Delaney AIDS Research Enterprise to Cure HIV

PROJECT SUMMARY/ABSTRACT The goals of the DARE Collaboratory are to develop a viable combination regimen that reduces the rebound- competent HIV/SIV reservoir during antiretroviral therapy (ART) and/or induces durable control of HIV/SIV in the absence of therapy. Our proposed work is based on two observations made our group. First, we found that virus- specific CD8+ T cells contribute to control of the virus at steady-state. These cells, however, have limited effect during and immediately post-ART. We believe and will seek to prove that effective remission strategies will require organization of a robust innate and adaptive immune response during the earliest stages of virus rebound, effectively intercepting and suppressing viral rebound prior to the massive systemic growth of SIV/HIV that overwhelms, damages and/or evades the immune system. Second, we and others have found that despite virus expression during ART (either naturally or in response to a latency reversal agent), the frequency of infected cells remains stable. We have found that infected cells are relatively resistant to cell death programs. We will develop therapies that render these cells to host-mediated clearance mechanisms, thus resulting in their reduction and perhaps elimination. To achieve our goals, we will (1) characterize in people transcriptionally active cells and proliferating infected cells, focusing on identifying mechanisms for persistence, (2) define in people the earliest immunologic and virologic events post-interruption of ART, focusing on post-treatment controllers, (3) develop in non-human primates (NHPs) a combination regimen that targets the reactivating virus during the immediate post-ART period and results in sustained control at set-point and (4) develop in vitro and in animal models therapies that render the reservoir more susceptible to death through the activation of intrinsic (cellular) and/or extrinsic (virus-specific) pro-apoptotic pathways. This work will leverage our deep investment in (1) the optimization of the SIV NHP model and a humanized mouse model, both developed specifically to support the types of studies we will pursue, (2) the development of a robust clinical cohort (SCOPE) designed to support intensive, biologic studies of people living with HIV (PWH), and (3) the implementation and conduct of several clinical trials designed in part to test our hypotheses in people and from which samples will be made available to our team for ex vivo studies. We anticipate meeting the following milestones and deliverables: (1) definition of the active reservoir in lymphoid tissues from SIV-infected monkeys and HIV-infected humans on effective ART, (2) determination of whether reservoir cells are resistant to intrinsic and extrinsic cell killing, (3) development of a viable and translatable remission strategy in NHPs, and (4) identification and pre-clinical development of interventions aimed at enhancing the cell death, either by making cells more susceptible to cell death and/or by optimizing the efficacy of the virus-specific T cell response.