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BACKGROUNDHerpes simplex virus type 1 (HSV-1) is prevalent worldwide and causes mucocutaneous infections of the oral area. We aimed to define the frequency and anatomic distribution of HSV-1 reactivation in the facial area in persons with a history of oral herpes. METHODSEight immunocompetent HSV-1 seropositive adults were evaluated for shedding of HSV-1 from 12 separate orofacial sites (8 from oral mucosa, 2 from nose, and 2 from conjunctiva) 5 days a week and from the oral cavity 7 days a week for approximately 5 consecutive weeks by a HSV DNA PCR assay. Symptoms and lesions were recorded by participants. RESULTSHerpes simplex virus type 1 was detected at least from 1 site on 77 (26.5%) of 291 days. The most frequent site of shedding was the oral mucosa, with widespread shedding throughout the oral cavity. Lesional shedding rate was 36.4% (4 of 11 days with lesions), and the asymptomatic rate was 27.1% (65 of 240 nonlesional days). In individual participants, the median rate of HSV shedding by HSV PCR was 19.7% of days (range, 11%–63%). CONCLUSIONSReactivation of HSV-1 on the oral mucosa is common and usually asymptomatic. However, HSV-1 is rarely found in tears and nasal mucosa. Frequent oral shedding of HSV-1 may increase the risk for transmitting the virus to both oral and genital mucosa of sexual partners.

Epstein-Barr virus (EBV) causes infectious mononucleosis and can lead to lymphoproliferative diseases. We evaluated the effects of valganciclovir on oral EBV shedding in a randomized, double-blind, placebo-controlled study. Twenty-six men received oral valganciclovir or daily placebo for 8 weeks, followed by a 2-week \"washout period\" and then 8 weeks of the alternative treatment. Valganciclovir reduced the proportion of days with EBV detected from 61.3% to 17.8% (relative risk, 0.28; 95% confidence interval [CI], .21–.41; P < .001), and quantity of virus detected by 0.77 logs (95% CI, .62–.91 logs; P < .001). Further investigations into the impact of valganciclovir on EBV-associated diseases are needed.

New treatments are needed for herpes simplex virus infection. In this placebo-controlled, randomized, dose-ranging trial, pritelivir, an inhibitor of the viral helicase–primase complex, reduced genital HSV-2 shedding in a dose-dependent fashion. Treatment of genital infections with the herpes simplex virus (HSV) relies on nucleoside analogues that inhibit the HSV DNA polymerase after phosphorylation by the viral thymidine kinase. 1 These compounds, which were developed three decades ago and are in widespread use today, ameliorate clinical disease. However, they do not abrogate viral shedding and only partially reduce the risk of transmission to sexual partners. 2 – 4 In immunocompromised persons, resistance to nucleoside analogues develops occasionally, and treatment options for acyclovir-resistant HSV are limited. 5 , 6 The thiazolylamide pritelivir (BAY 57-1293; AIC316) is the first in a new class of antiviral agents that inhibit HSV . . .

Co-infection with HIV can result in impaired control of cytomegalovirus (CMV) replication, increasing the likelihood of disease and onward transmission. The objective of this analysis was to measure the impact of HIV on CMV replication in an intensively-sampled cohort in Kampala, Uganda. CMV seropositive men and women aged 18-65, with or without HIV co-infection, were followed for one month. Daily oral swabs and weekly anogenital swabs and plasma were collected. Quantitative CMV PCR was performed on all samples. Eighty-five participants were enrolled and provided ≥1 oral swab; 43 (51%) were HIV-seropositive. People living with HIV (PLWH; median CD4 count 439 cells/mm3; none on antiretrovirals) had 2-4 times greater risk of CMV detection at each anatomical site assessed. At the oral site, 773 of 1272 (61%) of samples from PLWH had CMV detected, compared to 214 of 1349 (16%) among people without HIV. Similarly, the mean CMV quantity was higher among PLWH at all anatomical sites, with the largest difference seen for oral swabs (mean difference 1.63 log/mL; 95% CI 1.13-2.13). Among PLWH, absolute quantity of CD4+ T-cells was not associated with risk of CMV detection. HIV plasma RNA quantity was positively correlated with oral CMV shedding frequency, but not detection at other sites. Mucosal and systemic CMV replication occurs at higher levels in PLWH than people without HIV, particularly oral shedding, which is a major mode of CMV transmission. Increased CMV replication despite relatively preserved CD4+ T-cell counts suggests that additional interventions are required to improve CMV control in PLWH.

