Genital Herpes Simplex Virus Type Research Articles

Cervicovaginal HIV-1 and herpes simplex virus type 2 shedding during genital ulcer disease episodes

To investigate correlates of herpes simplex virus type 2 (HSV-2) DNA and HIV-1 RNA among women with genital ulcer disease (GUD). Baseline data from a randomized placebo-controlled trial of episodic herpes treatment in Ghana and the Central African Republic. GUD aetiology was determined by polymerase chain reaction (PCR) from a lesional swab. Real-time PCR was used to quantify HIV-1 RNA, and HSV-2 DNA in cervicovaginal lavages (CVL) and HIV-1 RNA in plasma. Genital infection was defined as the presence of virus in the lesion or CVL. Of 441 women enrolled, 79.0% were HSV-2 seropositive, 46.6% were HIV-1 seropositive, and 50.0% had an HSV-2 ulcer. Among 180 HSV-2/HIV-1 co-infected women, cervicovaginal HIV-1 RNA was detected more frequently in women with HSV-2 ulcers (67.9%) or cervicovaginal HSV-2 DNA only (72.3%) compared with women without genital HSV-2 infection (42.4%) (P = 0.004). Women with genital HSV-2 infection had higher median cervicovaginal HIV-1-RNA loads (3.14 log10 copies/mL versus 2.10 log10 copies/mL; P = 0.003), higher plasma HIV-1-RNA loads (median 5.10 versus 4.65 log10 copies/mL; P = 0.07), and lower median CD4 cell counts) (198 versus 409 cells/mm, P = 0.03). Cervicovaginal HIV-1 RNA and HSV-2 DNA were significantly correlated after adjusting for plasma HIV-1 RNA and CD4 cell counts (P < 0.001) and a 10-fold increase in cervicovaginal HSV-2 DNA was associated with a 1.7-fold increase in plasma HIV-1 RNA (P = 0.003). Genital HSV-2 infection is associated with increased cervicovaginal and plasma HIV-1 RNA among co-infected women with genital ulcers, independently of the level of immunodeficiency, highlighting the close interaction between these two viruses and the role of HSV-2 as a co-factor for the sexual transmission of HIV-1.

Polymorphisms inTLR2Are Associated with Increased Viral Shedding and Lesional Rate in Patients with Genital Herpes Simplex Virus Type 2 Infection

Clinical and virologic manifestations of genital herpes simplex virus type 2 (HSV-2) infection vary widely. We examined frequencies of single-nucleotide polymorphisms (SNPs) in Toll-like receptors (TLRs) 2, 3, 4, and 9 in a prospective cohort of 128 HSV-2-infected persons whose viral shedding and lesion frequency was measured by daily sampling from genital secretions. Two TLR2 haplotypes (2 and 4) were associated with increased lesional (P=.008 and P=.03) and shedding (P=.02 and P=.001) rates. An SNP in haplotype 2 (-15607A/G) was also associated with shedding (P=.01) and lesional (P=.008) rates. Polymorphisms in TLR2 may be in part responsible for differences in the severity of HSV-2 infection.

CXCL9 and CXCL10 Expression are Critical in Resistance to Genital Herpes Simplex Virus Type 2 (HSV-2) Infection (43.15)

Abstract The relevance of CXCL9 and CXCL10 expression in protection against genital herpes simplex virus type 2 (HSV-2) infection was investigated using mice deficient in CXCL9 (CXCL9−/−) or CXCL10 (CXCL10−/−) along with C57BL/6 wild type (WT) mice. Progesterone-sensitized mice infected with 2,000 pfu HSV-2 intravaginally were exsanguinated at times post infection (p.i.), and the vaginal tissue (VG), spinal cord (SC), and brain stem (BS) were removed and assayed for virus titer, leukocytes infiltration, and cytokine/chemokine content. CXCL10−/−, but not CXCL9−/− or WT mice were found to possess HSV-2 in the SC at day 3 following infection. By day 7 p.i., CXCL9−/− and CXCL10−/− mice harbored significantly more virus in the SC and the BS compared to WT mice. The increase in virus titer in the BS and SC of the chemokine deficient mice correlated with a decrease in NK cell mobilization to the nervous system at day 5 p.i. and CD8+ T cells mobilization at day 7 p.i. In addition, there was a noticeable increase in vaginal inflammation (measured by cytokine/chemokine levels and leukocyte infiltration) in the CXCL10−/− mice compared to the WT or CXCL9−/− mice. Antibody-mediated depletion of NK cells resulted in an increase in HSV-2 levels in the vagina, SC, and BS of wild type mice suggesting these cells contribute to resistance to infection. This work supported by AI053108.

