Cervical Shedding of Herpes Simplex Virus in Human Immunodeficiency Virus–Infected Women: Effects of Hormonal Contraception, Pregnancy, and Vitamin A Deficiency

Mostad, Sara B.; Kreiss, Joan K.; Ryncarz, Alexander J.; Mandaliya, Kishorchandra; Chohan, Bhavna; Ndinya‐Achola, Jeckoniah; Bwayo, Job J.; Corey, Lawrence

doi:10.1086/315188

Cited by 91 publications

(59 citation statements)

References 29 publications

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“…1). This novel concept of preventive medicine may not only be useful in industrialized countries with advanced possibilities for HSV-1 diagnosis and drug treatment but, because of its relative low costs, the concept may also be highly beneficial for countries where diagnosis and drug treatment is a prohibitive economic factor (16,36,49,64).…”

Section: Discussionmentioning

confidence: 99%

Protective T-Cell-Based Immunity Induced in Neonatal Mice by a Single Replicative Cycle of Herpes Simplex Virus

Franchini

Abril

Schwerdel

et al. 2001

J Virol

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Section: Discussionmentioning

confidence: 99%

Protective T-Cell-Based Immunity Induced in Neonatal Mice by a Single Replicative Cycle of Herpes Simplex Virus

Franchini

Abril

Schwerdel

et al. 2001

J Virol

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“…The difference in location and/or intensity of receptor expression may account for the variability in incidence of intravaginal HSV-2 infection throughout the sex hormone cycle. Although correlation between the phases of the menstrual cycle and susceptibility to HSV-2 infection has not been examined in humans, cervical shedding of HSV was significantly associated with oral contraception and depo-medroxyprogesterone acetate use (22).…”

mentioning

confidence: 99%

In Vivo Role of Nectin-1 in Entry of Herpes Simplex Virus Type 1 (HSV-1) and HSV-2 through the Vaginal Mucosa

Linehan¹,

Richman²,

Krummenacher

et al. 2004

J Virol

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Herpes simplex virus type 2 (HSV-2) is transmitted through the genital mucosa during sexual encounters. In recent years, HSV-1 has also become commonly associated with primary genital herpes. The mechanism of viral entry of HSV-1 and HSV-2 in the female genital tract is unknown. In order to understand the molecular interactions required for HSV entry into the vaginal epithelium, we examined the expression of herpesvirus entry mediator nectin-1 in the vagina of human and mouse at different stages of their hormonal cycle. Nectin-1 was highly expressed in the epithelium of human vagina throughout the menstrual cycle, whereas the mouse vaginal epithelium expressed nectin-1 only during the stages of the estrous cycle in which mice are susceptible to vaginal HSV infection. Furthermore, the ability of nectin-1 to mediate viral entry following intravaginal inoculation was examined in a mouse model of genital herpes. Vaginal infection with either HSV-1 or HSV-2 was blocked by preincubation of the virus with soluble recombinant nectin-1. Viral entry through the vaginal mucosa was also inhibited by preincubation of HSV-2 with antibody against gD. Together, these results suggest the importance of nectin-1 in mediating viral entry for both HSV-1 and HSV-2 in the genital mucosa in female hosts.Understanding the entry events of herpes simplex virus type 2 (HSV-2) at the genital mucosa is important in the development of preventative measures, such as topical microbicides, to stop its spread through sexual transmission. Although HSV-1 is classically associated with oral infection, an alarming increase in HSV-1 has been observed in association with primary genital herpes in recent years (14). The in vivo mechanism of viral entry in the female genital tract of HSV-1 and HSV-2 is unknown.The molecular mechanisms of virus attachment and entry have been a focus of intense investigations, especially for HSV-1 but also for HSV-2 (reviewed in reference 30). Currently, the model for HSV entry begins with the attachment of the virus to a target cell through binding of HSV glycoprotein C (gC) and/or gB to the cell surface heparan sulfate proteoglycans (reviewed in reference 28). Subsequently, the attached virus can begin its entry through interaction between gD and a variety of unrelated cell surface receptors, including the herpesvirus entry mediator A (HveA) (21), a member of the tumor necrosis factor receptor family, HveB (nectin-2) (33) and HveC (nectin-1) (4), both members of the immunoglobulin superfamily, and 3-O-sulfated heparan sulfate (27).Owing to its limited expression in lymphocytes and monocytes (13), HveA has been shown to mediate HSV entry into human activated T lymphocytes (21). Whether HveA participates in viral entry through genital epithelial cells is unknown. Human HveB mediates the entry of HSV-2 and certain mutant strains of HSV-1 but fails to mediate entry of wild-type HSV-1 (33). Furthermore, evidence indicates that the mouse homologue of HveB fails to mediate entry of either HSV-1 or HSV-2 (16). In contrast, necti...

