compiles all studies that have featured anti-HOHV properties of BBR along with promising preventive effects against the associated cancers. The mechanisms and pathways induced by BBR via targeting the herpesvirus life cycle and the pathogenesis of the linked malignancies are reviewed. Approaches to enhance the therapeutic efficacy of BBR and its use in clinical practice as an anti-herpesvirus drug are also discussed.
... 3 It is important to take this morphological variant into consideration not to delay the diagnosis of a viral infection, especially in an immunosuppressed patient. 4 Nodular genital herpes simplex is a very rare form of clinical presentation; only one case has been reported in the literature. 3,5 The authors describe a case of cutaneous HSV (herpes simplex virus) infection in an HIV patient that clinically presented with a nodular configuration, mimicking a tumor, supported by histopathology and microbiological cultures. ...
Article
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A 56-year-old man, HIV-positive, presented with a 3-day history of multiple indurated erythematous nodules with superficial and well-defined erosions on his right gluteus. Skin biopsy showed ballooning-necrotic keratinocytes and cultures were positive for herpes simplex 2. Genital herpes simplex infection recurrences may not be restricted to the anterior part of the genitalia and clinical presentation in the lumbar area or gluteus must be differentiated from varicella-zoster virus infection. Tumor-like presentation is a very rare manifestation of HSV cutaneous infection. It is important to take this morphological variant into consideration not to delay the diagnosis of a viral infection, especially in an immunosuppressed patient.
Article
Herpes simplex virus (HSV) infection in newborn infants is a potentially devastating disease leading to death and disability. Skin, eye and mouth (SEM) infections account for approximately half of the cases in the USA. The appearance of skin findings often guides clinicians towards early diagnosis of HSV infection, prompt interventions and life-saving management; however, less than half of neonates with proven disease present with characteristic vesicular lesions. Furthermore, if SEM infections are not treated promptly, there is significant risk of progression to central nervous system and disseminated disease. We present a case of HSV-2 infection in a neonate with an atypical zosteriform eruption on day 3 of life. This case demonstrates that neonatal HSV can unusually present in a zosteriform rash. By elucidating this unique presentation, we highlight atypical HSV skin presentation and emphasise on the importance of earlier diagnosis and antiviral treatment to prevent the associated morbidity and mortality.
Article
Background Herpes simplex virus type 2 (HSV-2) infection is a globally prevalent, life-long, sexually transmitted infection. This study characterized HSV-2 seroprevalence in Europe for various at-risk populations and proportions of HSV-2 detection in genital ulcer disease (GUD) and in genital herpes. Data on neonatal herpes and HSV-2's contribution to HIV transmission were also reviewed. Methods Cochrane and PRISMA guidelines were followed to systematically review, synthesize, and report HSV-2 related findings. The search was conducted in PubMed and Embase databases up to February 20, 2022. Any publication reporting data on the outcome measures was included. Meta-analyses and meta-regressions were conducted. Findings 211 relevant reports were identified, including 12 overall incidence measures, 294 overall (813 stratified by factors such as age and sex) seroprevalence measures, 13 overall (15 stratified by sex) proportions of HSV-2 detection in clinically diagnosed GUD, and 70 overall (183 stratified by factors such as age and sex) proportions of HSV-2 detection in laboratory-confirmed genital herpes. Pooled mean seroprevalence was 12.4% (95% CI: 11.5–13.3%) among general populations, 27.8% (95% CI: 17.5–39.4%) among men who have sex with men, 46.0% (95% CI: 40.1–51.8%) among people living with HIV and people in HIV discordant couples, and 63.2% (95% CI: 55.5–70.6%) among female sex workers. Most measures showed heterogeneity in HSV-2 seroprevalence. The pooled mean seroprevalence among general populations increased with age and was 0.65-fold (95% CI: 0.58–0.74) lower in men than women. Seroprevalence decreased by 1% per calendar year. Pooled mean proportions of HSV-2 detection in GUD and in genital herpes were 22.0% (95% CI: 15.3–29.6%) and 66.0% (95% CI: 62.9–69.1%), respectively. HSV-2 detection in genital herpes cases was 1.21-fold (95% CI: 1.10–1.32) higher in men compared to women and decreased by 1% per calendar year. Incidence of neonatal herpes indicated an increasing trend. Interpretation Although seroprevalence is declining, a significant proportion of Europe's population is infected with HSV-2. HSV-2 accounts for approximately one-fifth of GUD cases and two-thirds of genital herpes cases. Findings support the need to invest in HSV-2 vaccine development, and sexual and reproductive health services. Funding Qatar National Research Fund [NPRP 9-040-3-008] and pilot funding from the Biomedical Research Program at Weill Cornell Medicine in Qatar supported this study.
Article
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O presente trabalho teve por objetivo a realização de uma revisão integrativa da literatura a respeito da infecção pelos vírus causadores do herpes (HSV-1 e HSV-2), visando a elucidação de aspectos clínicos e complicações associadas à infecção, bem como a apresentação de dados epidemiológicos, formas de transmissão, características do patógeno e o cenário atual sobre o desenvolvimento de imunobiológicos, apresentado de uma maneira superficial. Além disso, há a apresentação de dados da enfermidade no Brasil entre o mês de janeiro de 2019 a abril de 2020 (em um momento pré-pandemia do SARS-CoV-2) e entre janeiro de 2021 a abril de 2022 (em um momento pós desenvolvimento de vacinas para o SARS-CoV-2). As bases de dados internacionais PubMed, SciELO e LILACS, foram utilizadas durante as buscas, bem como informações provenientes da Organização Mundial de Saúde, foram selecionadas. Dessa forma, houve a seleção de 30 artigos científicos para compor a base bibliográfica da vigente revisão, segundo os critérios de inclusão e exclusão pré-estabelecidos.
Chapter
Viruses are acellular obligate intracellular parasites that can infect humans, plants, animals, yeast, bacteria, protozoa, archaea, as well as other viruses. Transmission of viruses takes place in a variety of ways. Some viruses are transmitted through touch, air, and saliva and others are transmitted by insects (e.g., mosquitoes), sexual contact, sharing contaminated needles/blood, contaminated water and food, etc. Viral infections are managed either by antiviral vaccines or by using suitable antiviral drugs or they can also be controlled using phytomedicines. The present chapter provides an overview of viral infections and their transmission and management using various antiviral agents.
Chapter
Sexually transmitted infections (STIs) are an ongoing global health challenge, contributing to significant morbidity and mortality. Globally, nearly 1 million new curable STIs are diagnosed every day (Rowley et al., 2019). In 2016 alone, there were 127.2 million new diagnoses of Chlamydia trachomatis, 86.9 million diagnoses of Neisseria gonorrhoeae, 156 million diagnoses of Trichomonas vaginalis, and 6.3 million new diagnoses of syphilis among 15–49-year-old men and women (Rowley et al., 2019). In the U.S., adolescents and young adults remain heavily impacted by STIs, with an estimated half of new infections occurring in youth ages 15–25 years old (Satterwhite et al., 2013). Given the heavy burden of these STIs in adolescents and young adults, the focus of this chapter is on youth ages 13–24 years and the STIs most prevalent in this age group: C. trachomatis (chlamydia), N. gonorrhoeae (gonorrhea), Trichomonas vaginalis (trichomonas), syphilis, and genital herpes simplex virus (HSV; herpes). Numerous biological, psychological/behavioral, and social factors serve as risk and protective factors for STIs among youth and are discussed below. Although this chapter will not address human immunodeficiency virus (HIV) infection, it is important to note that both bacterial and viral STIs increase the transmission and acquisition of HIV infection (Centers for Disease Control and Prevention, 2021).
Article
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Human papillomaviruses (HPVs), the most oncogenic virus known to humans, are often associated with Herpes Simplex Virus-2 (HSV-2) infections. The involvement of the latter in cervical cancer is controversial but its long-term infections might modulate the mucosal microenvironment in a way that favors carcinogenesis. We know little about coinfections between HSV-2 and HPVs, and studying the immunological and microbiological dynamics in the early stages of these infections may help identify or rule out potential interactions. We report two cases of concomitant productive, although asymptomatic, HSV-2 and HPV infections in young women (aged 20 and 25). The women were followed up for approximately a year, with clinical visits every two months and weekly self-samples. We performed quantitative analyses of their HSV-2 and HPV viral loads, immunological responses (IgG and IgM antibodies and local cytokines expression profiles), vaginal microbiota composition, as well as demographic and behavior data. We detect interactions between virus loads, immune response, and the vaginal microbiota, which improve our understanding of HSV-2 and HPVs’ coinfections and calls for further investigation with larger cohorts.
Article
The herpes virus was named by the Greek physician Hippocrates who called it herpes because the lesions appeared near each other and were vesicular. Alphaherpesvirinae, Betaherpesvirinae, and Gammaherpesvirinae are subfamilies of the human herpes virus family. The Alphaherpesvirinae subfamily includes the simplex viruses-HSV-1 and HSV-2-and varicellovirus-varicella zoster virus. There are more than 200 members of the Herpesviridae family capable of infecting different species, 8 of which are known to cause disease in humans. The simplex viruses can cause lifelong genital infections, and despite the prevalence of HSV-1 and HSV-2 infections in the United States decreasing in the past 20 years, infections with these viruses continue to contribute to significant clinical and psychological morbidities.