Antibody-Mediated Protection against Genital Herpes Simplex Virus type 2 Disease in Mice by Fc gamma Receptor -Dependent and -Independent Mechanisms (41.8)

Abstract The requirement for Ab -Fcγ receptor (FcγR) interactions or for virus neutralization in protection against genital HSV-2 challenge was examined. Serum IgG Ab isolated from HSV-immune mice protected normal mice against HSV-2 disease when administered prior to challenge. However, protection was significantly diminished in mice lacking the γ chain subunit utilized in FcγRI, FcγRIII, FcγRIV, and FcεRI and in normal mice depleted of FcγR+, Gr-1+ immune cells suggesting protection was largely mediated by an FcγR-dependent mechanism. To test if FcγR-independent antibody-mediated mechanisms might manifest protection differently, a highly neutralizing, HSV glycoprotein D -specific monoclonal antibody (mAb) was utilized. Administration of IgG1, IgG2a, or IgG2b switch variants of the mAb did not prevent infection of the genital tract but resulted in lower virus loads in the vaginal epithelium and provided significant protection against disease and acute infection of the sensory ganglia independently of host FcγR expression. Together, these data demonstrate two distinct antibody effector mechanisms capable of providing substantial protection against genital HSV-2 disease. The presence of either FcγR -dependent Ab or strongly neutralizing Ab did not completely prevent HSV-2 infection but limited initial infection of genital and neuronal tissues and diminished HSV-2 disease. NIH Grants AI42815 and AI054444.

The estimated direct medical cost of sexually transmitted diseases among American youth, 2000.

Each year, millions of U.S. youth acquire sexually transmitted diseases (STDs). Estimates of the economic burden of STDs can help to quantify the impact of STDs on the nation's youth and on the payers of the cost of their medical care. We synthesized the existing literature on STD costs to estimate the lifetime medical cost per case of eight major STDs-HIV, human papillomavirus (HPV), genital herpes simplex virus type 2, hepatitis B, chlamydia, gonorrhea, trichomoniasis and syphilis. We then estimated the total burden of disease by multiplying these cost-per-case estimates by the approximate number of new cases of STDs acquired by youth aged 15-24. The total estimated burden of the nine million new cases of these STDs that occurred among 15-24-year-olds in 2000 was $6.5 billion (in year 2000 dollars). Viral STDs accounted for 94% of the total burden ($6.2 billion), and nonviral STDs accounted for 6% of the total burden ($0.4 billion). HIV and HPV were by far the most costly STDs in terms of total estimated direct medical costs, accounting for 90% of the total burden ($5.9 billion). The large number of infections acquired by persons aged 15-24 and the high cost per case of viral STDs, particularly HIV, create a substantial economic burden.

Susceptibility of CCR5-deficient mice to genital herpes simplex virus type 2 is linked to NK cell mobilization.

Following genital herpes simplex virus type 2 (HSV-2) exposure, NK cells and T cells are mobilized to sites of infection to control viral replication and spread. The present investigation sought to determine the role of the chemokine receptor CCR5 in this process. Mice deficient in CCR5 (CCR5-/-) displayed a significant reduction in cumulative survival following infection in comparison to wild-type, HSV-2-infected controls. Associated with decreased resistance to viral infection, CCR5-/- mice yielded significantly more virus and expressed higher levels of tumor necrosis factor alpha, CXCL1, CCL2, CCL3, and CCL5 in the vagina, spinal cord, and/or brain stem than did wild-type mice. Whereas there was no difference in absolute number of leukocytes (CD45high), CD4 T cells, or CD8 T cells residing in the draining lymph nodes, spleen, spinal cord, or brain stem comparing HSV-2-infected wild-type to CCR5-/- mice prior to or after infection, there were significantly more NK cells (NK1.1+ CD3-) residing in the brain stem and spleen of infected wild-type mice. Functionally, NK activity from cells isolated from the brain stem of HSV-2-infected wild-type mice was greater than that from HSV-2-infected CCR5-/- mice. In addition, antibody-mediated depletion of NK cells resulted in an increase in HSV-2 levels in the vaginal, spinal cord, and brain stem tissue of wild-type but not CCR5-/- mice. Collectively, the absence of CCR5 expression significantly impacts the ability of the host to control genital HSV-2 infection, inflammation, and spread associated with a specific reduction in NK cell expansion, infiltration, and activity in the nervous system.

