A new strategy to understand how HIV infects women: identification of a window of vulnerability during the menstrual cycle

Wira, Charles R.; Fahey, John V.

doi:10.1097/qad.0b013e3283060ea4

Cited by 215 publications

(277 citation statements)

References 51 publications

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“…Hormonal fluctuations during normal menstrual cycle cause changes in mucosal immunity that may predispose to genital viral infections. Increased susceptibility to infection with human immunodeficiency virus (HIV) or simian HIV (SHIV) was noted to occur during the time after ovulation corresponding to the diestrus stage of the reproductive cycle in rodents (21,22). The injectable medroxyprogesterone acetate formulation DepoProvera (DMPA) modulates menstrual cycle in humans and was shown to induce diestrus and to predispose small animals to more severe HSV-2 infection (23).…”

Section: Resultsmentioning

confidence: 99%

“…We focused mainly on the correlates of immunogenicity and protection that were used in the development of previous subunit vaccines and the role of humoral immunity. Next-generation vaccines will likely target broader systemic and tissue-specific T cell memory responses (10,22). Future cotton rat model development should include evaluation of T cell responses and mucosal responses and comparative studies of various vaccine platforms to better understand immunity of genital herpes and differences in the HSV-1 and HSV-2 genital herpes pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

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Efficacy of the Herpes Simplex Virus 2 (HSV-2) Glycoprotein D/AS04 Vaccine against Genital HSV-2 and HSV-1 Infection and Disease in the Cotton Rat Sigmodon hispidus Model

Boukhvalova

McKay

Mbaye

et al. 2015

J Virol

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Subunit vaccines based on the herpes simplex virus 2 (HSV-2) glycoprotein D (gD-2) have been the major focus of HSV-2 vaccine development for the past 2 decades. Based on the promising data generated in the guinea pig model, a formulation containing truncated gD-2, aluminum salt, and MPL (gD/AS04) advanced to clinical trials. The results of these trials, however, were unexpected, as the vaccine protected against HSV-1 infection but not against HSV-2. To address this discrepancy, we developed a Depot medroxyprogesterone acetate (DMPA)-treated cotton rat Sigmodon hispidus model of HSV-2 and HSV-1 genital infection. The severity of HSV-1 genital herpes was less than that of HSV-2 genital herpes in cotton rats, and yet the model allowed for comparative evaluation of gD/AS04 immunogenicity and efficacy. Cotton rats were intramuscularly vaccinated using a prime boost strategy with gD/AS04 (Simplirix vaccine) or control vaccine formulation (hepatitis B vaccine FENDrix) and subsequently challenged intravaginally with HSV-2 or HSV-1. The gD/AS04 vaccine was immunogenic in cotton rats and induced serum IgG directed against gD-2 and serum HSV-2 neutralizing antibodies but failed to efficiently protect against HSV-2 disease or to decrease the HSV-2 viral load. However, gD/AS04 significantly reduced vaginal titers of HSV-1 and better protected animals against HSV-1 compared to HSV-2 genital disease. The latter finding is generally consistent with the clinical outcome of the Herpevac trial of Simplirix. Passive transfer of serum from gD/AS04-immunized cotton rats conferred stronger protection against HSV-1 genital disease. These findings suggest the need for alternative vaccine strategies and the identification of new correlates of protection. IMPORTANCEIn spite of the high health burden of genital herpes, there is still no effective intervention against the disease. The significant gap in knowledge on genital herpes pathogenesis has been further highlighted by the recent failure of GSK HSV-2 vaccine Simplirix (gD/AS04) to protect humans against HSV-2 and the surprising finding that the vaccine protected against HSV-1 genital herpes instead. In this study, we report that gD/AS04 has higher efficacy against HSV-1 compared to HSV-2 genital herpes in the novel DMPA-synchronized cotton rat model of HSV-1 and HSV-2 infection. The findings help explain the results of the Simplirix trial.T he disease burden associated with herpes simplex virus 2 (HSV-2) infection, an important cause of genital herpes worldwide, is high and presents an additional threat due to its association with an increased risk of HIV acquisition and transmission (1-3). Globally, HSV-2 is a major health threat, with 16% of the U.S. population infected by age 30 and 50 to 90% of the population in sub-Saharan Africa infected (3-5). Recent reports emphasize the importance of HSV-1 as an important etiologic agent of genital herpes particularly in the United States and other developed countries (6-8). Seroprevalence of HSV-1 among 14-to 49-year-olds in the Uni...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Efficacy of the Herpes Simplex Virus 2 (HSV-2) Glycoprotein D/AS04 Vaccine against Genital HSV-2 and HSV-1 Infection and Disease in the Cotton Rat Sigmodon hispidus Model