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Purpose. The purpose is to find out the common and different features of the clinical course of erysipelas from other diseases that can imitate it. Materials and methods. 114 case histories of patients who were hospitalized in the center of purulent-septic surgery in the Non-profit municipal enterprise “City Hospital № 3” in Zaporizhzhia for the period 2019-2020 were analyzed. 123 patients, who underwent hospital treatment in the center during this period of time, were with post-injection abscesses of soft tissue, 184 - with soft tissue abscesses, 203 - with phlegmons of various localizations, 49 - with complicated panaritium, 3 of which - subcutaneous. Over the past 5 years, 127 patients were consulted in the clinic and other therapeutic, infectious, neurological and other departments of the city. A number of criteria and signs have been identified to differentiate erysipelas from diseases that may have similar clinical symptoms and a number of circumstances that need to be clarified. Results. It is established that the diagnosis of erysipelas does not require special laboratory examination and is made on the basis of examination of the patient, epidemiological history and medical history. Provoking factors in the development of erysipelas are: violation of the integrity of the skin (abrasions, scratches, abrasions, cracks, bruises, injuries); mycoses; a sharp change in temperature (supercooling, overheating); emotional stress; increased insolation. Erysipelas has a characteristic summer-autumn seasonality. In people engaged in physical labor, the disease is registered more often than in other types of work. Hereditary predisposition to the disease is observed in 10-15% of cases. In this regard, the presence of such factors as congenital and acquired venous insufficiency of the lower extremities, fungal infection of the lower extremities, the presence of postoperative and post-traumatic scars, lymphostasis, diabetes, cardiovascular disease and diseases accompanied by the development of edema, intake of corticosteroids or cytostatics are of essential significance in the development of the disease. Conclusions. Mathematical modeling between erysipelas and other diseases that have similar syndromes in their clinical picture may be useful in making a differential diagnosis between them.
Chapter
Each of the currently known eight herpes viruses can be associated with skin diseases, and depending on the type, certain lesions are typical. All herpes viruses remain in the host (latency) after acute infection, and can show recurrences despite cellular immune response. The possible diseases vary greatly; the type and severity of the disease depends on the age and immune status of the patient, and whether it is a primary or secondary infection. Trigger factors, such as fever, sunlight, trauma, or stress are possible causes of recurrences; the herpes simplex virus is a case in point. Various antivirals are available for treatment, and additional active substances have recently been developed, although these have not been licensed yet.
Article
Infections caused by herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) remain a serious global health issue, and the medical countermeasures available thus far are limited. Virus-neutralizing monoclonal antibodies (NAbs) are crucial tools for studying host-virus interactions and designing effective vaccines, and the discovery and development of these NAbs could be one approach to treat or prevent HSV infection. Here, we report the isolation of five HSV NAbs from mice immunized with both HSV-1 and HSV-2. Among these were two antibodies that potently cross-neutralized both HSV-1 and HSV-2 with the 50% virus-inhibitory concentrations (IC50) below 200 ng/ml, one of which (4A3) exhibited high potency against HSV-2, with an IC50 of 59.88 ng/ml. 4A3 neutralized HSV at the prebinding stage and prevented HSV infection and cell-to-cell spread. Significantly, administration of 4A3 completely prevented weight loss and improved survival of mice challenged with a lethal dose of HSV-2. Using structure-guided molecular modeling combined with alanine-scanning mutagenesis, we observed that 4A3 bound to a highly conserved continuous epitope (residues 216 to 220) within the receptor-binding domain of glycoprotein D (gD) that is essential for viral infection and the triggering of membrane fusion. Our results provide guidance for developing NAb drugs and vaccines against HSV.
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Article
Background: Herpes simplex virus (HSV) is a widely distributed human pathogen that is known for its ulcerative lesions at the infection site. HSV can cause persistent infection in the host that is often followed by a period of latency within the neurons. Considering the high rate of HIV infection in South Africa, it is important to assess the seroprevalence of HSV with a focus to determine the epidemiological association between HSV-DNA and HIV-1 in the population. Methods: A total of 44 sera samples were screened for HSV and HIV-1 using the highly sensitive enzyme-linked immunosorbent assay (ELISA). The ELISA positive samples were characterized using polymerase chain reaction (PCR) to confirm the positivity of both viruses and to further differentiate HSV into HSV-1 and -2. Thereafter, the samples were analysed for relatedness using phylogenetic analysis. Results: Of the 44 samples, 36 (81.8%) were positive for HIV-1, while 35 (79.5%) were positive for HSV when screened with ELISA kits. The PCR results, with the use of type specific primers, showed that 4/35 (11.4%) samples were specific for HSV-1 while 30/35 (85.7%) were specific for HSV-2. Statistical analysis performed using the chi-squared goodness-of-fit test showed that there is a significant relationship between HSV-2 and HIV-1 transmission. Conclusions: There is a significant positive association between HSV-2 and HIV-1 in the study population. Our study shows that some of the HSV-2 isolates are not related to the clinical isolate SD90e from South Africa, suggesting diversity in HSV-2 viral transmission.
Article
Background: Herpes simplex virus (HSV) is a widely distributed human pathogen that is known for its ulcerative lesions at the infection site. HSV can cause persistent infection in the host that is often followed by a period of latency within the neurons. Considering the high rate of HIV infection in South Africa, it is important to assess the seroprevalence of HSV with a focus to determine the epidemiological association between HSV-DNA and HIV-1 in the population. Methods: A total of 44 sera samples were screened for HSV and HIV-1 using the highly sensitive enzyme-linked immunosorbent assay (ELISA). The ELISA positive samples were characterized using polymerase chain reaction (PCR) to confirm the positivity of both viruses and to further differentiate HSV into HSV-1 and -2. Thereafter, the samples were analysed for relatedness using phylogenetic analysis. Results: Of the 44 samples, 36 (81.8%) were positive for HIV-1, while 35 (79.5%) were positive for HSV when screened with ELISA kits. The PCR results, with the use of type specific primers, showed that 4/35 (11.4%) samples were specific for HSV-1 while 30/35 (85.7%) were specific for HSV-2. Statistical analysis performed using the chi-squared goodness-of-fit test showed that there is a significant relationship between HSV-2 and HIV-1 transmission. Conclusions: There is a significant relationship between HSV-2 and HIV-1 in the study population. Our study shows that some of the HSV-2 isolates are not related to the clinical isolate SD90e from South Africa, suggesting diversity in HSV-2 viral transmission.
Chapter
Herpes simplex viruses (HSV), papillomaviruses (HPV), and human immunodeficiency virus (HIV) are among the most important human viruses known to be spread through sexual contact.
Article
Background: Herpes simplex virus (HSV) is a widely distributed human pathogen that is known for its ulcerative lesions at the infection site. HSV can cause persistent infection in the host that is often followed by a period of latency within the neurons. Considering the high rate of HIV infection in South Africa, it is important to assess the seroprevalence of HSV with a focus to determine the epidemiological association between HSV-DNA and HIV-1 in the population. Methods: A total of 44 sera samples were screened for HSV and HIV-1 using the highly sensitive enzyme-linked immunosorbent assay (ELISA). The ELISA positive samples were characterized using polymerase chain reaction (PCR) to confirm the positivity of both viruses and to further differentiate HSV into HSV-1 and -2. Thereafter, the samples were analysed for relatedness using phylogenetic analysis. Results: Of the 44 samples, 36 (81.8%) were positive for HIV-1, while 35 (79.5%) were positive for HSV when screened with ELISA kits. The PCR results, with the use of type specific primers, showed that 4/35 (11.4%) samples were specific for HSV-1 while 30/35 (85.7%) were specific for HSV-2. Statistical analysis performed using the chi-squared goodness-of-fit test showed that there is a significant relationship between HSV-2 and HIV-1 transmission. Conclusions: The prevalence of HSV in the population is high with an increased HSV-2 infection in women. Our study shows that some of the HSV-2 isolates are not related to the clinical isolate SD90e from South Africa, suggesting diversity in HSV-2 viral transmission.
Article
Full-text available
Objective. The aim is to find out the common and different features of the clinical course of erysipelas from other diseases that can imitate it. Materials and methods. 114 case histories of patients who were hospitalized in the center of purulent-septic surgery in the City Hospital No 3 in Zaporizhzhia for the period 2019-2020 were analyzed. 123 patients, who underwent hospital treatment in the center during this period of time, were with post-injection abscesses of soft tissue, 184 - with soft tissue abscesses, 203 - with phlegmons of various localizations, 49 - with complicated panaritium, 3 of which - subcutaneous. Over the past 5 years, 127 patients were consulted in the clinic and other therapeutic, infectious, neurological and other departments of the city. A number of criteria and signs have been identified to differentiate erysipelas from diseases that may have similar clinical symptoms and a number of circumstances that need to be clarified. Results. It is established that the diagnosis of erysipelas does not require special laboratory examination and is made on the basis of examination of the patient, epidemiological history and medical history. Provoking factors in the development of erysipelas are: violation of the integrity of the skin (abrasions, scratches, abrasions, cracks, bruises, injuries); mycoses; a sharp change in temperature (supercooling, overheating); emotional stress; increased insolation. Erysipelas has a characteristic summer-autumn seasonality. In people engaged in physical labor, the disease is registered more often than in other types of work. Hereditary predisposition to the disease is observed in 10-15% of cases. In this regard, the presence of such factors as congenital and acquired venous insufficiency of the lower extremities, fungal infection of the lower extremities, the presence of postoperative and post-traumatic scars, lymphostasis, diabetes, cardiovascular disease and diseases accompanied by the development of edema, intake of corticosteroids or cytostatics are of essential significance in the development of the disease. Conclusions. Mathematical modeling between erysipelas and other diseases that have similar syndromes in their clinical picture may be useful in making a differential diagnosis between them.
Article
The variety and complexity of ocular infections have increased significantly in the last decade since the publication of Cumitech 13B, Laboratory Diagnosis of Ocular Infections (L. D. Gray, P. H. Gilligan, and W. C. Fowler, Cumitech 13B, Laboratory Diagnosis of Ocular Infections, 2010). The purpose of this practical guidance document is to review, for individuals working in clinical microbiology laboratories, current tools used in the laboratory diagnosis of ocular infections. This document begins by describing the complex, delicate anatomy of the eye, which often leads to limitations in specimen quantity, requiring a close working bond between laboratorians and ophthalmologists to ensure high-quality diagnostic care. Descriptions are provided of common ocular infections in developed nations and neglected ocular infections seen in developing nations. Subsequently, preanalytic, analytic, and postanalytic aspects of laboratory diagnosis and antimicrobial susceptibility testing are explored in depth.
