Effects of PrEP Drugs on Female Genital HIV Infection and Women's Reproductive Health

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PROJECT SUMMARY Worldwide, young reproductive age women account for the majority of new HIV infections, which is often transmitted through heterosexual intercourse. Pre-exposure prophylactic (PrEP) drugs have been highly effective in preventing HIV transmission in men who have sex with men (MSM). However, PrEP efficacy in women has been much more variable, which has been attributed to societal reasons, low adherence, and due to biological and anatomical differences of the female reproductive tract (FRT) relative to the gastrointestinal (GI) tract. A number of FRT mucosal factors – including FRT fibroblasts, factors in semen, and inflammation – can increase HIV infection rates. These same factors can also diminish the anti-HIV activity of PrEP drugs. As many women at risk of HIV are of reproductive age, it is also important to determine the extent to which PrEP may affect fertility. Indeed, some PrEP drugs have been reported to impair processes essential for pregnancy. PrEP has also been shown to elicit interferon signaling in mucosal tissues, which could affect the functions of FRT T and Natural Killer (NK) cells. Of note, T and NK cells are effector cells that play critical roles in both viral defense and pregnancy. These observations suggest a better understanding of PrEP within the FRT microenvironment, and of potential adverse effects of PrEP on pregnancy, is needed. I am pursuing the K99 Award in order to gain further training to meet my long-term career goals: to become an independent investigator conducting research on infectious diseases and reproductive disorders affecting women. The environment at Gladstone Institutes and the University of California at San Francisco are exceptional and will provide the essential resources to successfully complete my career development plan and achieve my career goals. The objective of this research proposal is to determine how the environment of the FRT can influence PrEP efficacy, and conversely how PrEP can influence the FRT to affect fertility. My hypothesis is that FRT mucosal factors adversely affect the anti-HIV activities of PrEP, and that some but not all PrEP regimens can disrupt FRT processes important for pregnancy. In Aim 1, I will use FRT infection models and CyTOF to determine how the activity of PrEP is affected by the environment of the FRT mucosa. In Aim 2, I will use ex vivo tissue culture and organoid models, as well as in vivo mouse models, to determine how PrEP drugs affect pregnancy and processes important for pregnancy establishment and maintenance. In Aim 3, I will use multi-omics approaches to characterize T and NK cells from FRT of HIV-seronegative, reproductive-age women who are on or off PrEP, in order to assess to what extent PrEP alters the phenotypes of these cells. Identifying the mechanisms underlying HIV infection of susceptible cells in FRT in the context of suboptimal concentrations of PrEP (which is more common in the FRT than in the GI tract) will be crucial for the development of effective PrEP that young women can safely use without worrying about potential pregnancy complications. This could dramatically reduce the rate of transmission in reproductive- age women and have a significant impact on global public health.