The goal of our Collaboratory is to develop novel combined immunologic approaches to cure HIV-1 through a highly collaborative and multifaceted research program involving leading investigators in academia, government, and industry. Our overall hypothesis is that a combined immunologic approach that optimizes antiviral humoral and cellular immune responses, together with latency reversal and possibly lymphoid sanctuary disruption, will effectively reduce or control the viral reservoir in ART- suppressed, SHIV-infected rhesus monkeys and in ART-suppressed, HIV-1-infected humans to achieve a functional cure. We propose two interactive Research Foci and five Scientific Research Support Sections (Clinical, Nonhuman Primate, Virology, Immunology, and Biostatistics and Bioinformatics). Focus 1: Efficacy of Combined Immunologic Approaches to Target the Viral Reservoir In this Focus, we will evaluate the efficacy of best-in-class broadly neutralizing monoclonal antibodies (bnMAbs), therapeutic vaccines, and latency reversing agents (LRAs) in both SHIV-infected rhesus monkeys and HIV-1-infected humans. These studies will fill a critical knowledge gap by defining the capacity of leading immunologic interventions to target viral reservoirs and to contribute to an HIV-1 cure.
Specific Aim 1. To evaluate two leading therapeutic vaccines in ART-suppressed, HIV-1-infected humans treated during acute HIV-1 infection;
Specific Aim 2. To evaluate the combination of bnMAbs and a therapeutic vaccine in ART-suppressed, SHIV- infected rhesus monkeys;
and Specific Aim 3. To evaluate the combination of optimal bnMAbs and a therapeutic vaccine in ART- suppressed, HIV-1-infected humans treated during both acute and chronic HIV-1 infection. Focus 2: Mechanisms and Next Generation Strategies to Target the Viral Reservoir A major knowledge gap is that we currently do not know which anatomic viral sanctuary gives rise to viral rebound following discontinuation of ART. In this Focus, we will evaluate the impact of bnMAbs, therapeutic vaccines, and LRAs on the viral reservoir, and we will define the anatomic location of the residual viral reservoir that persists despite these interventions with the goal of developing next generation HIV-1 cure strategies.
Specific Aim 1. To define the mechanism of action of leading bnMAbs, therapeutic vaccines, and LRAs in depleting the viral reservoir in ART-suppressed, SHIV-infected rhesus monkeys;
Specific Aim 2. To develop more effective bnMAbs for reservoir depletion;
and Specific Aim 3. To test an improved HIV-1 cure strategy in ART-suppressed, SHIV-infected rhesus monkeys.

Public Health Relevance

The goal of our Collaboratory is to develop novel combined immunologic approaches to cure HIV-1 through a highly collaborative and multifaceted research program involving leading investigators in academia, government, and industry. We will assess the efficacy of state-of-the-art therapeutic vaccines, broadly neutralizing antibodies, and latency reversing agents to contribute to a functional cure in both preclinical and clinical studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project with Complex Structure Cooperative Agreement (UM1)
Project #
5UM1AI126603-04
Application #
9728878
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Mcdonald, David Joseph
Project Start
2016-07-14
Project End
2021-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Barouch, Dan H; Tomaka, Frank L; Wegmann, Frank et al. (2018) Evaluation of a mosaic HIV-1 vaccine in a multicentre, randomised, double-blind, placebo-controlled, phase 1/2a clinical trial (APPROACH) and in rhesus monkeys (NHP 13-19). Lancet 392:232-243
Wang, Zheng; Simonetti, Francesco R; Siliciano, Robert F et al. (2018) Measuring replication competent HIV-1: advances and challenges in defining the latent reservoir. Retrovirology 15:21
Badamchi-Zadeh, Alexander; Moynihan, Kelly D; Larocca, Rafael A et al. (2018) Combined HDAC and BET Inhibition Enhances Melanoma Vaccine Immunogenicity and Efficacy. J Immunol 201:2744-2752
Wang, Zheng; Gurule, Evelyn E; Brennan, Timothy P et al. (2018) Expanded cellular clones carrying replication-competent HIV-1 persist, wax, and wane. Proc Natl Acad Sci U S A 115:E2575-E2584
Alter, Galit; Barouch, Dan (2018) Immune Correlate-Guided HIV Vaccine Design. Cell Host Microbe 24:25-33
Badamchi-Zadeh, Alexander; Tartaglia, Lawrence J; Abbink, Peter et al. (2018) Therapeutic Efficacy of Vectored PGT121 Gene Delivery in HIV-1-Infected Humanized Mice. J Virol 92:
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
Borducchi, Erica N; Liu, Jinyan; Nkolola, Joseph P et al. (2018) Antibody and TLR7 agonist delay viral rebound in SHIV-infected monkeys. Nature 563:360-364
Sengupta, Srona; Siliciano, Robert F (2018) Targeting the Latent Reservoir for HIV-1. Immunity 48:872-895
Abbink, Peter; Stephenson, Kathryn E; Barouch, Dan H (2018) Zika virus vaccines. Nat Rev Microbiol 16:594-600

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