Quantification of Poly(I:C)-Mediated Protection against Genital Herpes Simplex Virus Type 2 Infection

Alternative strategies for controlling the growing herpes simplex virus type 2 (HSV-2) epidemic are needed. A novel class of immunomodulatory microbicides has shown promise as antiherpetics, including intravaginally applied CpG-containing oligodeoxynucleotides that stimulate toll-like receptor 9 (TLR9). In the current study, we quantified protection against experimental genital HSV-2 infection provided by an alternative nucleic acid-based TLR agonist, polyinosine-poly(C) (PIC) (TLR3 agonist). Using a protection quantification paradigm, groups of mice were PIC treated and then subdivided into groups challenged with escalating doses of HSV-2. Using this paradigm, a temporal window of PIC efficacy for single applications was defined as 1 day prior to (prophylactic) through 4 h after (therapeutic) viral challenge. PIC treatment within this window protected against 10-fold-higher HSV-2 challenges, as indicated by increased 50% infectious dose values relative to those for vehicle-treated controls. Disease resolution and survival were significantly enhanced by repetitive PIC doses. Using optimal PIC regimens, cytokine induction was evaluated in murine vaginal lavages and in human vaginal epithelial cells. Similar induction patterns were observed, with kinetics that explained the limited durability of PIC-afforded protection. Daily PIC delivery courses did not generate sustained cytokine levels in murine vaginal fluids that would be indicative of local immunotoxicity. No evidence of immunotoxicity was observed in selected organs that were analyzed following repetitive vaginal PIC doses. Animal and in vitro data indicate that PIC may prove to be a valuable preventative microbicide and/or therapeutic agent against genital herpes by increasing resistance to HSV-2 and enhancing disease resolution following a failure of prevention.

Subtly Impaired Humoral Immunity Predisposes to Frequently Recurring Genital Herpes Simplex Virus Type 2 Infection and Herpetic Neuralgia

Immunogenetic factors predisposing to recurrent genital herpes remain poorly characterized. In a prospective case-control study, 52 consecutive patients with frequently recurring outbreaks of genital herpes were compared with 80 herpes simplex virus (HSV)-seropositive (types 1 and 2) and 70 HSV-seronegative control subjects. Immunoglobulins (Igs), type-specific anti-HSV-2 IgG and IgG subclass antibodies against glycoprotein G, levels of C3 and C4, and classical pathway hemolytic complement activity were measured, and IgG1 and IgG3 allotyping; C4 immunophenotyping; C4* real-time polymerase chain reaction (PCR) genotyping; and HLA-A*, B*, and DR* typing were performed. The G3m(g),G1m(a/a(x)) haplotype was more frequent in patients than in HSV-seronegative control subjects (P=.047). Compared with all control subjects, low levels of total IgG1 (odds ratio [OR], 4.9 [95% confidence interval {CI}, 2.0-12.5]; P=.001) and IgG3 (OR 3.6 [95% CI 1.7-7.8]; P=.001), but not of anti-HSV-2 antibodies, were associated with recurrences. Levels of complement were lowest in patients. The C4* null type was negatively associated with neuralgia (OR, 0.2 [95% CI, 0.06-0.81]; P=.022). Low levels of antibody-dependent cellular cytotoxicity-mediating IgG1 and IgG3 antibodies, partly dependent of allotype, may predispose to recurrent genital herpes. Antibodies produced by T helper type 1 responses, potentially against an unknown epitope, appear to be relevant in recurrences. In patients, C4* deficiencies are associated with protection from herpetic neuralgias, possibly through reduced inflammation.