Boukhvalova

McKay

Mbaye

et al. 2015

J Virol

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“…16 At the time coinciding with ovulation, Wira and colleagues have identified a potential 'window of vulnerability' during the progesterone-dominant luteal phase for optimal viral infection. 17,18 Through analysis of multiple immunologic parameters, they identified this 7-to 10-day 19 showed in a recent study utilizing cervical tissue explants that HIV infection was associated with the luteal phase. White and colleagues found that cytotoxic activity in the upper reproductive tract was present during the follicular phase of the cycle prior to ovulation, but was absent in the consequent luteal phase.…”

Section: Impact Of the Menstrual Cycle On Hiv Susceptibilitymentioning

confidence: 99%

Anatomic and Hormonal Changes in the Female Reproductive Tract Immune Environment during the Life Cycle: Implications for HIV/STI Prevention Research

Venkatesh

Cu‐Uvin

2014

American J Rep Immunol

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“…14 Much of the data supporting mucosal vulnerability to HIV infection in the LUT phase come from evidence of immune suppression, increases in HIV target cells, 15 or other interactions between the immune and endocrine systems found in studies of endometrial explants [15][16][17] (reviewed in Wira and Fahey 11 ) or data showing increases in proinflammatory cytokines in endocervical mucus. 18 However, there is a paucity of data regarding the effect of the menstrual cycle on immune cell recruitment and activation in the lower reproductive tract, including the ectocervix and vagina, 19,20 with some studies showing no changes in CD4 and CCR5-positive cells, based on the menstrual cycle, in ectocervical explants.…”

Section: Introductionmentioning

confidence: 99%

Comparison of Follicular and Luteal Phase Mucosal Markers of HIV Susceptibility in Healthy Women

Thurman

Chandra

Yousefieh

et al. 2016

AIDS Research and Human Retroviruses

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The purpose of this study was to evaluate differences in vaginal immune cell populations, vaginal tissue gene expression, antimicrobial activity of the cervicovaginal (CV) lavage (CVL), vaginal flora, and p24 antigen production from CV tissues after ex vivo human immunodeficiency virus (HIV) infection between follicular (FOL) and luteal (LUT) phases of the menstrual cycle. CV tissue biopsies, CV secretions, and blood samples were obtained as part of two longitudinal clinical trials of healthy women (CONRAD D11-119 and A12-124 studies). Participants (n = 39) were HIV-seronegative women not using exogenous hormone supplementation, with normal menstrual cycles, who were screened to exclude sexually transmitted and reproductive tract infections. Serum levels of estradiol and progesterone were significantly higher in the LUT versus the FOL phase of the menstrual cycle. Controlling for race, reported contraceptive use/sexual practices, and clinical trial, we found no differences in vaginal tissue immune cell populations and activation status, transcriptomes, inhibition of HIV, herpes simplex virus type 2 and Escherichia coli by the CVL, vaginal pH or Nugent score, or production of p24 antigen after ex vivo infection by HIV-1 BaL between CV samples obtained in the FOL phase versus the LUT phase of the menstrual cycle. There were no significant correlations between serum estradiol and progesterone levels and CV endpoints. The hypothesis that the LUT phase of the menstrual cycle represents a more vulnerable stage for mucosal infection with HIV was not supported by data from samples obtained from the lower genital tract (ectocervix and vagina) from these two clinical trials.

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A new strategy to understand how HIV infects women: identification of a window of vulnerability during the menstrual cycle

Cited by 215 publications

References 51 publications

Efficacy of the Herpes Simplex Virus 2 (HSV-2) Glycoprotein D/AS04 Vaccine against Genital HSV-2 and HSV-1 Infection and Disease in the Cotton Rat Sigmodon hispidus Model

Efficacy of the Herpes Simplex Virus 2 (HSV-2) Glycoprotein D/AS04 Vaccine against Genital HSV-2 and HSV-1 Infection and Disease in the Cotton Rat Sigmodon hispidus Model

Anatomic and Hormonal Changes in the Female Reproductive Tract Immune Environment during the Life Cycle: Implications for HIV/STI Prevention Research

Comparison of Follicular and Luteal Phase Mucosal Markers of HIV Susceptibility in Healthy Women

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