Abstract Persistent HIV infection of long lived resting memory CD4+ T-cells, unresponsive to current antiretroviral therapy (ART) and unaffected by immune surveillance remains a formidable barrier towards efforts to achieve an HIV cure . 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. Given the continuous expansion of the number of HIV-infected individuals on lifelong ART worldwide, modalities to disrupt persistent HIV infection in combination with immunotherapies to clear cells containing reactivated virus remains a high priority in the quest to cure HIV infection. Immune augmentation is an indispensable component of effective clearance of persistently infected cells. Such an undertaking requires broad knowledge of not only effective methods to more robustly induce HIV antigen expression from latently infected cells, but also of factors that may hinder the clearance of cells containing virus emerging from latency. Defining the effect latency reversal agents (LRAs) on the various functions of the immune system is critical if such combination therapies are to be deployed. While several studies have focused on methodologies to improve the adaptive arm of the immune response in the context of latency reversal, there have been minimal studies on innate immunity. Type I interferons influences both the innate and adaptive immune response. They induce cell intrinsic factors to limit the spread of pathogens, including viruses, they modulate the innate immune responses and promote activation of the adaptive immune system. Likewise, little is known about the effect of biological sex on the ability of augmented immunity to effectively clear cells containing reactivated latent HIV. Sex-based differences in innate immunity may influence not only the outcome of HIV infection, but also the ability to clear reactivated cells. Our preliminary data indicate both type I IFN and estrogen signaling are modulated by LRAs. In this project we will employ a comprehensive approach, including the use of state of the art tools such as scRNAseq and ERα specific PROteolysis TArgeting Chimeras (PROTACs) to 1) define the effect of emerging and benchmark LRAs on type I interferon signaling; 2) query the role of type I interferon signaling, on the fate of virus emerging from latency and 3) examine the interplay of type I interferon and estrogen signaling to modulate the immune response and define the effects of LRAs on the process. Knowledge gained from this project will advance the field towards developing successful therapeutics for HIV cure in all populations of people. .