Oral Herpes Simplex Virus Type 2 Reactivation in HIV‐Positive and ‐Negative Men

Previous studies using viral cultures rarely reported herpes simplex virus type 2 (HSV-2) isolation from the mouth. We sought to characterize oral HSV-2 shedding as detected by HSV DNA polymerase chain reaction among HSV-2-seropositive men. Participants collected daily swabs from oral and anogenital areas for HSV detection with a quantitative polymerase chain reaction assay. A total of 109 HSV-2-seropositive men (59 of whom were human immunodeficiency virus [HIV] negative, and 50 of whom were HIV positive) were sampled for a median of 64 consecutive days. Forty-four (40.4%) had HSV-2 detected from oral swabs on at least 1 day. Oral HSV-2 was detected on 148 (2.3%) of 6,422 days, genital HSV-2 was detected on 1,110 (17%) of 6,505 days, oral HSV-1 was detected on 220 (5.5%) of 4,018 days, and genital HSV-1 was detected on 88 (2.2%) of 4,073 days. Oral HSV-2 shedding was never associated with an oral lesion, but it was often concurrent with genital HSV-2 shedding. Both oral and genital HSV-2 were detected on 90 (61%) of 148 days with oral HSV-2 shedding. Oral HSV-2 shedding occurred on 90 (8.2%) of 1,110 days with genital HSV-2 shedding, versus 58 (1.1%) of 5,316 days without genital HSV-2 shedding (P<.001). The HIV-positive men shed HSV-2 orally more frequently than did the HIV-negative men (odds ratio, 2.7 [95% confidence interval, 1.1-7.1]). Oral HSV-2 reactivation was common (especially among HIV-positive men), was always asymptomatic, and often occurred on days of genital HSV-2 reactivation.

The lack of RNA‐dependent protein kinase enhances susceptibility of mice to genital herpes simplex virus type 2 infection

Mice deficient in RNA-dependent protein kinase (PKR-/-) or deficient in PKR and a functional 2',5'-oligoadenylate synthetase (OAS) pathway (PKR/RL-/-) are more susceptible to genital herpes simplex virus type 2 (HSV-2) infection than wild-type mice or mice that are deficient only in a functional OAS pathway (RL-/-) as measured by survival over 30 days. The increase in susceptibility correlated with an increase in virus titre recovered from vaginal tissue or brainstem of infected mice during acute infection. There was also an increase in CD45+ cells and CD8+ T cells residing in the central nervous system of HSV-2-infected PKR/RL-/- mice in comparison with RL-/- or wild-type control animals. In contrast, there was a reduction in the HSV-specific CD8+ T cells within the draining lymph node of the PKR/RL-/- mice. Collectively, activation of PKR, but not of OAS, contributes significantly to the local control and spread of HSV-2 following genital infection.

Protective Immunity to Genital Herpes Simplex Virus Type 1 and Type 2 Provided by Self-Adjuvanting Lipopeptides That Drive Dendritic Cell Maturation and Elicit a Polarized Th1 Immune Response

Genital herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2) infections are a significant health problem worldwide. While it is believed that CD4+ Th1 cells are among the effectors to herpes immunity, developing an epitope-based clinical vaccine capable of inducing an effective anti-herpes CD4+ Th1-mediated protection is still under investigation. Few molecules achieve this target without the aid of external immuno-adjuvant. The present study was undertaken to examine the immunogenicity in mice of five CD4+ T cell epitope peptides (gD1-29, gD49-82, gD146-179, gD228-257, and gD332-358), recently identified from the HSV-1 glycoprotein D (gD), covalently linked to a palmitic acid moiety (lipopeptides) using the high-yielding chemoselective ligation method and delivered subcutaneously in free-adjuvant saline. Their protective efficacy was evaluated in a progestin-induced susceptibility mouse model of genital herpes following intravaginal challenge with either HSV-1 or HSV-2. Four out of five gD lipopeptides effectively induced virus-specific CD4+ Th1 responses associated with a reduction of virus replication in the genital tract and protection from overt signs of genital disease. A cocktail of three highly immunogenic lipopeptides provoked maturation of dendritic cells, induced interferon gamma (IFN-gamma)-producing CD4+ T cells, and protected against both HSV- 1 and HSV-2 infections. Depletion of specific T cell subsets from lipopeptideimmunized mice before intravaginal HSV challenges demonstrated that CD4+ T cells were primarily responsible for this protection. The strength of induced T cell immunity, together with the ease of construction and safety of these totally synthetic self-adjuvanting lipopeptides, provide a molecularly defined formulation that could combat genital herpes and other human viral infections for which induction of Th1 immunity is crucial.

