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

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IntroductionAlthough 85% of new HIV cases are due to sexual transmission from men to women, little attention is being paid to the immune system in the female reproductive tract (FRT), and to how it meets the conflicting challenges of protecting from pathogens and permitting procreation. As a new approach we have tried to envision how HIV evades FRT mucosal immune protection and have been led to the unexpected conclusion that in a normal menstrual cycle, there is a window of vulnerability (7–10 days following ovulation) in which the potential for viral infectivity in the FRT is enhanced. During that period, aspects of the innate, humoral, and cell-mediated immune systems are suppressed by sex hormones to optimize conditions for procreation. Suppression occurs in the upper (Fallopian tubes, uterus, endocervix) and lower (ectocervix and vagina) FRT, and coincides with the recruitment of potentially infectable cells and upregulation of coreceptors essential for viral uptake. Implications of these findings are that the entire FRT is a potential target for HIV infection, immune cells and antibodies in blood are not surrogate markers for immune protection in the FRT, and immune protection against HIV will require an understanding of the hormone-induced regulation of humoral, cell-mediated, and innate immune systems throughout the FRT.The need to understand the interplay between the immune and endocrine systems in the human female reproductive tractDespite unprecedented efforts by scientists worldwide, the solution to the ever-growing HIV/AIDS crisis remains elusive. HIV/AIDS is unique in modern human history in its rapid spread, its extent, and the depth of its impact. Since the first AIDS case was diagnosed in 1981, the world has struggled to come to grips with its extraordinary toll. Approaching 25 million deaths worldwide with an additional 33.2 million (of which 15.4 million are women) estimated to be infected worldwide, HIV/AIDS will soon be the world's worst pandemic [1].With the recent failures of the Diaphragm trial, the Merck vaccine trial, and the Microbicide gel trial [2–6] along with recognition that for each person treated with antiretrovirals, six are newly infected with HIV [7], it remains unclear when safe and effective protection will become available. The failure of apparently promising approaches highlights the urgency to better understand how to prevent HIV transmission in women. Women are approximately twice as likely to contract HIV infection from men as men are from women during vaginal intercourse [8]. Each year brings an increase in the percentage of women infected with HIV. In particular, women and girls make up about 57% of all people infected with HIV in sub-Saharan Africa, where a striking 76% of those with HIV in the 15–24 year age group are female [9]. In the United States, the proportion of AIDS cases reported among women increased from 7% in 1985 to 28% in 2005 [1,8].Our interest in the reproductive tract immune system over the past 25 years has been refocused by the human tragedy of AIDS. As 80% of new HIV infections are due to heterosexual transmission, our efforts are concentrated on mucosal protection [10]. What is difficult to reconcile is that whereas the number of women infected has reached 20 million, the estimated rate of HIV transmission per coital act is low, 1: 122 to 1: 1000 [11,12]. These findings suggest that, while transmission is related to the viral load [13], exposure time following seroconversion [14] and pre-existence of other sexually transmitted infections (STIs), there exists within the FRT a window of vulnerability through which HIV, and probably other STI, can gain access to the body.

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