The suppression of Human Immunodeficiency Virus (HIV-1) from infected individuals is the ultimate goal of antiretroviral therapy (ART). Major advances have been made towards this end with the advent of ART regimens. However, despite the sustained suppression of plasma viremia below detectable limits in infected patients for many years on ART regimens, replication competent virus can still be recovered from a variety of sites within the host, and most notably from long-lived quiescent memory CD4+ T lymphocytes. This viral reservoir represents the final impediment to the eradication and clearance of HIV infection or to a sustained virologic remission in the absence of ART. Currently, our understanding of HIV reservoirs in ART recipients is incomplete. Data assessing the impact of early ART initiation during acute infection on reservoir size are limited, especially in the tissues, as are virologic and immunologic surrogates of remission or control of HIV-1. Recent data from my laboratory has shown that persistent viral reservoirs are established very early in SIV infection [1]. However, very early ART can limit the seeding and expansion of cellular reservoirs of HIV [2-4]. Moreover, ART initiated in the earliest stages could significantly limit the size, location and genetic diversity of the HIV-1 reservoir, thereby improving the chance of a virologic remission. The efficacy of potent latency reversal agents (LRAs) or other immunotherapy delivered to very these early ART-treated reservoirs is unclear. Thus, detailed mechanistic studies are needed to define the impact of early ART on virological and immunologic outcomes that are relevant to achieving HIV remission and durable virus control after the cessation of ART [5]. Such investigations are detailed in this proposal. To investigate these hypotheses, we propose the following Specific Aims: 1. Determine the impact of early ART on the nature and distribution of the SIV reservoir during early viral establishment. 2. Assess SIV distribution and clonal expansion during ART initiation and after ART cessation. 3. Determine the impact of combination immunotherapy (TLR7 agonist and PD-L1) on the stability of the viral reservoir after ART cessation.

Public Health Relevance

Although HIV-1 can be effectively suppressed with antiretroviral therapy, it is not eradicated from the body. The majority of HIV-1 infected persons who cease therapy have resurgent viremia due to the presence of long-lived HIV-1 reservoirs. The mechanism(s) by which these reservoirs are seeded, maintained, and are subject to sustained virologic remission or rebound upon ART cessation is not understood. A detailed understanding of HIV reservoir genesis, and the factors that dictate viral control or rebound, in the absence of ART, is critical to develop approaches to therapeutically foster HIV-1 remission in patients on long-term antiretroviral therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI131365-04
Application #
9989773
Study Section
Special Emphasis Panel (ZAI1)
Project Start
2017-08-11
Project End
2022-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Cao, Youfang; Lei, Xue; Ribeiro, Ruy M et al. (2018) Probabilistic control of HIV latency and transactivation by the Tat gene circuit. Proc Natl Acad Sci U S A 115:12453-12458
Hill, Alison L; Rosenbloom, Daniel I S; Nowak, Martin A et al. (2018) Insight into treatment of HIV infection from viral dynamics models. Immunol Rev 285:9-25
Lim, So-Yon; Osuna, Christa E; Hraber, Peter T et al. (2018) TLR7 agonists induce transient viremia and reduce the viral reservoir in SIV-infected rhesus macaques on antiretroviral therapy. Sci Transl Med 10:
Whitney, James B; Lim, So-Yon; Osuna, Christa E et al. (2018) Prevention of SIVmac251 reservoir seeding in rhesus monkeys by early antiretroviral therapy. Nat Commun 9:5429
Ke, Ruian; Conway, Jessica M; Margolis, David M et al. (2018) Determinants of the efficacy of HIV latency-reversing agents and implications for drug and treatment design. JCI Insight 3:
Hill, Alison L (2018) Mathematical Models of HIV Latency. Curr Top Microbiol Immunol 417:131-156
Hill, Alison L (2018) Modeling HIV persistence and cure studies. Curr Opin HIV AIDS 13:428-434