Knowledge of Partners’ Genital Herpes Protects against Herpes Simplex Virus Type 2 Acquisition

Prospective studies of herpes simplex virus type 2 (HSV-2) infection in discordant couples have shown a low rate of transmission. However, unlike partners with genital herpes in prospectively monitored couples, most persons who transmit genital herpes are not aware of having the infection. Because HSV has a short incubation period and most persons who acquire genital herpes can identify the transmitting partner, a time-to-event design was used to assess risks of HSV acquisition among patients with newly acquired genital herpes. Among 199 persons with laboratory-documented newly acquired genital herpes, the median duration of the sexual relationship with the transmitting partner was 3.5 months, and the median number of sex acts before transmission was 40. The median time to HSV-2 acquisition was greater among participants whose partners disclosed that they had genital herpes, compared with participants whose partners did not disclose their status (270 vs. 60 days; P = .03). In multivariate models, having a partner who disclosed that he or she had genital herpes remained a strong protective factor against genital HSV-2 acquisition (hazard ratio, 0.48 [95% confidence interval, 0.25-0.91]). These findings suggest that testing persons with HSV type-specific serologic assays and encouraging disclosure may result in a decreased risk of HSV-2 transmission to sex partners.

Decline in sexually transmitted infection prevalence and HIV incidence in female barworkers attending prevention and care services in Mbeya Region, Tanzania

To assess trends in sexually transmitted infection (STI) prevalence and HIV incidence and associated factors in a cohort of female barworkers exposed to behavioural interventions and STI screening and treatment. An open cohort of 600 female barworkers in Mbeya Region, Tanzania was offered 3-monthly information and education sessions on HIV/STI and reproductive health, voluntary HIV counselling and testing and clinical health check-ups including STI syndromic management with simple STI laboratory support. Outcome assessments included HIV, herpes simplex virus type 2 (HSV-2) and syphilis serology, polymerase chain reaction for Neisseria gonorrhoeae, Chlamydia trachomatis and ulcerative STI, microscopy for Trichomonas vaginalis, Candida albicans and bacterial vaginosis and interviews on sociodemographic and behavioural characteristics. Over a period of 30 months 600 barworkers were enrolled at the baseline examination round and 153 thereafter as replacements for losses to follow-up. At 3-monthly examinations the prevalence of gonorrhoea declined steadily from 22.2 to 6.8% (odds ratio for trend per quarter: 0.81; P < 0.001). The prevalence of all other STI/RTI, except for genital herpes and bacterial vaginosis, also decreased significantly. HIV incidence declined from 13.9/100 to 5.0/100 person-years over three consecutive 9-month periods. HIV incidence was significantly associated with genital ulcers and positive syphilis serology, but not with genital herpes or HSV-2 seropositivity. A relatively simple intervention consisting of regular 3-monthly STI screening and syndromic management in combination with HIV/STI information and counselling sessions was well accepted and effective in reducing STI among barworkers. Such interventions should be implemented more widely in high-risk environments in sub-Saharan Africa.

Impact of Immunization with Glycoprotein D2/AS04 on Herpes Simplex Virus Type 2 Shedding into the Genital Tract in Guinea Pigs That Become Infected

In recent clinical trials, a vaccine that contained herpes simplex virus type 2 (HSV-2) glycoprotein D (gD2) and the adjuvant AS04 afforded HSV-seronegative women significant protection against HSV-2 genital disease and limited protection against infection. Similarly, in guinea pigs, immunization with the vaccine provided significant protection against genital HSV-2 disease but did not prevent mucosal infection. We explored the impact of immunization on the magnitude of latent virus infection and on the frequency and magnitude of virus reactivation as measured by both recurrent disease and viral shedding into the genital tract. Guinea pigs immunized with gD2/AS04 were shown by quantitative polymerase chain reaction (qPCR) analysis to have significantly less latent viral DNA in the ganglia than did naive control guinea pigs and to have a reduced incidence and frequency of recurrent disease. By contrast, all immunized guinea pigs shed virus into the genital tract with a frequency comparable to that seen in control guinea pigs. However, the amount of virus shed was significantly reduced, as measured by qPCR. These data suggest that immunization could affect transmission by altering viral shedding patterns.

