Asymptomatic Shedding Of Herpes Simplex Virus Research Articles

Virologic and Immunologic Evidence of Multifocal Genital Herpes Simplex Virus 2 Infection

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. 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.

Herpes Simplex Virus in African American Heterosexual Males: The Roles of Age and Male Circumcision

Male circumcision is protective against human immunodeficiency virus (HIV) and select other STIs. The protective role of male circumcision in genital herpes simplex virus (HSV) infection and disease, however, remains controversial. We evaluated data from a sample of heterosexual black men attending a sexually transmitted diseases clinic to determine if circumcision status influenced HSV-1 and HSV-2 seroprevalence, clinical genital disease, or asymptomatic shedding. Consenting participants answered questionnaires detailing sexual history, then underwent a focused physical examination, serological testing for HSV-1 and HSV-2, and collection of genital swabs for virus detection. Univariate and multivariate analyses were performed to assess the relationship of circumcision status to HSV seroprevalence. Of 460 men, 335 (73%) were circumcised and 125 (27%) were not circumcised; 61% were HSV-1 positive and 46% were HSV-2 positive. HSV-2 seroprevalence did not significantly differ between circumcised and uncircumcised men. However, uncircumcised men had a significantly higher HSV-1 seroprevalence than circumcised men (OR: 1.85; CI: 1.15-2.96). This difference in seroprevalence occurred only in men between 18 and 25 years of age (OR: 2.83; CI: 1.38-5.83) with men over 26 years of age having similar HSV-1 seroprevalence. Lack of circumcision remained independently associated with higher HSV-1 seroprevalence after adjusting for age, years since sexual debut, and lifetime number of sexual partners. For both groups, 20% of men had genital lesions on physical examination. Of circumcised and uncircumcised men with genital lesions, 33% and 31% were actively shedding HSV-1 or HSV-2 from lesions, respectively. Asymptomatic HSV shedding was observed in 12 participants, all of whom were circumcised. Lack of male circumcision is associated with higher HSV-1, but not HSV-2, seroprevalence in young black heterosexual men.

Effect of Treatment of Asymptomatic Bacterial Vaginosis on HIV‐1 Shedding in the Genital Tract among Women on Antiretroviral Therapy: A Pilot Study

Bacterial vaginosis (BV) is a common and recurrent condition, often characterized by an asymptomatic disturbance of the vaginal flora. Studies have shown that BV is relatively common among HIV-infected women[1], and is a risk factor for both HIV acquisition and HIV shedding in the genital tract [2, 3]. Current recommendations do not advocate treatment of asymptomatic BV [4]. This pilot study investigated whether treatment of asymptomatic BV would have an additional impact on HIV-1 shedding in the genital tract of women already receiving highly active antiretroviral therapy (HAART). The study included 30 women on HAART with plasma viral load <75 copies/mL during the 3 months prior to enrollment . Asymptomatic BV was defined by satisfying 3 out of 4 Amsel’s criteria or having a Nugent score (NS) greater than seven, and absence of gynecologic symptoms. These women were randomly assigned (non-blinded) in a 1-to-1 ratio to a treatment or observation arm. The treatment arm received metronidazole 500 mg twice a day for 7 days at the initial visit while the observation arm received no treatment. Participants returned 1 month later for follow-up. At enrollment and follow-up visits, women were tested for HIV plasma viral load (PVL), genital tract (GT) HIV-RNA (Nuclisens, BioMerieux), STIs, and BV (Nugent Score/Gram stain GS, and Amsel’s score). Women in the treatment and observation groups had similar age (median 42.5 years), race (53% white, 20% black), and baseline PVL distributions (27% detectable). At enrollment, all women met Amsel’s definition for BV, 24 women had NS greater than 7, and 4 women (13%, 95% CI = 3.7–31%) had HIV genital tract shedding. None of the women had other STIs including asymptomatic herpes simplex virus shedding. Although insignificant, at the follow-up visit more women in the treatment arm (9/15; 60%) than the observation arm (5/15; 33%) had a negative Amsel’s score (p=0.27). Women in the treatment arm had a median change in NS of −6 (range -10 to 2, p 0.05). The Wilcoxon rank-sum test comparing the mean changes was significant (p<0.001). Treatment also increased the probability of having a NS < 7 at the second time point (87% vs 27%) (p<0.01). Although statistically insignificant, the large effect size observed (log odds ratio −2.17, s.e.=1.3, p=0.10) support the conclusion that treatment of BV may be associated with a decrease in the odds of genital tract shedding (logistic regression, adjusting for detectable PVL at follow up).. Of the 4 women (3 observation; 1 treatment) who had GT shedding at enrollment, 1 woman in the observation arm did not have GT shedding on follow-up. The logistic regression analysis showed that detectable PVL positively correlated with GT shedding (log odds ratio 3.58, s.e.=1.4, p<0.05). The current study demonstrates that the prevalence of HIV genital tract shedding is low among women on HAART with a diagnosis of asymptomatic BV. Treatment with Metronidazole decreases the rate of asymptomatic BV among these women. Our finding is consistent with the few related studies that assessed the impact of STI treatment on HIV-1 viral load. Wang et al. found that neither the shedding of HIV-1 RNA nor the prevalence of DNA changed following treatment of bacterial vaginosis among HIV-infected women[5]. Wolday et al noticed a modest reduction in shedding of HIV-1 related to overall syndromic treatment of STIs, and reductions in cervical HIV viral load among those women with clinical improvement[6]. The high prevalence of asymptomatic BV infection and evidence that BV facilitates HIV shedding make BV an area where interventions could have significant implications for HIV prevention. However, based on the results of our intention-to-treat analysis of this pilot study, future studies will need to be powered with larger sample sizes (about 500 per arm) and screening an even larger number of women to detect asymptomatic BV (6–8 per each case in the present study) due to low levels of detected genital tract HIV shedding among women on HAART.

