Rapidly Cleared Episodes of Herpes Simplex Virus Reactivation in Immunocompetent Adults

Department of Medicine, University of Washington, Seattle, Washington 98122, USA.
The Journal of Infectious Diseases (Impact Factor: 6). 10/2008; 198(8):1141-9. DOI: 10.1086/591913
Source: PubMed


Herpes simplex virus (HSV) remains latent in nerve root ganglia of infected persons and is thought to reactivate several times yearly. Recent in situ data show the localization of HSV-specific CD8(+) T cells at the dermal epidermal junction next to peripheral sensory nerve endings, suggesting that viral reactivation may occur more frequently than previously appreciated.
Twenty-five HSV-2-seropositive and 18 HSV-1-seropositive healthy adults collected anogenital and oral swabs, respectively, 4 times per day for 60 days. Swabs were assayed for HSV, using a quantitative polymerase chain reaction assay.
Twenty-four percent of anogenital reactivations and 21% of oral reactivations lasted < or =6 h, and 49% of anogenital reactivations and 39% of oral reactivations lasted < or =12 h. Lesions were reported in only 3 (7%) of 44 anogenital reactivations and 1 (8%) of 13 oral reactivations lasting < or =12 h. The median HSV DNA levels at initial and last detection were 10(3.5) and 10(3.3) copies/mL, respectively, during anogenital reactivation and 10(3.7) and 10(3.0) copies/mL, respectively, during oral reactivation.
This high frequency of short subclinical HSV reactivation in immunocompetent hosts strongly suggests that the peripheral mucosal immune system plays a critical role in clearing HSV reactivations.

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    • "Reactivation of HSV-2 is most frequent during the first years after primary infection. As much as 75% of these events may be short asymptomatic shedding lasting for approximately 12 hours [19]. "
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    ABSTRACT: Herpes simplex virus type 2 (HSV-2) is sexually transmitted, leading to blisters and ulcers in the genito-anal region. After primary infection the virus is present in a latent state in neurons in sensory ganglia. Reactivation and production of new viral particles can cause asymptomatic viral shedding or new lesions. Establishment of latency, maintenance and reactivation involve silencing of genes, continuous suppression of gene activities and finally gene activation and synthesis of viral DNA. The purpose of the present work was to study the genetic stability of the virus during these events. HSV-2 was collected from 5 patients with true primary and recurrent infections, and the genes encoding glycoproteins B,G,E and I were sequenced. No nucleotide substitution was observed in any patient, indicating genetic stability. However, since the total number of nucleotides in these genes is only a small part of the total genome, we cannot rule out variation in other regions. Although infections of cell cultures and animal models are useful for studies of herpes simplex virus, it is important to know how the virus behaves in the natural host. We observed that several glycoprotein gene sequences are stable from primary to recurrent infection. However, the virus isolates from the different patients were genetically different.
    BMC Infectious Diseases 02/2014; 14(1):63. DOI:10.1186/1471-2334-14-63 · 2.61 Impact Factor
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    • "In fact, our experimental system using fibroblasts probably represents a particularly rigorous test for HE efficacy, since in neurons the viral genome is not as repressed as in latently infected primary fibroblasts.25 Furthermore, recent studies from Wald and colleagues demonstrated that HSV-1 or HSV-2 seropositive healthy individuals have high frequency short subclinical HSV reactivation, suggesting that HSV may reactivate more frequently than previously reported.41 Therefore, virus genomes may be more accessible to endonuclease in vivo than during our in vitro experiments. "
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    ABSTRACT: Following acute infection, herpes simplex virus (HSV) establishes latency in sensory neurons, from which it can reactivate and cause recurrent disease. Available antiviral therapies do not affect latent viral genomes; therefore, they do not prevent reactivation following therapy cessation. One possible curative approach involves the introduction of DNA double strand breaks in latent HSV genomes by rare-cutting endonucleases, leading to mutagenesis of essential viral genes. We tested this approach in an in vitro HSV latency model using the engineered homing endonuclease (HE) HSV1m5, which recognizes a sequence in the HSV-1 gene UL19, encoding the virion protein VP5. Coexpression of the 3'-exonuclease Trex2 with HEs increased HE-mediated mutagenesis frequencies up to sixfold. Following HSV1m5/Trex2 delivery with adeno-associated viral (AAV) vectors, the target site was mutated in latent HSV genomes with no detectable cell toxicity. Importantly, HSV production by latently infected cells after reactivation was decreased after HSV1m5/Trex2 exposure. Exposure to histone deacetylase inhibitors prior to HSV1m5/Trex2 treatment increased mutagenesis frequencies of latent HSV genomes another two- to fivefold, suggesting that chromatin modification may be a useful adjunct to gene-targeting approaches. These results support the continuing development of HEs and other nucleases (ZFNs, TALENs, CRISPRs) for cure of chronic viral infections.Molecular Therapy-Nucleic Acids (2014) 3, e1; doi:10.1038/mtna.2013.75; published online 4 February 2014.
    Molecular Therapy - Nucleic Acids 02/2014; 3(2):e146. DOI:10.1038/mtna.2013.75 · 4.51 Impact Factor
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    • "We used a strategy of intense sampling over intervals ranging from every 5 min to every 24 hr, to characterize temporal and spatial dynamics of genital HSV-2 replication. While we previously identified that a majority of HSV-2 reactivations last less than a day (Mark et al., 2008), our current findings demonstrate that the cardinal feature of HSV-2 shedding is extraordinary episode heterogeneity. Longer and higher copy number episodes, which often manifest with genital lesions, are notable for multiple erratic peaks and wide viral dispersion. "
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    ABSTRACT: Herpes simplex virus-2 (HSV-2) is shed episodically, leading to occasional genital ulcers and efficient transmission. The biology explaining highly variable shedding patterns, in an infected person over time, is poorly understood. We sampled the genital tract for HSV DNA at several time intervals and concurrently at multiple sites, and derived a spatial mathematical model to characterize dynamics of HSV-2 reactivation. The model reproduced heterogeneity in shedding episode duration and viral production, and predicted rapid early viral expansion, rapid late decay, and wide spatial dispersion of HSV replication during episodes. In simulations, HSV-2 spread locally within single ulcers to thousands of epithelial cells in <12 hr, but host immune responses eliminated infected cells in <24 hr; secondary ulcers formed following spatial propagation of cell-free HSV-2, allowing for episode prolongation. We conclude that HSV-2 infection is characterized by extremely rapid virological growth and containment at multiple contemporaneous sites within genital epithelium. DOI:
    eLife Sciences 04/2013; 2(2):e00288. DOI:10.7554/eLife.00288 · 9.32 Impact Factor
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