In this study of serial saliva specimens from 277 children, 40 percent were infected with human herpesvirus 6 (HHV-6) by 12 months of age and 77 percent were infected by 2 years of age. Nearly all primary infections were symptomatic, with almost 40 percent leading to clinic visits for symptoms such as fever, fussiness, and diarrhea. In this study of serial saliva specimens from 277 children, 40 percent were infected with human herpesvirus 6 by 12 months of age and 77 percent were infected by 2 years of age. Human herpesvirus 6 (HHV-6) infects over 90 percent of people within the first two years of life. 1 Studies of febrile children in the emergency department indicate that primary HHV-6 infection accounts for a large proportion of visits and febrile seizures. 2 Despite the interest in HHV-6 as an important pathogen, 3 – 5 no prospective, population-based study has evaluated the acquisition of HHV-6 outside the acute care setting. Thus, the full spectrum of illness and virologic aspects of primary HHV-6 infection remain unknown. We developed a noninvasive method of testing serially collected saliva specimens for HHV-6 6 and used it prospectively in children from . . .

Herpes simplex virus (HSV) causes chronic infection in the human host, characterized by self-limited episodes of mucosal shedding and lesional disease, with latent infection of neuronal ganglia. The epidemiology of genital herpes has undergone a significant transformation over the past two decades, with the emergence of HSV-1 as a leading cause of first-episode genital herpes in many countries. Though dsDNA viruses are not expected to mutate quickly, it is not yet known to what degree the HSV-1 viral population in a natural host adapts over time, or how often viral population variants are transmitted between hosts. This study provides a comparative genomics analysis for 33 temporally-sampled oral and genital HSV-1 genomes derived from five adult sexual transmission pairs. We found that transmission pairs harbored consensus-level viral genomes with near-complete conservation of nucleotide identity. Examination of within-host minor variants in the viral population revealed both shared and unique patterns of genetic diversity between partners, and between anatomical niches. Additionally, genetic drift was detected from spatiotemporally separated samples in as little as three days. These data expand our prior understanding of the complex interaction between HSV-1 genomics and population dynamics after transmission to new infected persons.

Background. Human herpesvirus (HHV) infections are common during infancy. Primary infections are frequently asymptomatic and best studied prospectively by using direct viral detection. Methods. Oropharyngeal swab specimens were collected weekly from Ugandan newborn infants, their mothers, and other children in the household. Blood specimens were collected every 4 months. Samples were tested for herpes simplex virus (HSV) types 1 and 2, Epstein-Barr virus (EBV), cytomegalovirus (CMV), HHV-6A, HHV-6B, and HHV-8, using quantitative polymerase chain reaction. Results. Thirty-two infants, 32 mothers, and 49 other household children were followed for a median of 57 weeks. Seventeen mothers had human immunodeficiency virus type 1 (HIV) infection; no infants acquired HIV-1. The 12-month incidence of postnatal infection was 76% for HHV-6B, 59% for CMV, 47% for EBV, 8% for HSV-1, and 0% for HHV-8. The quantity of oropharyngeal shedding by contacts was associated with HHV-6A or HHV-6B transmission. Maternal HIV-1 infection was associated with EBV transmission, while breastfeeding and younger child contacts were associated with CMV transmission. Except for HSV-1, primary HHV infections were subclinical. Conclusions. By capturing exposures and acquisition events, we found that the incidence and risk factors of infection vary by HHV type. HSV-1 infection, unlike other HHV infections, caused acute clinical illness in these infants.