Herpes simplex virus

Herpes simplex virus (HSV) infection is prevalent worldwide. Herpes labialis, caused predominantly by HSV-1, and herpes vulvovaginitis, caused predominantly by HSV-2, may result in significant morbidity and mortality for infected neonates exposed during delivery. The diagnosis of HSV infection is made by serological testing, viral culture, or polymerase chain reaction. Women with primary herpes vulvovaginitis exhibit a painful vesicular rash which is self-limited but may be followed by multiple recurrences. Women at greatest risk to transmit HSV to their neonates are those who experience their first episode of HSV during the latter stage of pregnancy. If infected, their neonates may have localized skin, eye and mucosal lesions, invasive central nervous system infection, or disseminated disease. Because of the potentially devastating outcome for a baby infected with HSV, pregnant women with active HSV lesions at delivery should be offered a cesarean section. Still, many neonates who are infected with HSV are born to women with asymptomatic HSV shedding. Therefore, prevention of HSV during pregnancy is exceedingly important.

Famciclovir for the Suppression of Symptomatic and Asymptomatic Herpes Simplex Virus Reactivation in HIV-Infected Persons: A Double-Blind, Placebo-Controlled Trial

Herpes simplex virus (HSV) infection is one of the most common opportunistic infections in HIV-infected persons. However, most documentation of the effectiveness of antiviral therapy in reducing HSV reactivation is anecdotal. To evaluate the quantitative effect of antiviral therapy on the frequency of HSV reactivation in HIV-infected persons. Double-blind, placebo-controlled, crossover trial. Research clinic at a university hospital. 48 persons (45 men and 3 women) who were HIV positive and HSV seropositive. Patients were randomly assigned to receive famciclovir, 500 mg orally twice daily, or placebo for 8 weeks. They then crossed over to receive the other regimen after a 1-week washout period. Patients obtained daily cultures of their perirectal, urethral, oral, and genital areas and kept dairy records of signs and symptoms of genital and oral-labial herpes. The median CD4 cell count at study entry was 384 cells/mm3. In the intention-to-treat analysis of the first study period, HSV was isolated on 122 of 1114 (11%) placebo days compared with 9 of 1071 (1%) famciclovir days (relative risk, 0.15; P < 0.001). For patients who completed the crossover, the median difference in days with symptoms between placebo and famciclovir was 13.8% of days and the median difference in days on which HSV was isolated was 5.4% of days (P < 0.001 for both). Percentage of days with HSV-2 shedding was reduced from 9.7% to 1.3%. Breakthrough reactivations that occurred while patients were receiving famciclovir were infrequent, short, and often asymptomatic, HSV-2 isolates from these reactivations were susceptible to penciclovir in vitro. Antiviral chemotherapy with famciclovir results in clinically and statistically significant reductions in the symptoms associated with HSV infection and the symptomatic and asymptomatic shedding of HSV among HIV-positive persons.