RNA-Dependent Protein Kinase Is Required for Alpha-1 Interferon Transgene-Induced Resistance to Genital Herpes Simplex Virus Type 2

We investigated the mechanism of resistance to genital herpes simplex virus type 2 (HSV-2) infection in mice transfected with the murine alpha-1 interferon (IFN-alpha1) transgene. In situ transfection of mice with the IFN-alpha1 transgene resulted in an elevation in an IFN-responsive gene, RNA-dependent protein kinase (PKR), but not 2',5'-oligoadenylate synthetases (OAS), in vaginal tissue. Coupled with the finding that mice lacking a functional PKR pathway were no longer resistant to genital HSV-2 infection following transfection with the IFN-alpha1 transgene in comparison to wild-type mice or mice lacking a functional OAS pathway, these results suggest that PKR is the dominant antiviral pathway activated by the IFN-alpha1 transgene.

NK and NKT Cell-Independent Contribution of Interleukin-15 to Innate Protection against Mucosal Viral Infection

Interleukin-15 (IL-15) is essential for the development, maturation, and function of NK and NKT cells, which are critical components of the innate immune defense against viral infections. We recently showed that mice lacking IL-15 and/or NK/NKT cells are significantly more susceptible to intravaginal (IVAG) herpes simplex virus type 2 (HSV-2) infection than control mice. For this study, we examined whether IL-15 has any direct antiviral activity, independent of NK/NKT cells, in innate protection against HSV-2 infection. A sensitive enzyme-linked immunosorbent assay for murine IL-15 was developed and used to show that IVAG HSV-2 infection induces IL-15 in vaginal washes. Using immunohistochemistry, we detected IL-15-positive cells in the submucosa and vaginal epithelium following IVAG HSV-2 infection. Local, but not systemic, delivery of murine recombinant IL-15 (mrIL-15) to the genital mucosae of IL-15(-/-) and RAG-2(-/-) gamma(c)(-/-) mice, which both lack NK and NKT cells, resulted in significant reductions in HSV-2 titers in genital washes and 60% survival following IVAG HSV-2 challenge. Furthermore, we showed that IL-15 is important for CpG oligodeoxynucleotide (ODN)-induced innate protection against genital HSV-2 infection. While 100% of CpG ODN-treated RAG2(-/-) gamma(c)(-/-) mice, which are capable of producing IL-15 but lack NK/NKT cells, survived an IVAG HSV-2 challenge, only 60% of CpG ODN-treated IL-15(-/-) mice survived, and all of these mice had similar vaginal viral titers to those in control mice by day 3 postchallenge. Lastly, a treatment of RAW264.7 cells with mrIL-15 induced the production of tumor necrosis factor alpha and beta interferon (IFN-beta), but not IFN-alpha, and significantly protected them against HSV-2 infection in vitro. The results of these studies indicate that IL-15 can act independently of NK/NKT cells in mediating the innate defense against viral infection.

Estradiol Regulates Susceptibility following Primary Exposure to Genital Herpes Simplex Virus Type 2, while Progesterone Induces Inflammation

We report here that sex hormones modulate susceptibility to a sexually transmitted viral agent, herpes simplex virus type 2 (HSV-2), in a mouse model. Ovariectomized mice were administered either saline (control), estradiol (E(2)), progesterone (P(4)), or a combination of both estradiol and progesterone (E+P) and infected intravaginally with HSV-2. With an inoculation dose of 10(5) PFU, the saline- and P(4)-treated mice were found to be highly susceptible to genital HSV-2 infection. Both groups had extensive pathology and high viral titers in vaginal secretions, and 100% of mice succumbed by day 4 postinfection. E(2)-treated mice were protected from HSV-2 infection at the same dose and did not display any vaginal pathology or viral shedding. There was a slow progression of genital pathology in the combination hormone-treated group, along with prolonged viral shedding; 80% of animals succumbed by day 13. With lower inoculation doses of 10(3) and 10(2) PFU, 50 and 100%, respectively, of the combination hormone-treated mice survived. Localization of HSV-2 infection showed extensive infection in the vaginal epithelium of P(4)- and saline-treated animals within 24 h of inoculation. E(2)-treated animals were clear of infection, while the E+P-treated group had focal infection at 24 h that had progressed extensively by day 3. Infection was accompanied by persistent inflammation and infiltration of neutrophils in the P(4)-treated group. An analysis of the genes in the vaginal tissue showed that inflammation in the P(4)-treated group correlated with local induction of chemokines and chemokine receptors that were absent in the E(2)-treated mice and in uninfected P(4)-treated mice. The results show that sex hormones regulate initiation of infection and immune responses to genital HSV-2 infection.