Chapter
Herpes simplex viruses type 1 (HSV-1) and type 2 (HSV-2) are highly prevalent in the human population and elicit lifelong infections by remaining latent in neurons from where they sporadically reactivate. These viruses have evolved numerous molecular mechanisms to evade the host's immediate antiviral response, as well as innate and adaptive immune components. Although multiple drugs exist for treating HSV infection, they are somewhat poorly effective for some clinical manifestations and drug-resistant variants may emerge in both, immunosuppressed and immunocompetent individuals. Here, we review and discuss the epidemiology of HSV infection, the diseases they produce, vaccine and drug research over these viruses, their replication cycle and the evasion of host antiviral responses.
Article
Résumé L’herpès génital constitue la première cause d’ulcères génitaux dans le monde. Il est provoqué par des virus largement répandus dans la population générale : les virus herpès simplex 1 et 2 (HSV-1 et HSV-2). Cette infection peut affecter la qualité de vie des individus infectés. De plus, l’herpès génital constitue un cofacteur favorisant la transmission du virus de l’immuno-déficience humaine (HIV) par voie sexuelle. La transmission du HSV, au moment de l’accouchement, peut être responsable de l’herpès néonatal. Le diagnostic de l’herpès génital repose sur deux types de tests biologiques : la détection du génome viral par biologie moléculaire (PCR) dans les écouvillonnages des voies génitales et la détection d’anticorps spécifiques (sérologie) pour connaître le statut immunitaire des patients. La prise en charge thérapeutique de l’herpès génital repose essentiellement sur des traitements antiviraux par le valaciclovir, médicament très actif et très peu toxique. À ce jour, il n’existe aucun vaccin spécifique et l’utilisation du préservatif reste la mesure la plus efficace pour prévenir cette infection virale.
Article
Background: Herpes Simplex Virus Type-2 (HSV-2) seropositive persons have a 3-5 fold higher risk of acquiring HIV, possibly due to HSV-2 induced inflammation and recruitment of susceptible immune cells to exposure sites. We hypothesized cervical HSV-2 activation (i.e., viral DNA shedding and/or ulcers) preceded HIV acquisition in the Hormonal Contraception and HIV cohort. Methods: Zimbabwean women who acquired HIV were matched to HIV-negative women on visit, age, and bacterial sexually transmitted infections (STIs). Up to 5 cervical swabs bracketing first PCR detection of HIV DNA, the index visit, were selected (t-6months, t-3months, tindex, t+3months, t+6months). Women with HSV-2 IgG+ before tindex were PCR-tested for viral shedding. Self-reported and clinician-diagnosed ulcers were documented. Multivariable logistic regression, accounting for matching, estimated adjusted odds ratios [aOR] and 95% confidence intervals [CI] at each visit. Results: Of 387 HSV-2 seropositive women, most had prevalent as compared to incident HSV-2 (91% vs. 9%, respectively). HSV-2 viral shedding was more common among HIV seroconverters than HIV-negative women (26% vs. 14%, p<0.01). Shedding occurred around HIV acquisition (t-3months aOR: 2.7, 95% CI: 0.8-8.8; tindex aOR: 2.6, 95% CI: 1.1-6.5; t+3months aOR: 2.6, 95% CI: 1.0-6.6). Genital ulcers were reported more often among HIV seroconverters than HIV-negative women (13% vs. 7%, p=0.06) and detection was after HIV acquisition (t+6months aOR: 14.5, 95% CI: 1.6-133.9). Conclusions: HSV-2 shedding appeared synergistic with HIV acquisition followed by presentation of ulcers. Evaluating all STIs rather than HSV-2 alone may clarify the relationship between inflammation and HIV acquisition.
Article
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Background: Herpes simplex viruses (HSVs) are highly pervasive and show a strong synergistic interaction with human immunodeficiency virus (HIV). High prevalence of HSV type 1 (HSV-1) has been reported in Africa with a prevalence rate of 20-80% in women and 10-50% in men. Studies on the prevalence of HSV in South Africa are few considering the rate of HIV infection in the country. Our focus was to determine the molecular prevalence of HSV-DNA in HIV-1 sera. Methods: In total, 44 convenience samples were screened for HSV and HIV-1 using the highly sensitive enzyme-linked immunosorbent assay (ELISA). The ELISA positive samples were characterized using polymerase chain reaction (PCR) to confirm the positivity of both viruses and to further differentiate HSV into HSV-1 and -2. Thereafter, the samples were analysed for relatedness using phylogenetic analysis. Results: Of 44 samples, 36 (81.8%) were positive for HIV-1, while 35 (79.5%) were positive for HSV when screened with ELISA kits. The results of PCR with type specific primers showed that 4/35 (11.4%) samples were specific for HSV-1 while 30/35 (85.7%) were specific for HSV-2. Statistical analysis performed using chi-squared goodness-of-fit test showed that there is a significant relationship between HSV-2 and HIV-1 transmission. Conclusions: High prevalence of HSV-2 recorded in HIV-1 sera corroborate with similar studies conducted within different cohorts in the continent. SPSS Pearson’s chi-squared test established that there is a significant relationship between HSV-2 and HIV-1 transmission.
Article
Herpes Simplex virus (HSV) infection is one of the most common sexually transmitted infections among women of the reproductive age. It is estimated to affect about 2-3% of pregnant women. Vertical transmission during pregnancy is rare occurring in less than 1% of cases but for those with active lesions or shedding the virus asymptomatically the risk of vertical transmission intrapartum is high. Neonates with HSV may develop severe consequences such as disseminated, central nervous system and skin, eye mouth/mucous disease or suffer mortality. A high index of suspicion, timely diagnosis and institution of appropriate treatment during acute and recurrent episodes will reduce the risk of vertical transmission and therefore neonatal consequences. Routine screening for HSV in pregnancy is not recommended. This review provides an overview of HSV in pregnancy, diagnosis and management especially around unique scenarios such as prelabour preterm rupture of fetal membranes and presentation with active disease in labour.
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Background: Data from randomized trials are lacking on the benefits and risks of initiating antiretroviral therapy in patients with asymptomatic human immunodeficiency virus (HIV) infection who have a CD4+ count of more than 350 cells per cubic millimeter. Methods: We randomly assigned HIV-positive adults who had a CD4+ count of more than 500 cells per cubic millimeter to start antiretroviral therapy immediately (immediate-initiation group) or to defer it until the CD4+ count decreased to 350 cells per cubic millimeter or until the development of the acquired immunodeficiency syndrome (AIDS) or another condition that dictated the use of antiretroviral therapy (deferred-initiation group). The primary composite end point was any serious AIDS-related event, serious non-AIDS-related event, or death from any cause. Results: A total of 4685 patients were followed for a mean of 3.0 years. At study entry, the median HIV viral load was 12,759 copies per milliliter, and the median CD4+ count was 651 cells per cubic millimeter. On May 15, 2015, on the basis of an interim analysis, the data and safety monitoring board determined that the study question had been answered and recommended that patients in the deferred-initiation group be offered antiretroviral therapy. The primary end point occurred in 42 patients in the immediate-initiation group (1.8%; 0.60 events per 100 person-years), as compared with 96 patients in the deferred-initiation group (4.1%; 1.38 events per 100 person-years), for a hazard ratio of 0.43 (95% confidence interval [CI], 0.30 to 0.62; P<0.001). Hazard ratios for serious AIDS-related and serious non-AIDS-related events were 0.28 (95% CI, 0.15 to 0.50; P<0.001) and 0.61 (95% CI, 0.38 to 0.97; P=0.04), respectively. More than two thirds of the primary end points (68%) occurred in patients with a CD4+ count of more than 500 cells per cubic millimeter. The risks of a grade 4 event were similar in the two groups, as were the risks of unscheduled hospital admissions. Conclusions: The initiation of antiretroviral therapy in HIV-positive adults with a CD4+ count of more than 500 cells per cubic millimeter provided net benefits over starting such therapy in patients after the CD4+ count had declined to 350 cells per cubic millimeter. (Funded by the National Institute of Allergy and Infectious Diseases and others; START ClinicalTrials.gov number, NCT00867048.).
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Unlabelled: Herpes simplex virus 2 (HSV-2), the principal causative agent of recurrent genital herpes, is a highly prevalent viral infection worldwide. Limited information is available on the amount of genomic DNA variation between HSV-2 strains because only two genomes have been determined, the HG52 laboratory strain and the newly sequenced SD90e low-passage-number clinical isolate strain, each from a different geographical area. In this study, we report the nearly complete genome sequences of 34 HSV-2 low-passage-number and laboratory strains, 14 of which were collected in Uganda, 1 in South Africa, 11 in the United States, and 8 in Japan. Our analyses of these genomes demonstrated remarkable sequence conservation, regardless of geographic origin, with the maximum nucleotide divergence between strains being 0.4% across the genome. In contrast, prior studies indicated that HSV-1 genomes exhibit more sequence diversity, as well as geographical clustering. Additionally, unlike HSV-1, little viral recombination between HSV-2 strains could be substantiated. These results are interpreted in light of HSV-2 evolution, epidemiology, and pathogenesis. Finally, the newly generated sequences more closely resemble the low-passage-number SD90e than HG52, supporting the use of the former as the new reference genome of HSV-2. Importance: Herpes simplex virus 2 (HSV-2) is a causative agent of genital and neonatal herpes. Therefore, knowledge of its DNA genome and genetic variability is central to preventing and treating genital herpes. However, only two full-length HSV-2 genomes have been reported. In this study, we sequenced 34 additional HSV-2 low-passage-number and laboratory viral genomes and initiated analysis of the genetic diversity of HSV-2 strains from around the world. The analysis of these genomes will facilitate research aimed at vaccine development, diagnosis, and the evaluation of clinical manifestations and transmission of HSV-2. This information will also contribute to our understanding of HSV evolution.
