Persistent HIV infection of long lived resting memory CD4+ T-cells, unresponsive to current anti- retroviral therapy (ART) and unaffected by immune surveillance remains a formidable barrier to efforts to achieve HIV eradication. The latent state of the virus is established within days of infection, and decays very slowly with a half-life of 40-44 months, necessitating life-long antiviral therapy to suppress recrudescence of infection. Modalities to disrupt persistent HIV infection have become a priority in the quest to cure HIV infection. Such an undertaking requires broad knowledge of the nature of the reservoir in all populations of people. However, our knowledge of the reservoir in women is greatly limited as this group is traditionally under- represented in HIV cure related studies. Several characteristics associated with HIV infection in women, such as low viremia during early infection and preserved CD4 T cell count could impact the HIV reservoir. Factors specific to women, including differences in innate and adaptive immunity, genetics and cyclical hormonal changes may affect HIV pathogenesis, immune function, and thereby ultimately affect the character of the latent reservoir, and influence therapeutic approaches to clear persistent infection. In this project, we seek to a) characterize the frequency of infection of replication competent latent HIV in subpopulations of resting CD4 T- cells in both the periphery and anatomical tissues in women; b) determine the stability of the HIV reservoir in subpopulations of resting T-cells over time; c) investigate potential sex hormone-influenced differences in responsiveness to agents that disrupt HIV latency; d) investigate the ability of effector cells to clear reactivated infection in the presence of physiological levels of sex hormones; and e) examine the role of the Type I interferon, IFN-? in modulating establishment of the latent reservoir in women. Knowledge gained from this project will advance the field towards developing successful therapeutics for HIV eradication in all populations of people.
Therapeutic interventions to clear persistence HIV infection will require broad knowledge of the nature of the latent reservoir in all people. Most studies aimed at characterizing the reservoir have been limited to male participants. Thus, while women constitute greater than 50% of people living with HIV disease, very little is known about the characteristics of the reservoir in this population. Factors such as cyclical hormonal levels could impact HIV persistent in women. This study outlines a comprehensive approach to rigorously characterize the distribution of the replication competent HIV reservoirs in different memory T-cell subpopulations in the periphery and in tissues of women. This study will also assess the stability of the reservoir in women and identify factors that contribute to the establishment of this reservoir and evaluate effective approaches that can be undertaken to disrupt latency in women. As such this study will further the understanding of persistent HIV infection in women and generate new ideas that may eventually lead to the development of therapeutics to eradicate HIV in all people.