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“…In both cross-sectional and longitudinal studies, oral hormonal contraceptive use was associated with an increased frequency of HSV detection in the lower genital tract (7,23,24). During pregnancy, HSV-2 seropositive women denying any prior history of herpetic outbreaks were at increased risk for symptomatic episodes of HSV reactivation (12).…”

mentioning

confidence: 99%

17-β Estradiol Promotion of Herpes Simplex Virus Type 1 Reactivation Is Estrogen Receptor Dependent

Miguel

Sheridan

Harvey³

et al. 2010

J Virol

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Correlations between estrogen and herpes simplex virus (HSV) reactivation from latency have been suggested by numerous clinical reports, but causal associations are not well delineated. In a murine HSV-1 corneal infection model, we establish 17-␤ estradiol (17-␤E) treatment of latently infected ovariectomized mice induces viral reactivation, as demonstrated by increased viral load and increased immediate-early viral gene expression in the latently infected trigeminal ganglia (TG). Interestingly, the increased HSV reactivation occurred in the absence of inhibition of viral specific CD8؉ T-cell effector function. 17-␤E administration increased HSV reactivation in CD45؉ cell-depleted TG explant cultures, providing further support that leukocyte-independent effects on latently infected neurons were responsible for the increased reactivation. The drug-induced increases in HSV copy number were not recapitulated upon in vivo treatment of latently infected estrogen receptor alpha-deficient mice, evidence that HSV reactivation promoted by 17-␤E was estrogen receptor dependent. These findings provide additional framework for the emerging conceptualization of HSV latency as a dynamic process maintained by complex interactions among multiple cooperative and competing host, viral, and environmental forces. Additional research is needed to confirm whether pregnancy or hormonal contraceptives containing 17-␤E also promote HSV reactivation from latency in an estrogen receptor-dependent manner.Herpes simplex viruses (HSV) are ubiquitous pathogens of humans characterized by their propensity to establish latency in sensory neurons of the peripheral nervous system. Intermittent reactivation of HSV from latency, followed by recurrent shedding onto body surfaces in close proximity to sites of primary infection, often produces epithelial and mucosal ulcerations, while less frequently causing keratitis, retinal necrosis, meningitis, and encephalitis (9,16,17,37). Although increased levels of emotional stress, UV radiation exposure, and immunosuppression have been identified as risk factors (15,28,30,32), delineation of the underlying mechanisms responsible for HSV reactivation from latency is incomplete.Data accumulated from clinical research suggests that elevated levels of estrogen may also be included among the risk factors that promote increased HSV reactivation from latency. In both cross-sectional and longitudinal studies, oral hormonal contraceptive use was associated with an increased frequency of HSV detection in the lower genital tract (7,23,24). During pregnancy, HSV-2 seropositive women denying any prior history of herpetic outbreaks were at increased risk for symptomatic episodes of HSV reactivation (12). More frequent asymptomatic genital tract shedding of HSV has also been correlated with the escalating serum estrogen concentrations found in each successive trimester of pregnancy (5). Taken together, these clinical data support a plausible role for estrogen as a risk factor for HSV reactivation from latency.Adequate expl...

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Cervical Shedding of Herpes Simplex Virus in Human Immunodeficiency Virus–Infected Women: Effects of Hormonal Contraception, Pregnancy, and Vitamin A Deficiency

Cited by 91 publications

References 29 publications

Protective T-Cell-Based Immunity Induced in Neonatal Mice by a Single Replicative Cycle of Herpes Simplex Virus

Protective T-Cell-Based Immunity Induced in Neonatal Mice by a Single Replicative Cycle of Herpes Simplex Virus

In Vivo Role of Nectin-1 in Entry of Herpes Simplex Virus Type 1 (HSV-1) and HSV-2 through the Vaginal Mucosa

17-β Estradiol Promotion of Herpes Simplex Virus Type 1 Reactivation Is Estrogen Receptor Dependent

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