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Herpes simplex virus type 2 (HSV-2) is a major global pathogen, infecting 16% of people, 15-49 years old worldwide, causing recurrent, genital ulcers. Little is known about viral factors contributing to virulence, and there are currently only two genomic sequences available. In this study we determined nearly complete genomic sequences of six additional HSV-2 isolates, using the Illumina MiSeq. We report that HSV-2 has genomic overall mean distance of 0.2355%, which is lower than HSV-1. There were approximately 100 amino acid encoding SNPs/INDELs per genome. Microsatellite mapping found a bias towards intergenic regions in the non-conserved microsatellites, and a genic bias in all detected tandem repeats. Extensive recombination between the HSV-2 strains was also strongly implied. This is the first study to analyze multiple HSV-2 sequences, and will be valuable in future evolutionary, virulence, and structure-function studies. Herpes simplex virus type 2 (HSV-2) is an significant worldwide pathogen, causing recurrent, genital ulcers. Here we present six nearly complete HSV-2 genomic sequences, and with the addition of two previously sequenced strains, for the first time genomic, phylogenetic, and recombination analysis was performed on multiple HSV-2 genomes. Our results show that microsatellite mapping found a bias towards intergenic regions in the non-conserved microsatellites, a genic bias in all detected tandem repeats, confirm that ChHV-1 is a separate species, and that each of the HSV-2 strains is genomic mosaic. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
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The burden of HSV type 2 varies substantially by region, with the highest incidence and prevalence in sub-Saharan Africa. We undertook a systematic review to identify studies reporting prospective data on incidence rates in men and women in Africa. Of 18 eligible studies, 7 were conducted in high-risk populations. Among women, incidence rates appeared to be higher in those with high-risk sexual behavior, with rates ranging from 3 to 23 per 100 person-years. In contrast, incidence rates in men appeared to be lower, ranging from 1 to 12 per 100 person-years. Risk factors for HSV-2 in women included prevalent human immunodeficiency virus (HIV) infection, younger age at sexual initiation, and sexual activity. Among men, condom use and circumcision had a protective effect, whereas prevalent HIV increased the risk of HSV-2 acquisition. This review draws attention to the high HSV-2 acquisition rates reported in Africa, thereby identifying an efficient setting for preventative HSV-2 vaccine trials.
Article
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Objective Atypical presentations of herpes simplex genitalis are becoming more frequent. We aimed to investigate the atypical clinical manifestations and treatment of this infection. Methods We retrospectively reviewed the charts of patients with herpes simplex genitalis who attended our clinics between January 2009 and December 2013. Results Of 294 patients, 147 (50%) were male with a mean (SD) age of 48.3 (16.8) years. Ulcerative lesion was the most common symptom (48.3%), followed by vesicle clusters (36.4%). Mean symptom duration at first visit was 6 days. Oral acyclovir was administered to 87.6% of patients. Hypertrophic manifestation was observed in 4.8% (14/294) of patients; 50% (7/294) were male with a mean age of 44.5 (9) years. All patients with hypertrophic manifestation were infected with HIV. Hypertrophic manifestations had a mean onset duration of 53.3 days. Acyclovir was prescribed to 11 (78.6%) patients. Mean duration to cure was 40.9 days. Topical imiquimod was given in 6 resistant cases (42.9%) as adjunctive therapy. Conclusions Atypical manifestations of herpes simplex genitalis require careful consideration because their frequency is rising, particularly in patients with HIV infection. Although acyclovir is important in their treatment, imiquimod provides an additional benefit in resistant cases. Copyright © 2015. Published by Elsevier Ltd.
Article
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Herpes simplex virus type 2 (HSV-2) infection causes significant disease globally. Adolescent and adult infection may present as painful genital ulcers. Neonatal infection has high morbidity and mortality. Additionally, HSV-2 likely contributes substantially to the spread of HIV infection. The global burden of HSV-2 infection was last estimated for 2003. Here we present new global estimates for 2012 of the burden of prevalent (existing) and incident (new) HSV-2 infection among females and males aged 15-49 years, using updated methodology to adjust for test performance and estimate by World Health Organization (WHO) region. We conducted a literature review of HSV-2 prevalence studies world-wide since 2000. We then fitted a model with constant HSV-2 incidence by age to pooled HSV-2 prevalence values by age and sex. Prevalence values were adjusted for test sensitivity and specificity. The model estimated prevalence and incidence by sex for each WHO region to obtain global burden estimates. Uncertainty bounds were computed by refitting the model to reflect the variation in the underlying prevalence data. In 2012, we estimate that there were 417 million people aged 15-49 years (range: 274-678 million) living with HSV-2 infection world-wide (11.3% global prevalence), of whom 267 million were women. We also estimate that in 2012, 19.2 million (range: 13.0-28.6 million) individuals aged 15-49 years were newly-infected (0.5% of all individuals globally). The highest burden was in Africa. However, despite lower prevalence, South-East Asia and Western Pacific regions also contributed large numbers to the global totals because of large population sizes. The global burden of HSV-2 infection is large, leaving over 400 million people at increased risk of genital ulcer disease, HIV acquisition, and transmission of HSV-2 to partners or neonates. These estimates highlight the critical need for development of vaccines, microbicides, and other new HSV prevention strategies.
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HIV disproportionately affects black men who have sex with men, and herpes simplex virus type 2 is known to increase acquisition of HIV. However, data on racial disparities in herpes simplex virus type 2 prevalence and risk factors are limited among men who have sex with men in the United States. InvolveMENt was a cohort study of black and white HIV-negative men who have sex with men in Atlanta, GA. Univariate and multivariate cross-sectional associations with herpes simplex virus type 2 seroprevalence were assessed among 455 HIV-negative men who have sex with men for demographic, behavioural and social determinant risk factors using logistic regression. Seroprevalence of herpes simplex virus type 2 was 23% (48/211) for black and 16% (38/244) for white men who have sex with men (p = 0.05). Education, poverty, drug/alcohol use, incarceration, circumcision, unprotected anal intercourse, and condom use were not associated with herpes simplex virus type 2. In multivariate analyses, black race for those ≤25 years, but not >25 years, and number of sexual partners were significantly associated. Young black men who have sex with men are disproportionately affected by herpes simplex virus type 2, which may contribute to disparities in HIV acquisition. An extensive assessment of risk factors did not explain this disparity in herpes simplex virus type 2 infection suggesting differences in susceptibility or partner characteristics.
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Objectives Herpes simplex virus type 2 (HSV-2) is a common sexually transmitted disease, but there is limited data on its epidemiology among urban populations. The urban Emergency Department (ED) is a potential venue for surveillance as it predominantly serves an inner city minority population. We evaluate the seroprevalence and factors associated with HSV-2 infection among patients attending the Johns Hopkins Hospital Adult Emergency Department (JHH ED). Methods An identity unlinked-serosurvey was conducted between 6/2007 and 9/2007 in the JHH ED; sera were tested by the Focus HerpeSelect ELISA. Prevalence risk ratios (PRR) were used to determine factors associated with HSV-2 infection. Results Of 3,408 serum samples, 1,853 (54.4%) were seropositive for HSV-2. Females (adjPRR = 1.47, 95% CI 1.38–1.56), non-Hispanic blacks (adjPRR = 2.03, 95% CI 1.82–2.27), single (adjPRR = 1.15, 95% CI 1.07–1.25), divorced (adjPRR = 1.28, 95% CI 1.15–1.41), and unemployed patients (adjPRR = 1.13, 95% CI 1.05–1.21) had significantly higher rates of HSV-2 infection. Though certain zip codes had significantly higher seroprevalence of HSV-2, this effect was completely attenuated when controlling for age and gender. Conclusions Seroprevalence of HSV-2 in the JHH ED was higher than U.S. national estimates; however, factors associated with HSV-2 infection were similar. The high seroprevalence of HSV-2 in this urban ED highlights the need for targeted testing and treatment. Cross-sectional serosurveys in the urban ED may help to examine the epidemiology of HSV-2.
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Herpesviruses have been infecting and co-diverging with their vertebrate hosts for hundreds of millions of years. The primate simplex viruses exemplify this pattern of virus-host co-divergence, at a minimum, as far back as the most recent common ancestor of New World monkeys, Old World monkeys, and apes. Humans are the only primate species known to be infected with two distinct herpes simplex viruses: HSV-1 and HSV-2. Human herpes simplex viruses are ubiquitous, with over two-thirds of the human population infected by at least one virus. Here, we investigated whether the additional human simplex virus is the result of ancient viral lineage duplication or cross-species transmission. We found that standard phylogenetic models of nucleotide substitution are inadequate for distinguishing among these competing hypotheses; the extent of synonymous substitutions causes a substantial underestimation of the lengths of some of the branches in the phylogeny, consistent with observations in other viruses (e.g. avian influenza, Ebola, and coronaviruses). To more accurately estimate ancient viral divergence times, we applied a Branch-Site Random Effects Likelihood model of molecular evolution that allows the strength of natural selection to vary across both the viral phylogeny and the gene alignment. This selection-informed model favored a scenario in which HSV-1 is the result of ancient co-divergence and HSV-2 arose from a cross-species transmission event from the ancestor of modern chimpanzees to an extinct Homo precursor of modern humans, around 1.6 million years ago. These results provide a new framework for understanding human herpes simplex virus evolution and demonstrate the importance of using selection-informed models of sequence evolution when investigating viral origin hypotheses.
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Herpes simplex virus (HSV)-2 is periodically shed in the human genital tract, most often asymptomatically, and most sexual transmissions occur during asymptomatic shedding. It would be helpful to identify a genital viral load threshold necessary for transmission, as clinical interventions that maintain viral quantity below this level would be of high utility. However, because viral expansion, decay and re-expansion kinetics are extremely rapid during shedding episodes, it is impossible to directly measure genital viral load at the time of sexual activity. We developed a mathematical model based on reproducing shedding patterns in transmitting partners, and median number of sex acts prior to transmission in discordant couples, to estimate infectivity of single viral particles in the negative partner's genital tract. We then inferred probability estimates for transmission at different levels of genital tract viral load in the transmitting partner. We predict that transmission is unlikely at viral loads less than 10(4) HSV DNA copies. Moreover, most transmissions occur during prolonged episodes with high viral copy numbers. Many shedding episodes that result in transmission do not reach the threshold of clinical detection, because the ulcer remains very small, highlighting one reason why HSV-2 spreads so effectively within populations.
