In order to end the epidemic in the US and worldwide a combination of approaches must be implemented that include early detection, prevention strategies, higher treatment efficacy and accessibility, outreach, and hopefully a vaccine and a cure. The existence of a latent reservoir of HIV-infected cells constitutes the major impediment towards finding an HIV cure. Latent infection is associated with undetectable levels of viral gene expression and appears to be non-cytopathic. Several therapeutic interventions against latent HIV are under investigation. Among them, ‘shock and kill’ strategies have reached clinical trials in people living with HIV (PLWH). The development of these and other interventions to curb the epidemic has to consider different populations and whether the efficacy of these strategies may vary in function of specific biological factors. Sex hormones, including estrogen, testosterone and progesterone, are critical mediators of sexual development. Besides their main role in sexual development, sex hormone receptors are present in immune cells and can influence HIV infection, HIV transcription as well as immune cell function. However, we are limited in our understanding whether and how sex hormones could influence cure strategies. This is crucial in the development of therapeutic interventions aimed towards an HIV cure in PLWH, including women and transgender. Women represent more than half of all the infections worldwide and transgender, which account for up to 0.6% of reproductive age adults in the US, are at approximately 49-fold higher risk of acquiring HIV infection. These populations will tremendously benefit from cure approaches. However, whether sex hormones and hormonal replacement therapies used during gender reassignment could potentially interfere with cure strategies is completely unknown. In Aim 1, we proposed to use a primary cell model of HIV latency to address whether sex hormones as well as antiandrogens used in hormonal replacement therapy for transgender individuals could influence the establishment of HIV latency. We will also evaluate whether sex hormones and antiandrogens influence the activity of a panel of latency-reversing agents (LRAs), including LRAs used in clinical trials for HIV eradication. In Aim 2, we intend to evaluate whether the activity of toll-like receptors (TLRs) agonists currently under clinical trials to eradicate HIV could be influenced by sex hormones and antiandrogens. Finally, in Aim 3 we will explore whether sex hormones and antiandrogens influence NK cell activity. NK cells are part of the innate immune system and play an important role in controlling HIV infection. Sex hormones have been shown to detrimentally affect NK anti-tumoral activity. However, less is known on whether sex hormones could influence their anti-HIV activity. Our studies will be of particular interests at the time of designing strategies aimed towards eliminating the HIV latent reservoir in different PLWH, including women and transgender, and will inform of the role that sex hormones could play in current and future HIV cure approaches.

The existence of latent reservoirs of HIV-infected cells constitutes the major impediment towards viral eradication. This application seeks to rigorously investigate whether and how sex hormones and hormone replacement therapies could influence HIV cure strategies for people living with HIV, including women and transgender.