Rapid host immune response and viral dynamics in herpes simplex virus-2 infection.
ABSTRACT Herpes simplex virus-2 (HSV-2) is periodically shed throughout the human genital tract. Although a high viral load correlates with the development of genital ulcers, shedding also commonly occurs even when ulcers are absent, allowing for silent transmission during coitus and contributing to high seroprevalence of HSV-2 worldwide. Frequent viral reactivation occurs within ganglia despite diverse and complementary host and viral mechanisms that predispose toward latency, suggesting that viral replication may be constantly occurring in a small minority of neurons at these sites. Within genital mucosa, the in vivo expansion and clearance rates of HSV-2 are extremely rapid. Resident dendritic cells and memory HSV-2 specific T cells persist at prior sites of genital tract reactivation and, in conjunction with prompt innate recognition of infected cells, lead to rapid containment of infected cells. The fact that immune responses usually control viral replication in genital skin before lesions develop provides hope that enhancing such responses could lead to effective vaccines and immunotherapies.
SourceAvailable from: Staffan Görander[Show abstract] [Hide abstract]
ABSTRACT: In this study we describe that six rat models (SD, WIST, LEW, BN, F344 and DA) are susceptible to intravaginal herpes simplex virus-2 (HSV-2) infection after pre-treatment with progesterone. At a virus dose of 5 × 10(6) PFU of HSV-2, all rat models were infected presenting anti-HSV-2 antibodies, infectious virus in vaginal washes, and HSV-2 DNA genome copies in lumbosacral dorsal root ganglia and the spinal cord. Most of the LEW, BN, F344, and DA rats succumbed in systemic progressive symptoms at day 8-14 post infection, but presented no or mild genital inflammation while SD and WIST rats were mostly infected asymptomatically. Infected SD rats did not reactivate HSV-2 spontaneously or after cortisone treatment. In an HSV-2 virus dose reduction study, F344 rats were shown to be most susceptible. We also investigated whether an attenuated HSV-1 strain (KOS321) given intravaginally, could protect from a subsequent HSV-2 infection. All LEW, BN, and F344 rats survived a primary HSV-1 infection and no neuronal infection was established. In BN and F344 rats, anti-HSV-1 antibodies were readily detected while LEW rats were seronegative. In contrast to naïve LEW, BN, and F344 rats where only 3 of 18 animals survived 5 × 10(6) PFU of HSV-2, 23 of 25 previously HSV-1 infected rats survived a challenge with HSV-2. The described models provide a new approach to investigate protective effects of anti-viral microbicides and vaccine candidates, as well as to study asymptomatic primary genital HSV-2 infection.Archives of Virology 02/2015; DOI:10.1007/s00705-015-2365-7 · 2.28 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Herpes Simplex Virus type-1 (HSV-1) and type-2 (HSV-2) establish life-long infections and cause significant orofacial and genital infections in humans. HSV-1 is the leading cause of infectious blindness in the western world. Currently, there are no available vaccines to protect against herpes simplex infections. Recently, we showed that a single intramuscular immunization with an HSV-1(F) mutant virus lacking expression of the viral glycoprotein K (gK), which prevents the virus from entering into distal axons of ganglionic neurons, conferred significant protection against either virulent HSV-1(McKrae) or HSV-2(G) intravaginal challenge in mice. Specifically, 90% of the mice were protected against HSV-1(McKrae) challenge, while 70% of the mice were protected against HSV-2(G) challenge. We constructed the recombinant virus VC2 that contains specific mutations in gK and the membrane protein UL20 preventing virus entry into axonal compartments of neurons, while allowing efficient replication in cell culture, unlike the gK-null virus, which has a major defect in virus replication and spread. Intramuscular injection of mice with 10(7) VC2 plaque forming units did not cause any significant clinical disease in mice. A single intramuscular immunization with the VC2 virus protected 100% of mice against lethal intravaginal challenge with either HSV-1(McKrae) or HSV-2(G) viruses. Importantly, vaccination with VC2 produced robust cross protective humoral and cellular immunity that fully protected vaccinated mice against lethal disease. Quantitative PCR did not detect any viral DNA in ganglionic tissues of vaccinated mice, while unvaccinated mice contained high levels of viral DNA. The VC2 virus may serve as an efficient vaccine against both HSV-1 and HSV-2 infections, as well as a safe vector for the production of vaccines against other viral and bacterial pathogens.PLoS ONE 10/2014; DOI:10.1371/journal.pone.0109890 · 3.53 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: 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.International Journal of Infectious Diseases 02/2015; 33. DOI:10.1016/j.ijid.2015.02.002 · 2.33 Impact Factor