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In addition to protecting against HIV acquisition, antiretroviral preexposure prophylaxis (PrEP) using topical 1% tenofovir gel reduced Herpes simplex virus type 2 (HSV-2) acquisition by 51% among women in the CAPRISA 004 study. We examined the effect of daily oral emtricitabine/tenofovir (FTC/TDF) PrEP on HSV-2 seroincidence and ulcer occurrence among men who have sex with men (MSM) in the iPrEx trial. HSV-2 serum testing was performed at screening and every six months. Among HSV-2-seronegative individuals, we used Cox regression models to estimate hazard ratios (HRs) of HSV-2 seroincidence associated with randomization to FTC/TDF. We used multiple imputation and Cox regression to estimate HRs for HSV-2 seroincidence accounting for drug exposure. We assessed ulcer occurrence among participants with prevalent or incident HSV-2 infection. Of the 2,499 participants, 1383 (55.3%) tested HSV-2-seronegative at baseline, 892 (35.7%) tested positive, 223 (8.9%) had indeterminate tests, and one test was not done. Of the 1,347 HSV-2-seronegative participants with follow-up, 125 (9.3%) had incident HSV-2 infection (5.9 per 100 person-years). Compared with participants receiving placebo, there was no difference in HSV-2 seroincidence among participants receiving FTC/TDF (HR 1.1, 95% CI: 0.8-1.5; P = 0.64) or among participants receiving FTC/TDF with a concentration of tenofovir diphosphate >16 per million viable cells (HR 1.0, 95% CI: 0.3-3.5; P = 0.95). Among participants with HSV-2 infection, the proportion with ≥1 moderate or severe ulcer adverse event was twice as high in the placebo vs. active arm (5.9% vs. 2.9%, P = 0.02), but there were no differences in the proportions with ≥1 clinical examination during which perianal or groin ulcers were identified. Tenofovir in daily oral FTC/TDF PrEP may reduce the occurrence of ulcers in individuals with HSV-2 infection but does not protect against HSV-2 incidence among MSM.
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Unlabelled: Genital herpes simplex virus (HSV) reactivation is thought to be anatomically and temporally localized, coincident with limited ganglionic infection. Short, subclinical shedding episodes are the most common form of HSV-2 reactivation, with host clearance mechanisms leading to rapid containment. The anatomic distribution of shedding episodes has not been characterized. To precisely define patterns of anatomic reactivation, we divided the genital tract into a 22-region grid and obtained daily swabs for 20 days from each region in 28 immunocompetent, HSV-2-seropositive persons. HSV was detected via PCR, and sites of asymptomatic HSV shedding were subjected to a biopsy procedure within 24 h. CD4(+) and CD8(+) T cells were quantified by immunofluorescence, and HSV-specific CD4(+) T cells were identified by intracellular cytokine cytometry. HSV was detected in 868 (7%) of 11,603 genital swabs at a median of 12 sites per person (range, 0 to 22). Bilateral HSV detection occurred on 83 (67%) days with shedding, and the median quantity of virus detected/day was associated with the number of sites positive (P < 0.001). In biopsy specimens of asymptomatic shedding sites, we found increased numbers of CD8(+) T cells compared to control tissue (27 versus 13 cells/mm(2), P = 0.03) and identified HSV-specific CD4(+) T cells. HSV reactivations emanate from widely separated anatomic regions of the genital tract and are associated with a localized cellular infiltrate that was demonstrated to be HSV specific in 3 cases. These data provide evidence that asymptomatic HSV-2 shedding contributes to chronic inflammation throughout the genital tract. Importance: This detailed report of the anatomic patterns of genital HSV-2 shedding demonstrates that HSV-2 reactivation can be detected at multiple bilateral sites in the genital tract, suggesting that HSV establishes latency throughout the sacral ganglia. In addition, genital biopsy specimens from sites of asymptomatic HSV shedding have increased numbers of CD8(+) T cells compared to control tissue, and HSV-specific CD4(+) T cells are found at sites of asymptomatic shedding. These findings suggest that widespread asymptomatic genital HSV-2 shedding is associated with a targeted host immune response and contributes to chronic inflammation throughout the genital tract.
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Background: Previously we conducted a double-blind controlled, randomized efficacy field trial of gD-2 HSV vaccine adjuvanted with ASO4 in 8323 women. Subjects had been previously selected to be seronegative for HSV-1 and HSV-2. We found that vaccine was 82% protective against HSV-1 genital disease, but offered no significant protection against HSV-2 genital disease. Methods: To better understand the results of the efficacy study, post-vaccination anti-gD-2 antibody concentrations from all HSV infected subjects and matched uninfected controls were measured. Three models were used to determine whether thes responses correlated with protection against HSV infection or disease. Similarly, cellular immune responses from a subset of subjects and matched controls were evaluated for a correlation with HSV protection. Results: Antibodies to gD-2 correlated with protection against HSV-1 infection with higher antibody concentration associated with higher efficacy. Cellular immune responses to gD-2 did not correlate with protection. Conclusions: The protection against HSV-1 infection observed in the Herpevac Trial for Women was associated with antibodies directed against the vaccine. Clinical Trials Registration NCT00057330.
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Herpes simplex virus 1 (HSV-1) causes a chronic, lifelong infection in >60% of adults. Multiple recent vaccine trials have failed, with viral diversity likely contributing to these failures. To understand HSV-1 diversity better, we comprehensively compared 20 newly sequenced viral genomes from China, Japan, Kenya, and South Korea with six previously sequenced genomes from the United States, Europe, and Japan. In this diverse collection of passaged strains, we found that one-fifth of the newly sequenced members share a common gene deletion and one-third exhibit homopolymeric frameshift mutations (HFMs). Individual strains exhibit genotypic and potential phenotypic variation via HFMs, deletions, short sequence repeats, and single-nucleotide polymorphisms; although protein sequence identity between strains exceeds 90% on average. In the first genome-scale analysis of positive selection in HSV-1, we found signs of selection in specific proteins and residues, including the fusion protein glycoprotein H. We also confirmed previous results suggesting that recombination has occurred with high frequency throughout the HSV-1 genome. Despite this, the HSV-1 strains analyzed clustered by geographic origin during whole-genome distance analysis. These data shed light on likely routes of HSV-1 adaptation to changing environments, and will aid in the selection of vaccine antigens that are invariant worldwide.
Article
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This study sought to assess if there is a meaningful way in which variations in sexually transmitted infection (STI) prevalence can be classified at the level of world regions. Linear regression was performed to assess if the incidence and prevalence of six STIs (HIV, herpes simplex virus type 2, chlamydia, gonorrhea, syphilis, and trichomoniasis) by world region was positively correlated. Partitioning around medoids (PAM) was then used to assess if the regions of the world can be classified according to the incidence and prevalence of these STIs. We found evidence that STI incidence/prevalence varies considerably in different regions around the world. Linear regression revealed that the incidence and prevalence of certain STIs by world region was positively correlated (Pearson's correlation coefficient varied from 0.664 to 0.985). PAM provided support for dividing the world regions into two, three, or four STI incidence/prevalence categories, but it provided most support for the two-category system. In each of these systems the East Asia/Pacific and North Africa/Middle East regions were in the lowest STI category and Sub-Saharan Africa was the only region in the high STI category. The incidence and prevalence of certain STIs by world region are positively correlated. The world regions can be meaningfully classified according to STI incidence/prevalence.
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Background: The association between initiation of antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection and possible herpes simplex virus type 2 (HSV-2) shedding and genital ulcer disease (GUD) has not been evaluated. Methods: GUD and vaginal HSV-2 shedding were evaluated among women coinfected with HIV and HSV-2 (n = 440 for GUD and n = 96 for HSV-2 shedding) who began ART while enrolled in a placebo-controlled trial of HSV-2 suppression with acyclovir in Rakai, Uganda. Monthly vaginal swabs were tested for HSV-2 shedding, using a real-time quantitative polymerase chain reaction assay. Prevalence risk ratios (PRRs) of GUD were estimated using log binomial regression. Random effects logistic regression was used to estimate odds ratios (ORs) of HSV-2 shedding. Results: Compared with pre-ART values, GUD prevalence increased significantly within the first 3 months after ART initiation (adjusted PRR, 1.94; 95% confidence interval [CI], 1.04-3.62) and returned to baseline after 6 months of ART (adjusted PRR, 0.80; 95% CI, .35-1.80). Detection of HSV-2 shedding was highest in the first 3 months after ART initiation (adjusted OR, 2.58; 95% CI, 1.48-4.49). HSV-2 shedding was significantly less common among women receiving acyclovir (adjusted OR, 0.13; 95% CI, .04-.41). Conclusions: The prevalence of HSV-2 shedding and GUD increased significantly after ART initiation, possibly because of immune reconstitution inflammatory syndrome. Acyclovir significantly reduced both GUD and HSV-2 shedding and should be considered to mitigate these effects following ART initiation.
Article
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To determine the etiology of genital ulcers and to assess the prevalence of human immunodeficiency virus (HIV) infection in ulcer patients in 10 US cities, ulcer and serum specimens were collected from ∼50 ulcer patients at a sexually transmitted disease clinic in each city. Ulcer specimens were tested using a multiplex polymerase chain reaction assay to detect Haemophilus ducreyi, Treponema pallidum, and herpes simplex virus (HSV); sera were tested for antibody to HIV. H. ducreyi was detected in ulcer specimens from patients in Memphis (20% of specimens) and Chicago (12%). T. pallidum was detected in ulcer specimens from every city except Los Angeles (median, 9% of specimens; range, 0%–46%). HSV was detected in ≥50% of specimens from all cities except Memphis (42%). HIV seroprevalence in ulcer patients was 6% (range by city, 0%–18%). These data suggest that chancroid is prevalent in some US cities and that persons with genital ulcers should be a focus of HIV prevention activities.
