The failure to cure HIV infection is believed to be the result of (1) low level viral production/replication, (2) the presence of latent, replication-competent provirus in quiescent cells, and/or (3) immune dysfunction stemming from chronic activation. None of the currently available antiviral therapies will address the long-lived reservoir of latently infected cells or immune dysregulation. Insights into the cellular mechanisms that control HIV gene expression and chronic immune activation suggest that inflammation-mediated upregulation of negative regulators of T cell activation contribute to the establishment of long-lived latently-infected cells. In this Project, we will explore the role of negative regulators including PD-1 in maintaining latency.
In Aim 1 we will determine if, in addition to PD-1, other negative regulators contribute to HIV persistence in blood and tissues from HIV infected individuals receiving suppressive ART. We will assess whether blocking these negative pathways can reactivate viral production in vitro. To optimize this strategy, we will in Aim 2 determine if other therapies can act in concert with PD-1 blockade to disrupt viral latency and/or limit the replenishment of the viral reservoir in vitro. Our studies will focus on the use of agents that are either licensed for use in humans or have progressed sufficiently through preclinical testing at Merck to support chronic dosing in the rhesus model and evaluation in future human trials. Specifically, we will target the IL-10, IFN- a and Notch pathways as these factors impact the proliferation and differentiation of T cells and have an impact upon viral replication. Finally, in Aim 3, we will evaluate the capacity of a PD-1 blocking antibody (in combination with other reagents identified in Aim 2) to impact on latent reservoirs in SIV-infected rhesus macaques receiving suppressive ART. Well characterized, clinical grade anti-PD-1 mAbs are available to test this hypothesis in the rhesus model and will be used to inform rapid progression to clinical studies as appropriate. These studies will address whether blocking PD-1/PDL-1 interactions can result in functional cure, point to adjunct approaches for future studies, and provide potential biomarkers for human clinical trials.

Public Health Relevance

Exploiting the multiple roles of PD-1 in reversing latent infection is unique among the proposed approaches to eradicate HIV. Identification and validation of additional negative regulators will maximize the effectiveness of this approach through novel combinations. These studies will provide proof-of-concept data for targeting these negative regulators to eliminate latent HIV infection as well as a rational basis for human clinical trials aimed at eradication.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-JBS-A)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
San Francisco
United States
Zip Code
Okoye, Afam A; Hansen, Scott G; Vaidya, Mukta et al. (2018) Early antiretroviral therapy limits SIV reservoir establishment to delay or prevent post-treatment viral rebound. Nat Med 24:1430-1440
Winckelmann, Anni; Morcilla, Vincent; Shao, Wei et al. (2018) Genetic characterization of the HIV-1 reservoir after Vacc-4x and romidepsin therapy in HIV-1-infected individuals. AIDS 32:1793-1802
Wykes, Michelle N; Lewin, Sharon R (2018) Immune checkpoint blockade in infectious diseases. Nat Rev Immunol 18:91-104
Lee, Sulggi A; Elliott, Julian H; McMahon, James et al. (2018) Population Pharmacokinetics and Pharmacodynamics of Disulfiram on Inducing Latent HIV-1 Transcription in a Phase IIb Trial. Clin Pharmacol Ther :
Kumar, Nitasha A; van der Sluis, Renee M; Mota, Talia et al. (2018) Myeloid Dendritic Cells Induce HIV Latency in Proliferating CD4+ T Cells. J Immunol 201:1468-1477
Walters, Lucy C; Harlos, Karl; Brackenridge, Simon et al. (2018) Pathogen-derived HLA-E bound epitopes reveal broad primary anchor pocket tolerability and conformationally malleable peptide binding. Nat Commun 9:3137
Adland, Emily; Hill, Matilda; Lavandier, Nora et al. (2018) Differential Immunodominance Hierarchy of CD8+ T-Cell Responses in HLA-B*27:05- and -B*27:02-Mediated Control of HIV-1 Infection. J Virol 92:
Boyer, Zoe; Palmer, Sarah (2018) Targeting Immune Checkpoint Molecules to Eliminate Latent HIV. Front Immunol 9:2339
Wang, Chia-Ching; Thanh, Cassandra; Gibson, Erica A et al. (2018) Transient loss of detectable HIV-1 RNA following brentuximab vedotin anti-CD30 therapy for Hodgkin lymphoma. Blood Adv 2:3479-3482
Reeves, Daniel B; Duke, Elizabeth R; Wagner, Thor A et al. (2018) A majority of HIV persistence during antiretroviral therapy is due to infected cell proliferation. Nat Commun 9:4811

Showing the most recent 10 out of 190 publications