Comparative Efficacy and Immunogenicity of Replication-Defective, Recombinant Glycoprotein, and DNA Vaccines for Herpes Simplex Virus 2 Infections in Mice and Guinea Pigs

Many candidate vaccines are effective in animal models of genital herpes simplex virus type 2 (HSV-2) infection. Among them, clinical trials showed moderate protection from genital disease with recombinant HSV-2 glycoprotein D (gD2) in alum-monophosphoryl lipid A adjuvant only in HSV women seronegative for both HSV-1 and HSV-2, encouraging development of additional vaccine options. Therefore, we undertook direct comparative studies of the prophylactic and therapeutic efficacies and immunogenicities of three different classes of candidate vaccines given in four regimens to two species of animals: recombinant gD2, a plasmid expressing gD2, and dl5-29, a replication-defective strain of HSV-2 with the essential genes UL5 and UL29 deleted. Both dl5-29 and gD2 were highly effective in attenuating acute and recurrent disease and reducing latent viral load, and both were superior to the plasmid vaccine alone or the plasmid vaccine followed by one dose of dl5-29. dl5-29 was also effective in treating established infections. Moreover, latent dl5-29 virus could not be detected by PCR in sacral ganglia from guinea pigs vaccinated intravaginally. Finally, dl5-29 was superior to gD2 in inducing higher neutralizing antibody titers and the more rapid accumulation of HSV-2-specific CD8+ T cells in trigeminal ganglia after challenge with wild-type virus. Given its efficacy, its defectiveness for latency, and its ability to induce rapid, virus-specific CD8(+)-T-cell responses, the dl5-29 vaccine may be a good candidate for early-phase human trials.

Immunotherapeutic activity of a recombinant combined gB–gD–gE vaccine against recurrent HSV-2 infections in a guinea pig model

The guinea pig model of recurrent genital herpes simplex virus type 2 (HSV-2) infection was used to test the immunotherapeutic activity of a glycoprotein subunit vaccine. Vaccine formulation consisted of three recombinant herpes simplex virus (HSV) glycoproteins, namely gB1s, gD2t and gE1t, plus aluminium hydroxide [Al(OH) 3)] adjuvant. One month after viral challenge, infected animals were therapeutically immunised by seven subcutaneous injections of a low dose of antigens with a weekly interval for the first five and a fortnightly interval for the last two administrations. Results showed that the treatment was highly effective in ameliorating the recidivist pathology of animals, suggesting that this kind of vaccine formulation and administration may be helpful for therapeutic intervention in humans affected by recurrent herpes infections.

Neonatal genital herpes simplex virus type 1 infection after Jewish ritual circumcision: modern medicine and religious tradition.

Genital neonatal herpes simplex virus type 1 (HSV-1) infection was observed in a series of neonates after traditional Jewish ritual circumcision. The objective of this study was to describe neonate genital HSV-1 infection after ritual circumcision and investigate the association between genital HSV-1 after circumcision and the practice of the traditional circumcision. Eight neonates with genital HSV-1 infection after ritual circumcision were identified. The average interval from circumcision to clinical manifestations was 7.25 +/- 2.5 days. In all cases, the traditional circumciser (the mohel) had performed the ancient custom of orally suctioning the blood after cutting the foreskin (oral metzitzah), which is currently practiced by only a minority of mohels. Six infants received intravenous acyclovir therapy. Four infants had recurrent episodes of genital HSV infection, and 1 developed HSV encephalitis with neurologic sequelae. All four mohels tested for HSV antibodies were seropositive. Ritual Jewish circumcision that includes metzitzah with direct oral-genital contact carries a serious risk for transmission of HSV from mohels to neonates, which can be complicated by protracted or severe infection. Oral metzitzah after ritual circumcision may be hazardous to the neonate.