Article
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Most herpes simplex virus 2 (HSV-2) reactivations in humans are subclinical and associated with rapid expansion and containment of virus. Previous studies have shown that CD8(+) T cells persist in genital skin and mucosa at the dermal-epidermal junction (DEJ)-the portal of neuronal release of reactivating virus-for prolonged time periods after herpes lesions are cleared. The phenotype and function of this persistent CD8(+) T-cell population remain unknown. Here, using cell-type-specific laser capture microdissection, transcriptional profiling and T-cell antigen receptor β-chain (TCRβ) genotyping on sequential genital skin biopsies, we show that CD8αα(+) T cells are the dominant resident population of DEJ CD8(+) T cells that persist at the site of previous HSV-2 reactivation. CD8αα(+) T cells located at the DEJ lack chemokine-receptor expression required for lymphocyte egress and recirculation, express gene signatures of T-cell activation and antiviral activity, and produce cytolytic granules during clinical and virological quiescent time periods. Sequencing of the TCR β-chain repertoire reveals that the DEJ CD8αα(+) T cells are oligoclonal with diverse usage of TCR variable-β genes, which differ from those commonly described for mucosa-associated invariant T cells and natural killer T cells. Dominant clonotypes are shown to overlap among multiple recurrences over a period of two-and-a-half years. Episodes of rapid asymptomatic HSV-2 containment were also associated with a high CD8 effector-to-target ratio and focal enrichment of CD8αα(+) T cells. These studies indicate that DEJ CD8αα(+) T cells are tissue-resident cells that seem to have a fundamental role in immune surveillance and in initial containment of HSV-2 reactivation in human peripheral tissue. Elicitation of CD8αα(+) T cells may be a critical component for developing effective vaccines against skin and mucosal infections.
Article
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Context In the last 3 decades, herpes simplex virus type 2 (HSV-2) infection seroprevalence and neonatal herpes have increased substantially. An effective vaccine for the prevention of genital herpes could help control this epidemic.Objective To evaluate the efficacy of a vaccine for prevention of HSV-2 infection.Design Two randomized, double-blind, placebo-controlled multicenter trials of a recombinant subunit vaccine containing 30 µg each of 2 major HSV-2 surface glycoproteins (gB2 and gD2) against which neutralizing antibodies are directed, administered at months 0, 1, and 6. Control subjects were given a citrate buffer vehicle. Participants were followed up for 1 year after the third immunization.Setting and Participants We enrolled 2393 persons from December 10, 1993, to April 4, 1995, who were HSV-2 and human immunodeficiency virus seronegative. One trial with 18 centers enrolled 531 HSV-2–seronegative partners of HSV-2–infected persons; the other, with 22 centers, enrolled 1862 persons attending sexually transmitted disease clinics. A total of 2268 (94.8%) met inclusion criteria and were included in the analysis with 1135 randomized to placebo and 2012 to vaccine.Main Outcome Measure Time to acquisition of HSV-2 infection, defined by seroconversion or isolation of HSV-2 in culture during the study period by randomization group.Results Time-to-event curves indicated a 50% lower acquisition rate among vaccine vs placebo recipients during the initial 5 months of the trial; however, overall vaccine efficacy was 9% (95% confidence interval,−29% to 36%). Acquisition rates of HSV-2 were 4.6 and 4.2 per 100 patient-years in the placebo and vaccine recipients, respectively (P=.58). Follow-up of vaccine recipients acquiring HSV-2 infection showed vaccination had no significant influence on duration of clinical first genital HSV-2 episodes (vaccine, median of 7.1 days; placebo, 6.5 days; P>.10) or subsequent frequency of reactivation (median monthly recurrence rate with vaccine, 0.2; with placebo, 0.3; P>.10). The vaccine induced high levels of HSV-2–specific neutralizing antibodies in vaccinated persons who did and did not develop genital herpes.Conclusions Efficient and sustained protection from sexual acquisition of HSV-2 infection will require more than high titers of specific neutralizing antibodies. Protection against sexually transmitted viruses involving exposure over a prolonged period will require a higher degree of vaccine efficacy than that achieved in this study. Figures in this Article Herpes simplex virus type 2 (HSV-2) seroprevalence has increased by 32% in the last decade.1 Overall, HSV-2 seroprevalence is 22% in the general US adult population, and in some populations, such as sexually transmitted disease (STD) clinic attendees, seroprevalence varies between 30% and 50%.1- 5 Concomitant with this increase in genital herpes has been an increase in reported cases of neonatal herpes.6 Also, risk of neonatal HSV infection is greater in the setting of new maternal infection during the third trimester of pregnancy than in the setting of established maternal infection.7 Thus, an effective method for control of genital HSV is of major public health importance. A reduction in HSV-2 prevalence would also reduce the influence of HSV-2 infection in human immunodeficiency virus (HIV) 1 acquisition and transmission.8- 10 Several experimental and epidemiological factors indicate that development of an effective vaccine against HSV-2 should be possible. First, HSV-2–specific antibodies are associated with reduction of maternal-fetal transmission of HSV-2.6,11- 13 Also, new infection with the same HSV-2 subtype is rare,14- 15 and prior HSV-1 infection appears to ameliorate frequency and severity of subsequent HSV-2 disease.16- 18 In experimental models, both humoral and cellular immune responses have been effective in preventing HSV in experimental challenge.19 Passive immunization has been achieved with type-specific neutralizing antibodies, and monoclonal antibodies directed at major neutralizing epitopes of HSV-2 glycoproteins B2 (gB2) and D2 (gD2) protected against experimental challenge in mice.20- 21 Immunization with gD2 and gB2 proteins is similarly effective in a guinea pig model.22- 23 Phase 1 and 2 clinical trials with these recombinant proteins have shown that humans develop postimmunization neutralizing antibodies to HSV-2 that are similar to those that arise following natural infection.24 Based on these preclinical and phase 1 and 2 studies, we conducted 2 large, randomized, double-blind, placebo-controlled trials with 27 participating study sites to evaluate the efficacy of a recombinant glycoprotein subunit vaccine for the prevention of genital HSV-2 infection. The vaccine contained 30 µg each of gD2 and gB2 in combination with the adjuvant MF59, a 5% squalene oil-in-water emulsion.
Article
These guidelines for the treatment of persons who have or are at risk for sexually transmitted diseases (STDs) were updated by CDC after consultation with a group of professionals knowledgeable in the field of STDs who met in Atlanta on April 30-May 2, 2013. The information in this report updates the Sexually Transmitted Diseases Treatment Guidelines, 2010 (MMWR Recomm Rep 2010;59 [No. RR-12]). These updated guidelines discuss 1) alternative treatment regimens for Neisseria gonorrhoeae; 2) the use of nucleic acid amplification tests for the diagnosis of trichomoniasis; 3) alternative treatment options for genital warts; 4) the role of Mycoplasma genitalium in urethritis/cervicitis and treatment-related implications; 5) updated HPV vaccine recommendations and counseling messages; 6) the management of persons who are transgender; 7) annual testing for hepatitis C in persons with HIV infection; 8) updated recommendations for diagnostic evaluation of urethritis; and 9) retesting to detect repeat infection. Physicians and other health-care providers can use these guidelines to assist in the prevention and treatment of STDs.
Article
Globally, herpes simplex virus type 2 (HSV-2) infection is the most common cause of genital ulcer disease. Effective prevention strategies for HSV-2 infection are needed to achieve the goals of the World Health Organization global strategy for the prevention and control of sexually transmitted infections. We assessed the effectiveness of pericoital tenofovir gel, an antiviral microbicide, in preventing HSV-2 acquisition in a subgroup of 422 HSV-2-negative women enrolled in the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 study, a double-blind, randomized, placebo-controlled trial. Incident HSV-2 cases were identified by evidence of seroconversion on an HSV-2 IgG enzyme-linked immunosorbent assay between study enrollment and exit. A confirmatory analysis was performed by Western blot testing. The HSV-2 incidence rate was 10.2 cases per 100 person-years (95% confidence interval [CI], 6.8 to 14.7) among 202 women assigned to tenofovir gel, as compared with 21.0 cases per 100 person-years (95% CI, 16.0 to 27.2) among 222 women assigned to placebo gel (incidence rate ratio, 0.49; 95% CI, 0.30 to 0.77; P=0.003). The HSV-2 incidence rate among the 25 women with vaginal tenofovir concentrations of 10,000 ng per milliliter or more was 5.7 cases per 100 person-years, as compared with 15.5 cases per 100 person-years among the 103 women with no detectable vaginal tenofovir (incidence rate ratio, 0.37; 95% CI, 0.04 to 1.51; P=0.14). As confirmed by Western blot testing, there were 16 HSV-2 seroconversions among women assigned to tenofovir gel as compared with 36 among those assigned to the placebo gel (incidence rate ratio, 0.45; 95% CI, 0.23 to 0.82; P=0.005). In this study in South Africa, pericoital application of tenofovir gel reduced HSV-2 acquisition in women. (Funded by the U.S. Agency for International Development and others; ClinicalTrials.gov number, NCT00441298.).