The effect of UV therapy on immune function in patients with psoriasis

Ultraviolet radiation (UVR) is known to suppress some cell-mediated immune responses to antigens encountered during or soon after exposure. Phototherapy is widely used in psoriasis, and this study was undertaken to monitor changes in a range of immunological parameters during standard courses of treatment, with the aim of ascertaining whether such modulations contribute to the effectiveness of therapy. The responses of 17 patients with psoriasis undergoing UVB therapy, and four receiving PUVA therapy, were compared with 15 patients receiving coal tar treatment and four normal subjects undergoing UVB irradiation. In each case, samples were taken before starting therapy, after 4 weeks of therapy, and 4 weeks after completion of treatment. Serum immunoglobulin isotypes and complement components were within normal ranges in most of the psoriasis patients, and remained unchanged throughout therapy. Similarly, percentages of subsets of peripheral blood mononuclear cells (PBMC) were normal, and were unaltered by treatment. Patients who were already infected with herpes simplex virus (HSV), as demonstrated by a positive lymphoproliferation test in vitro, were monitored for asymptomatic HSV shedding and HSV recrudescences during therapy. There was little evidence that phototherapy caused reactivation of the virus. No significant alteration in lymphoproliferative response to HSV and to the mitogen concanavalin A was observed during therapy. Epidermal cells and blood adherent cells were used to present HSV to PBMC, depleted of adherent cells and enriched for T cells, in a lymphoproliferative assay. The functional antigen-presenting ability of adherent cells remained unchanged throughout therapy, whereas that of epidermal cells was suppressed during UVB irradiation and recovered, in most instances, after UVB therapy had been completed. The epidermis of patients with psoriasis contained about three times the quantity of urocanic acid (UCA) of normal subjects, whereas the UCA concentration in suction blister fluid did not differ between the two groups. During UVB irradiation, the percentage of cis-UCA rose in both the epidermis and suction blister fluid of all subjects, and it remained elevated in the blister fluid after therapy had finished. Tumour necrosis factor-alpha was measured in suction blister fluid, and its concentration did not alter consistently as a result of therapy. Whether any of the immunological parameters measured, and the changes noted, contribute to the effectiveness of phototherapy in the treatment of psoriasis remains uncertain.

Clinical Reactivation of Herpes Simplex Virus Type 2 Infection in Seropositive Pregnant Women with No History of Genital Herpes

To determine the risk for genital herpes and asymptomatic herpes simplex virus (HSV) shedding in late pregnancy and delivery in a population of HSV type 2 (HSV-2)-seropositive but previously asymptomatic pregnant women. A prospective inception cohort study. A total of 1355 pregnant women with no history of genital herpes referred from three private obstetrics practices between November 1985 and June 1988. Confidential questionnaires evaluated sexual risk factors in relation to HSV-2 serologic status as determined by Western blot analysis. Herpes simplex virus shedding was determined by viral culture of the cervix and vulva and of any suspicious lesions. Antibody to HSV-2 was detected in 439 of 1355 pregnant women (32%) with no history of genital herpes. Asymptomatic HSV shedding was detected in 5 of 1160 cultures (0.43%) obtained in late pregnancy and during delivery. A first episode of clinical genital herpes was recognized by 43 of 264 HSV-2-seropositive women (16%) during their pregnancy. Serologic evidence of unknown HSV-2 infection was common in pregnant women without a history of genital herpes. Asymptomatic viral shedding in these women occurred at a rate similar to that seen in women with symptomatic genital HSV-2 infection. To improve recognition of genital herpes near term, obstetricians should counsel pregnant women about the high prevalence and mild and diverse symptoms of genital HSV-2 infection.

Frequency of Asymptomatic Shedding of Herpes Simplex Virus in Women with Genital Herpes

Twenty-seven women with recurrent genital herpes simplex virus infection underwent daily home culturing to detect asymptomatic genital herpes simplex virus shedding. Asymptomatic herpes simplex virus shedding was documented on 1% of the days on which cultures were obtained. Asymptomatic shedding from the vulva was as frequent as asymptomatic cervicovaginal shedding, and 45% of asymptomatic episodes were identified only by positive results from vulvar cultures. All women who obtained samples on more than 100 days and 80% of women who obtained samples on more than 50 days had documented asymptomatic viral shedding, compared with only 6% of those who obtained samples for fewer than 25 days. Asymptomatic shedding was not related to contraceptive use or menstrual cycle. These data suggest that all women with recurrent genital herpes simplex virus infection should be instructed about the possible risk, albeit infrequent, of asymptomatically shedding virus from the genital tract.

Frequency of Asymptomatic Shedding of Herpes Simplex Virus in Women With Genital Herpes

Twenty-seven women with recurrent genital herpes simplex virus infection underwent daily home culturing to detect asymptomatic genital herpes simplex virus shedding. Asymptomatic herpes simplex virus shedding was documented on 1% of the days on which cultures were obtained. Asymptomatic shedding from the vulva was as frequent as asymptomatic cervicovaginal shedding, and 45% of asymptomatic episodes were identified only by positive results from vulvar cultures. All women who obtained samples on more than 100 days and 80% of women who obtained samples on more than 50 days had documented asymptomatic viral shedding, compared with only 6% of those who obtained samples for fewer than 25 days. Asymptomatic shedding was not related to contraceptive use or menstrual cycle. These data suggest that all women with recurrent genital herpes simplex virus infection should be instructed about the possible risk, albeit infrequent, of asymptomatically shedding virus from the genital tract.

Asymptomatic shedding of herpesvirus during labor

Cervical cultures of 2013 consecutive obstetric patients with no history of genital herpes simplex virus infection were used to determine the frequency of asymptomatic herpes simplex virus shedding in labor. Four (0.20%) of these patients had positive cultures. None of the exposed neonates developed clinical evidence of herpetic infection.