Skin and mucosal herpes simplex virus type 2 (HSV-2) shedding predominantly occurs in short subclinical episodes. We assessed whether standard-dose or high-dose antiviral therapy reduces the frequency of such shedding. HSV-2-seropositive, HIV-seronegative people were enrolled at the University of Washington Virology Research Clinic (WA, USA). We did three separate but complementary open-label cross-over studies comparing no medication with aciclovir 400 mg twice daily (standard-dose aciclovir), valaciclovir 500 mg daily (standard-dose valaciclovir) with aciclovir 800 mg three times daily (high-dose aciclovir), and standard-dose valaciclovir with valaciclovir 1 g three times daily (high-dose valaciclovir). The allocation sequence was generated by a random number generator. Study drugs were supplied in identical, numbered, sealed boxes. Study periods lasted 4–7 weeks, separated by 1 week wash-out. Participants collected genital swabs four times daily for quantitative HSV DNA PCR. Clinical data were masked from laboratory personnel. The primary endpoint was within-person comparison of shedding rate in each study group. Analysis was per protocol. The trials are registered at ClinicalTrials.gov (NCT00362297, NCT00723229, NCT01346475). Of 113 participants randomised, 90 were eligible for analysis of the primary endpoint. Participants collected 23 605 swabs; 1272 (5·4%) were HSV-positive. The frequency of HSV shedding was significantly higher in the no medication group (n=384, 18·1% of swabs) than in the standard-dose aciclovir group (25, 1·2%; incidence rate ratio [IRR] 0·05, 95% CI 0·03–0·08). High-dose aciclovir was associated with less shedding than standard-dose valaciclovir (198 [4·2%] vs 209 [4·5%]; IRR 0·79, 95% CI 0·63–1·00). Shedding was less frequent in the high-dose valaciclovir group than in the standard-dose valaciclovir group (164 [3·3%] vs 292 [5·8%]; 0·54, 0·44–0·66). The number of episodes per person-year did not differ significantly for standard-dose valaciclovir (22·6) versus high-dose aciclovir (20·2; p=0·54), and standard-dose valaciclovir (14·9) versus high-dose valaciclovir (16·5; p=0·34), but did for no medication (28·7) and standard-dose aciclovir (10·0; p=0·001). Median episode duration was longer for no medication than for standard-dose aciclovir (13 h vs 7 h; p=0·01) and for standard-dose valaciclovir than for high-dose valaciclovir (10 h vs 7 h; p=0·03), but did not differ significantly between standard-dose valaciclovir and high-dose aciclovir (8 h vs 8 h; p=0·23). Likewise, maximum log10 copies of HSV detected per mL was higher for no medication than for standard dose aciclovir (3·3 vs 2·9; p=0·02), and for standard-dose valaciclovir than for high-dose valaciclovir (2·5 vs 3·0; p=0·001), but no significant difference was recorded for standard-dose valaciclovir versus high-dose aciclovir (2·7 vs 2·8; p=0·66). 80% of episodes were subclinical in all study groups. Except for a higher frequency of headaches with high-dose valaciclovir (n=13, 30%) than with other regimens, all regimens were well tolerated. Short bursts of subclinical genital HSV reactivation are frequent, even during high-dose antiherpes therapy, and probably account for continued transmission of HSV during suppressive antiviral therapy. More potent antiviral therapy is needed to eliminate HSV transmission. NIH. Valaciclovir was provided for trial 3 for free by GlaxoSmithKline.

Antigen-specific T RM persist and protect against skin or female reproductive tract (FRT) HSV infection. As the pathogenesis of HSV differs between humans and model organisms, we focus on humans with well-characterized recurrent genital HSV-2 infection. Human CD8+ T RM persisting at sites of healed human HSV-2 lesions have an activated phenotype but it is unclear if T RM can be cultivated in vitro . We recovered HSV-specific T RM from genital skin and ectocervix biopsies, obtained after recovery from recurrent genital HSV-2, using ex vivo activation by viral antigen. Up to several percent of local T cells were HSV-reactive ex vivo. CD4 and CD8 T cell lines were up to 50% HSV-2-specific after sorting-based enrichment. CD8 T RM displayed HLA-restricted reactivity to specific HSV-2 peptides with high functional avidities. Reactivity to defined peptides persisted locally over several month and was quite subject-specific. CD4 T RM derived from biopsies, and from an extended set of cervical cytobrush specimens, also recognized diverse HSV-2 antigens and peptides. Overall we found that HSV-2-specific T RM are abundant in the FRT between episodes of recurrent genital herpes and maintain competency for expansion. Mucosal sites are accessible for clinical monitoring during immune interventions such as therapeutic vaccination.

Herpes simplex virus-2 (HSV-2) shedding episodes in humans vary markedly in duration and virologic titer within an infected person over time, an observation that is unexplained. To evaluate whether host or virological factors more closely accounted for this variability, we combined measures of viral replication and CD8⁺ lymphocyte density in genital biopsies, with a stochastic mathematical model of HSV-2 infection. Model simulations reproduced quantities of virus and duration of shedding detected in 1,003 episodes among 386 persons. In the simulations, local CD8⁺ lymphocyte density in the mucosa at episode onset predicted peak HSV DNA copy number and whether genital lesions or subclinical shedding occurred. High density of CD8⁺ T cells in the mucosa correlated with decreased infected cell lifespan and fewer infected epithelial cells before episode clearance. If infected cell lifespan increased by 15 min because of CD8⁺ lymphocyte decay, then there was potential for a thousandfold increase in the number of infected cells. The model suggests that the rate of containment of infected cells by the peripheral mucosal immune system is the major driver of duration and severity of HSV-2 reactivation in the immunocompetent host.