Article
Context Neonatal herpes most commonly results from fetal exposure to infected maternal genital secretions at the time of delivery. The risk of transmission from mother to infant as it relates to maternal herpes simplex virus (HSV) serologic status and exposure to HSV in the maternal genital tract at the time of labor has not been quantified. Furthermore, no data exist on whether cesarean delivery, the standard of care for women with genital herpes lesions at the time of delivery, reduces HSV transmission.Objective To determine the effects of viral shedding, maternal HSV serologic status, and delivery route on the risk of transmission of HSV from mother to infant.Design Prospective cohort of pregnant women enrolled between January 1982 and December 1999.Settings A university medical center, a US Army medical center, and 5 community hospitals in Washington State.Patients A total of 58 362 pregnant women, of whom 40 023 had HSV cultures obtained from the cervix and external genitalia and 31 663 had serum samples tested for HSV.Main Outcome Measure Rates of neonatal HSV infection.Results Among the 202 women from whom HSV was isolated at the time of labor, 10 (5%) had neonates with HSV infection (odds ratio [OR], 346; 95% confidence interval [CI], 125-956 for neonatal herpes when HSV was isolated vs not isolated). Cesarean delivery significantly reduced the HSV transmission rate among women from whom HSV was isolated (1 [1.2%] of 85 cesarean vs 9 [7.7%] of 117 vaginal; OR, 0.14; 95% CI, 0.02-1.08; P = .047). Other risk factors for neonatal HSV included first-episode infection (OR, 33.1; 95% CI, 6.5-168), HSV isolation from the cervix (OR, 32.6; 95% CI, 4.1-260), HSV-1 vs HSV-2 isolation at the time of labor (OR, 16.5; 95% CI, 4.1-65), invasive monitoring (OR, 6.8; 95% CI, 1.4-32), delivery before 38 weeks (OR, 4.4; 95% CI, 1.2-16), and maternal age less than 21 years (OR, 4.1; 95% CI, 1.1-15). Neonatal HSV infection rates per 100 000 live births were 54 (95% CI, 19.8-118) among HSV-seronegative women, 26 (95% CI, 9.3-56) among women who were HSV-1–seropositive only, and 22 (95% CI, 4.4-64) among all HSV-2–seropositive women.Conclusion Neonatal HSV infection rates can be reduced by preventing maternal acquisition of genital HSV-1 and HSV-2 infection near term. It can also be reduced by cesarean delivery and limiting the use of invasive monitors among women shedding HSV at the time of labor.
Article
The clinical course and complications of 268 patients with first episodes and 362 with recurrent episodes of genital herpes infection were reviewed. Symptoms of genital herpes were more severe in women than in men. Primary first-episode genital herpes was accompanied by systemic symptoms (67%), local pain and itching (98%), dysuria (63%), and tender adenopathy (80%). Patients presented with several bilaterally distributed postularulcerative lesions that lasted a mean of 19.0 days. Herpes simplex virus was isolated from the urethra, cervix, and pharynx of 82%, 88%, and 13% of women with first-episode primary genital herpes, and the urethra and pharynx of 28% and 7% of men. Complications included aseptic meningitis (8%), sacral autonomic nervous system dysfunction (2%), development of extragenital lesions (20%), and secondary yeast infections (11%). Recurrent episodes were characterized by small vesicular or ulcerative unilaterally distributed lesions that lasted a mean of 10.1 days. Systemic symptoms were uncommon and 25% of recurrent episodes were asymptomatic. The major concerns of patients were the frequency of recurrences and fear of transmitting infection to partners or infants.
Article
Background. Tenofovir is a potent anti-human immunodeficiency virus (HIV) agent that decreased risk of herpes simplex virus type 2 (HSV-2) acquisition in HIV pre-exposure prophylaxis trials. Whether tenofovir has utility in established HSV-2 disease is unclear. Methods. We randomized immunocompetent women with symptomatic HSV-2 infection to oral tenofovir disoproxil fumarate (TDF)/placebo vaginal gel, oral placebo/tenofovir (TFV) vaginal gel, or double placebo (ratio 2:2:1) in a one-way cross-over trial. Women collected genital swabs twice daily for HSV PCR during 4-week lead-in and 5-week treatment phases. The primary intent-to-treat end point was within-person comparison of genital HSV shedding and lesion rates. Results. 64 women completed the lead-in phase and were randomized. Neither TDF nor TFV gel decreased overall shedding or lesion rate in the primary analysis; TFV gel decreased quantity of HSV DNA by −0.50 (−0.86–0.13) log10 copies/mL. In the per-protocol analysis, TDF reduced shedding (relative risk [RR] = 0.74, P = .006) and lesion rates (RR = 0.75, P = .032); quantity of virus shed decreased by 0.41 log10 copies/mL. Conclusions. Oral TDF modestly decreased HSV shedding and lesion rate, and quantity of virus shed when used consistently. Vaginal TFV gel decreased quantity of virus shed by 60%. In contrast to effects on HSV-2 acquisition, tenofovir is unlikely to provide clinically meaningful reductions in the frequency of HSV shedding or genital lesions. Clinical Trials Registration. NCT01448616
Article
Context.— Genital ulcer disease has been epidemiologically linked as a risk factor in the transmission of the human immunodeficiency virus 1 (HIV-1). While herpes simplex virus 2 (HSV-2) is the most common cause of genital ulcers, no study has systematically evaluated the frequency or titer of HIV-1 virus in HSV-2 lesions. Objective.— To compare lesional HIV-1 RNA levels during and after genital HSV-2 reactivation and to evaluate the frequency, titer, and duration of HIV-1 RNA shedding in lesions due to HSV-2. Design.— Convenience sample. Setting.— Sexually transmitted disease research clinic at the University of Washington, Seattle. Patients.— Twelve HIV-infected men with a history of symptomatic HSV-2 infection who underwent daily sampling of genital lesions for HIV-1 RNA by polymerase chain reaction assay and HSV-2 by culture. Main Outcome Measure.— Detection of lesional HIV RNA and HSV-2. Results.— HIV-1 RNA was detected from lesional swabs in 25 of 26 consecutively studied HSV-2 episodes and on 67% of days in which genital lesions were noted. The HIV-1 RNA titers in lesional swabs exceeded 10000 copies/mL of swab sample in 75% of samples (range, 2.2-3.2×105 copies/mL of swab sample). HIV-1 RNA in genital lesion swabs was seen in persons with high and low titers of plasma HIV-1 RNA and was not associated with plasma HIV-1 RNA levels. Conclusions.— HIV-1 virions can consistently be detected in genital ulcers caused by HSV-2, which suggests that genital herpes infection likely increases the efficiency of the sexual transmission of HIV-1.
Article
Objective. —To investigate the prevalence and level of genital herpes simplex virus (HSV) among women at delivery.Design, Patients, and Setting. —A prospective analysis of HSV by culture and by polymerase chain reaction (PCR) of genital specimens and by HSV serologic studies in 100 asymptomatic women in labor; prospective analysis of HSV by PCR among 50 seronegative nonpregnant women at a student health center; and retrospective analysis of genital specimens for HSV by PCR from 17 HSV culture-positive women with uninfected neonates and from two HSV culture-negative women with HSV-infected neonates. All pregnant women were at a university hospital.Main Outcome Measures. —Presence of HSV by culture and levels of HSV by quantitative, type-specific PCR in cervical and vulvar specimens; HSV serologic testing by Western blot.Results. —All of the 100 asymptomatic women in labor who were studied prospectively were HSV culture negative. In nine HSV was recovered by PCR. Herpes simplex virus was recovered by PCR in one of the 50 seronegative nonpregnant women; she soon became seropositive. All 17 culture-positive women had HSV recovered by PCR. High levels of HSV DNA were obtained by PCR from the two culture-negative women with infected neonates. Among those from whom HSV was recovered by PCR, HSV DNA levels were 250 times higher from culture-positive samples than from culture-negative samples (11 571 genome equivalents vs 46 genome equivalents; P<.001).Conclusions. —The frequency of infant exposure to HSV DNA—containing secretions from HSV-seropositive mothers is about eight times higher than previously reported using HSV culture methods. High maternal levels of HSV DNA may be associated with an increased frequency of transmission of HSV to the infant.(JAMA. 1994;272:792-796)
Article
Background: Visits to physicians for genital herpes simplex virus (HSV) infection continue to increase. Most patients with symptomatic infections have recurrences, but no studies of the long-term clinical course of genital herpes are available. Objective: To determine whether the frequency of HSV recurrences decreases over time. Design: Observational cohort study. Setting: University-based research clinic. Patients: 664 persons with genital herpes followed for at least 14 months. Measurements: Patients were classified as having initial or recurrent HSV-1 or HSV-2 infection. Patient-reported recurrences and observed recurrences were recorded in a database; more than 12 000 recurrences were analyzed. Results: Median recurrence rates in the first year of follow-up were one and five per year in patients with newly acquired HSV-1 and HSV-2 infection, respectively; second-year rates were significantly lower in both groups. Patients presenting with recurrent HSV-2 infection had higher rates of recurrence in the first and second years and no significant decrease; significant decreases were detected with longer follow-up. One third of all patients experienced a decrease of two or more recurrences per year between years 1 and 2. Patients infected with HSV-2 who were followed for more than 4 years had a median decrease of two recurrences between years 1 and 5. However, 25% of these patients had an increase of at least one recurrence in year 5, illustrating the variability among HSV-infected persons. Decreases over time among patients who never received suppressive therapy were similar to decreases during untreated periods in patients who received suppressive therapy. Conclusions: Herpes simplex virus type 2 infection continues to be a chronic remitting illness. Over time, however, clinically significant reductions occur in a majority of patients. Physicians may wish to periodically assess the need for continued treatment with daily suppressive antiviral chemotherapy.
Article
Objective : To assess the effect of the antiviral drug acyclovir on the frequency of subclinical shedding of herpes simplex virus (HSV) in the genital tract. Design : A double-blind, placebo-controlled, crossover clinical trial. Setting : A university-based virology research clinic. Patients : 34 women with herpes simplex virus type 2 (HSV-2) antibody only and genital herpes of less than 2 years' duration. Intervention : Participants were randomly assigned to receive either acyclovir, 400 mg twice daily for 70 days, followed by a 14-day washout period, and then placebo for 70 days, or the study medications in the reverse order. Measurements : Women collected daily genital swabs of the vulvar, cervicovaginal, and perianal areas for HSV culture, maintained a diary of genital lesions, and were examined at the time of recurrences. Results : In an intent-to-treat analysis of the initial treatment period, 15 of the 17 women who received placebo and 3 of the 17 women who received acyclovir had at least 1 day of subclinical shedding (P < 0.001). Among the participants who received placebo, subclinical shedding occurred on 64 of 928 (6.9%) days compared with 3 of 1057 (0.3%) days among the participants who received acyclovir (P < 0.001). The relative risk for subclinical shedding was 0.09 (95% Cl, 0.03 to 0.35) for the women who received acyclovir compared with the women who received placebo. In a paired analysis of 26 women who completed both arms of the study, acyclovir therapy was associated with a decrease in the frequency of subclinical shedding ; subclinical shedding occurred on 83 of 1439 (5.8%) days with placebo, and on 6 of 1611 (0.37%) days with acyclovir (P < 0.001)-a 94% reduction. The frequency of subclinical shedding was reduced at all anatomic sites and in all patients. Conclusions : Daily therapy with oral acyclovir suppresses subclinical shedding of HSV-2 in the genital tract, suggesting that studies to evaluate the use of acyclovir in preventing HSV-2 transmission are warranted.
