<scp>SHIV</scp> susceptibility changes during the menstrual cycle of pigtail macaques

Kersh, Ellen N.; Henning, Tara; Vishwanathan, Sundaram A.; Morris, Monica; Butler, Katherine; Adams, Debra; Guenthner, Patricia C.; Srinivasan, Priya; Smith, James M.; Radzio, Jessica; Garcı́a-Lerma, J. Gerardo; Dobard, Charles; Heneine, Walid; McNicholl, Janet M.

doi:10.1111/jmp.12124

Cited by 57 publications

(77 citation statements)

References 15 publications

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“…14 No difference in vaginal tissue gene expression (greater than twofold) between FOL and LUT phases Using microarray, we found that gene expression in vaginal tissue was not significantly dysregulated by more than twofold in the FOL phase versus the LUT phase of the menstrual cycle. Only one gene, HAL, was significantly upregulated (2.4-fold) in the LUT phase compared with the FOL phase.…”

Section: No Differences In Vaginal Ph or Nugent Score Between Fol Andmentioning

confidence: 73%

“…Studies demonstrated that rhesus 12 and pigtail macaques 13,14 were more vulnerable to Simian human immunodeficiency virus (SHIV) infection in the LUT phase of the menstrual cycle 13 and this vulnerability to infection persisted during menstruation.…”

Section: Introductionmentioning

confidence: 99%

“…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%

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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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Section: No Differences In Vaginal Ph or Nugent Score Between Fol Andmentioning

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…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%

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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“…It has been hypothesized that such cycledependent changes in immune responses engender variable susceptibilities to sexually transmitted infections (STIs), including HIV-1. We have previously demonstrated using a repeat, lowdose virus challenge model that there are various susceptibilities to simian-human immunodeficiency virus (SHIV) during the different menstrual phases in female pig-tailed macaques (Macaca nemestrina) (6,7). With menstrual cycling patterns similar to those in humans, and the previously reported success in infecting the animals at low virus doses without hormonal intervention, pig-tailed macaques have become unique animal models for HIV studies; their importance is especially underscored in testing menstrual phase-dependent susceptibility to HIV, considering the difficulty in conducting such studies with normally cycling women.…”

mentioning

confidence: 99%

Cataloguing of Potential HIV Susceptibility Factors during the Menstrual Cycle of Pig-Tailed Macaques by Using a Systems Biology Approach

Vishwanathan

Burgener

Bosinger

et al. 2015

J Virol

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Our earlier studies with pig-tailed macaques demonstrated various simian-human immunodeficiency virus (SHIV) susceptibilities during the menstrual cycle, likely caused by cyclic variations in immune responses in the female genital tract. There is concern that high-dose, long-lasting, injectable progestin-based contraception could mimic the high-progesterone luteal phase and predispose women to human immunodeficiency type 1 (HIV-1) acquisition and transmission. In this study, we adopted a systems biology approach employing proteomics (tandem mass spectrometry), transcriptomics (RNA microarray hybridization), and other specific protein assays (enzyme-linked immunosorbent assays and multiplex chemokine and cytokine measurements) to characterize the effects of hormonal changes on the expression of innate factors and secreted proteins in the macaque vagina. Several antiviral factors and pathways (including acute-phase response signaling and complement system) were overexpressed in the follicular phase. Conversely, during the luteal phase there were factors overexpressed (including moesins, syndecans, and integrins, among others) that could play direct or indirect roles in enhancing HIV-1 infection. Thus, our study showed that specific pathways and proteins or genes might work in tandem to regulate innate immunity, thus fostering further investigation and future design of approaches to help counter HIV-1 acquisition in the female genital tract. IMPORTANCEHIV infection in women is poorly understood. High levels of the hormone progesterone may make women more vulnerable to infection. This could be the case during the menstrual cycle, when using hormone-based birth control, or during pregnancy. The biological basis for increased HIV vulnerability is not known. We used an animal model with high risk for infection during periods of high progesterone. Genital secretions and tissues during the menstrual cycle were studied. Our goal was to identify biological factors upregulated at high progesterone levels, and we indeed show an upregulation of genes and proteins which enhance the ability of HIV to infect when progesterone is high. In contrast, during low-progesterone periods, we found more HIV inhibitory factors. This study contributes to our understanding of mechanisms that may regulate HIV infection in females under hormonal influences. Such knowledge is needed for the development of novel prevention strategies. F emale acquisition of human immunodeficiency virus type 1 (HIV-1) is not an efficient process, and transmission events are estimated to occur at frequencies of 1/100 to 1/1,000 exposures (1; reviewed in reference 2). Despite this, the heterosexual route is the predominant mode of HIV-1 transmission worldwide (3), and the development of strategies to reduce male-to-female vaginal transmission rates remains a priority. Animal studies have demonstrated that the time between vaginal exposure and virus detection in draining lymph nodes is as little as 1 to 3 days. There is a small window of early protection whe...

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SHIV susceptibility changes during the menstrual cycle of pigtail macaques

Cited by 57 publications

References 15 publications

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

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

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

Cataloguing of Potential HIV Susceptibility Factors during the Menstrual Cycle of Pig-Tailed Macaques by Using a Systems Biology Approach

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