Article
Rapid detection and differentiation of herpes simplex viruses (HSV) is important for patient management and treatment, especially in HSV meningoencephalitis.Objectives Results of Simplexa HSV1 & 2 Direct kit (Focus Diagnostics), an FDA-cleared sample-to-result method providing results in ∼75 min, were compared to those of laboratory-developed real-time PCR assays (LDT) for detection of HSV1 and HSV2.Study designSamples tested included 168 cerebral spinal fluid (CSF) collected prospectively and 150 tested retrospectively: 81 from clinical testing and 69 from subjects in a neonatal herpes study; and 53 plasma and sera. Each sample was tested by both methods on the same day.ResultsThree of 318 CSF had invalid Simplexa Direct results and negative LDT results. Three neonatal samples with low HSV viral loads by LDT could not be typed; two were HSV2 positive and one was negative by Simplexa Direct. Of 312 CSF with valid, type-specific results, HSV1 was detected in 16 by LDT and in 17 by Simplexa Direct; HSV2 was detected in 48 by LDT and in 49 by Simplexa Direct. Concordance rates were 98.4% (κ 0.84) and 97.1% (κ 0.89) for HSV1 and HSV2, respectively. Positive percent agreements were 87.5% for HSV1 and 91.7% for HSV2. Two and four CSF were positive only by LDT and three and five were positive only by Simplexa Direct for HSV1 and HSV2, respectively.Conclusions Simplexa HSV1 & 2 assay performed well compared to an established LDT. The faster turn-around-time compared to LDT will allow for more rapid antiviral treatment and better patient management.
Article
Background HSV-2 diagnosis is typically by viral culture, viral DNA amplification of lesion material or by serology in cases of subclinical presentation. These methods can be time consuming and expensive. The Uni-Gold™ HSV-2 Rapid is a fast, point-of-care diagnostic test that can be performed outside a full service laboratory. Objective To evaluate the ability of the Uni-Gold™ HSV-2 Rapid to correctly diagnose the presence or absence of anti-HSV-2 antibodies in patient serum samples in comparison to the University of Washington HSV Western blot (UWWB). Study Design Sera from 100 adult patients in the USA were tested for HSV-2 specific antibodies by Uni-Gold™ HSV-2 Rapid and results were compared to those of the UWWB to determine the test's sensitivity and specificity. Results Of 18 patients seropositive for HSV-2 by UWWB, 17 were correctly identified as such by the Uni-Gold™ HSV-2 Rapid. Of 76 patients who were seronegative for HSV-2 by UWWB, 75 were correctly identified by the rapid test. Six sera had indeterminate results by UWWB. Sensitivity for the Uni-Gold™ HSV-2 Rapid was 94% and specificity was 99%. Conclusion The Uni-Gold™ HSV-2 Rapid had high sensitivity and specificity in a small sample of unselected, adults seeking care in the Seattle, USA area. An accurate, near-person test allows immediate counselling directed toward symptom recognition, treatment, and practices that can limit the risk of HSV-2 transmission.
Article
Maternal acquisition of genital herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2) near delivery accounts for most cases of neonatal herpes, although neonatal HSV incidence has remained stable in recent decades. A decline in HSV-1, but not HSV-2, seroprevalence has been reported among reproductive-aged women. This study was designed to evaluate trends in the seroprevalence of HSV-1 and HSV-2 among parturients who delivered between 1989 and 2010. Herpes simplex virus infection status was determined using Western blot within routine prenatal tests. The proportion of patients with prenatal HSV serologic results declined from 54.7% during 1989 to 1997 to 44.8% during 1998 to 2010. Yearly changes in HSV-1 and HSV-2 seroprevalence were estimated with Poisson regression. Models were adjusted for race/ethnicity, maternal age, parity, delivery type, and insurance status. Prenatal HSV serologic results were available for 18,993 pregnancies in 15,738 women (median age, 28 years; interquartile range, 23-33 years), of whom 43% were white, 12% were black, 11% were Asian, 7% were Hispanic, and 27% were other or unreported; 26% had private insurance. Nine percent of pregnancies involved women who were seropositive for HSV-2 only, 15% for both HSV-1 and HSV-2, and 53% for HSV-1 only; 24% were seronegative for HSV. Herpes simplex virus type 1 seroprevalence decreased from 69.1% during 1989 to 1999 to 65.5% during 2000 to 2010; HSV-2 seroprevalence decreased from 30.1% to 16.3%, for a 46% relative decline. After adjustment, no significant annual trend in HSV-1 seroprevalence was noted (0.1% per year; 95% CI, 0%-0.3% per year; P = 0.13). Rates of HSV-2 seroprevalence decreased significantly by 4.8% per year (95% CI, 4.3%-5.2% per year; P < 0.001). Herpes simplex virus type 1 seroprevalence increased slightly among black women only (0.9% per year; 95% CI, 0.4%-1.3% per year; P < 0.001). Herpes simplex virus type 2 seroprevalence decreased significantly among women of all races (P < 0.001). Rates per year decreased substantially less for black women relative to white women (2.6% per year vs 5.5% per year, respectively; P < 0.001). Seroprevalence of HSV-2 among pregnant women decreased between 1989 and 2010, with the decrease particularly noted for white women. Herpes simplex virus type 1 did not decrease overall and in fact increased slightly among black women. Women who are seronegative entering pregnancy and acquire HSV during late pregnancy are at higher risk for transmission of HSV to their infants than are seropositive women. These findings offer new data on HSV seroprevalence in the pregnant population.
Article
Background: Daily oral preexposure prophylaxis (PrEP) using the antiretroviral tenofovir disoproxil fumarate (TDF) alone or in combination with emtricitabine (FTC-TDF) reduces the risk for HIV-1 acquisition. Tenofovir has in vitro activity against herpes simplex virus type 2 (HSV-2). Objective: To assess the efficacy of daily oral PrEP with tenofovir and FTC-TDF in the prevention of HSV-2 acquisition. Design: Subgroup analysis of data from a randomized, placebo-controlled trial with concealed allocation. (ClinicalTrials.gov: NCT00557245). Setting: Multiple sites in Kenya and Uganda. Participants: Heterosexual men and women who were seronegative for HIV-1 and HSV-2 and at high risk for HIV-1 acquisition due to having an HIV-1-infected partner. Intervention: Once-daily oral tenofovir disoproxil fumarate (TDF), alone or combined with emtricitabine (FTC-TDF), compared with placebo. Measurements: HSV-2 seroconversion. Results: A total of 131 participants seroconverted to HSV-2 (79 of 1041 assigned to tenofovir or FTC-TDF PrEP [HSV-2 incidence, 5.6 per 100 person-years] and 52 of 481 assigned to placebo [HSV-2 incidence, 7.7 per 100 person-years]). The hazard ratio (HR) for HSV-2 acquisition with daily oral PrEP was 0.70 (95% CI, 0.49 to 0.99; P = 0.047) compared with placebo, and the absolute risk reduction was 2.1 per 100 person-years. Among the 1044 participants with HSV-2-infected partners, the HR for PrEP was 0.67 (CI, 0.46 to 0.98; P = 0.038) compared with placebo, and the absolute risk reduction was 3.1 per 100 person-years. Limitation: Randomization was not stratified by HSV-2 status, and diagnostic tests to exclude participants with acute HSV-2 at baseline are not available. Conclusion: Daily oral tenofovir-based PrEP significantly reduced the risk for HSV-2 acquisition among heterosexual men and women. Modest protection against HSV-2 is an added benefit of HIV-1 prevention with oral tenofovir-based PrEP. Primary funding source: Bill & Melinda Gates Foundation.
Article
HSV-2 infection is common and generally asymptomatic, but it is associated with increased HIV susceptibility and disease progression. This may relate to herpes-mediated changes in genital and systemic immunology. Cervical cytobrushes and blood were collected from HIV-uninfected African/Caribbean women in Toronto, and immune cell subsets were enumerated blindly by flow cytometry. Immune differences between groups were assessed by univariate analysis and confirmed using a multivariate model. Study participants consisted of 46 women, of whom 54% were infected with HSV-2. T cell activation and expression of the mucosal homing integrin α4β7 (19.60% versus 8.76%; p < 0.001) were increased in the blood of HSV-2-infected women. Furthermore, expression of α4β7 on blood T cells correlated with increased numbers of activated (coexpressing CD38/HLA-DR; p = 0.004) and CCR5(+) (p = 0.005) cervical CD4(+) T cells. HSV-2-infected women exhibited an increase in the number of cervical CD4(+) T cells (715 versus 262 cells/cytobrush; p = 0.016), as well as an increase in the number and proportion of cervical CD4(+) T cells that expressed CCR5(+) (406 versus 131 cells, p = 0.001; and 50.70% versus 34.90%, p = 0.004) and were activated (112 versus 13 cells, p < 0.001; and 9.84% versus 4.86%, p = 0.009). Mannose receptor expression also was increased on cervical dendritic cell subsets. In conclusion, asymptomatic HSV-2 infection was associated with significant systemic and genital immune changes, including increased immune activation and systemic α4β7 expression; correlation of the latter with highly HIV-susceptible CD4(+) T cell subsets in the cervix may provide a mechanism for the increased HIV susceptibility observed in asymptomatic HSV-2-infected women.