Research Focus 1
Objectives 1 and 2: Dynamic of the HIV reservoir
Leaders: Drs. Nicolas Chomont and Lillie Cohn
Collaborators: Drs. Steve Deeks, Mathias Lichterfeld, Xu Yu, Sarah Palmer, Bob Siliciano
The goal of this project is to understand how HIV persists in blood and tissues during antiretroviral therapy. Using blood, gut and lymph node samples from people living with HIV, we propose to determine whether HIV is truly latent during ART or whether it still produces some viral products and can escape elimination by the immune system. In addition, since HIV also persists in cells that divide, we will identify the cause of this proliferation.
Our objective is to identify vulnerabilities in HIV-infected cells persisting after prolonged ART that can be harnessed to accelerate the decay of the reservoir.
Objective 3: Immune control of virus rebound at the intercept
Leaders: Drs. Rachel Rutishauser and Gaurav Gaiha
Collaborators: Drs. Steve Deeks, Jonathan Li, Michael Peluso, Timothy Henrich, Janet and Bob Siliciano, Michael Gale
The goal of this project is to understand how various arms of the immune system respond to HIV – at what we are calling the "intercept" – as the virus emerges after stopping ART. We are using unique clinical samples from people with HIV on ART who control viral rebound either on their own without any intervention, or after receiving therapies (eg. therapeutic vaccination, CAR-T cell infusion, or other immune-modifying treatments).
We expect the knowledge gained from these studies will help us to develop improved immune-based strategies for HIV cure.
Research Focus 2
Developing combinatorial therapeutic strategies to establish durable post-ART viral remission
Leaders: Drs. Louis Picker and Afam Okoye
Collaborators: Drs. Jeffrey Lifson, Brandon Keele, Jacob Estes
This goal of this project is to develop interventions that allow for the host immune system to control or impede HIV recrudescence after ART is withdrawn. Using nonhuman primate models, we are evaluating ways to provide an earlier and more effective intercept of rebounding virus by the immune system (e.g., vaccines, latent-reversing agents, adjuvants, cytokines, immune checkpoint inhibitors) while also slowing post-ART viral outgrowth (neutralizing antibodies), with the goal of tilting the balance between the immune system and the virus to the host’s advantage.
We believe these studies will help in the development of novel therapeutic strategies to cure HIV.
Research Focus 3
Identifying novel strategies to enhance cell death of infected cells that persist on ART using inhibitors of inhibitors of apoptosis and BCL2 antagonists to significantly reduce the reservoir
Leaders: Drs. Sharon Lewin and Jake Estes
Collaborators: Drs. Afam Okoye, Louis Picker, Marc Pelligrini, Thomas Rasmussen, Michael Roche, Youry Kim, Matthias Lichterfeld and Michael Gale together with Abbvie and Genentech
The overall goal of Research Focus 3 is to reduce the size of the rebound-competent reservoir during antiretroviral therapy (ART) by rendering the reservoir more susceptible to pro-apoptotic signaling and therefore cell death. We will assess two classes of compounds – SMAC mimetics (which we hypothesise both reverse latency and enhance cell death in the transcriptionally active reservoir) and BCL2 antagonists (which inhibit the pro-survival protein BCL2). These compounds will be assessed alone or in combination, using cells from PWH on ART, a humanised mouse model of HIV and finally SIV-infected rhesus macaques.
Objective 1: Determine the effect of the monovalent SMAC mimetics GDC-0152 and GDC-0917 on latency reversal and cell death
Objective 2: Determine the effect of venetoclax on selective depletion of infected cells when administered alone and in combination with latency reversal agents
Objective 3: Identify therapeutic interventions that facilitate reduction of SIV reservoirs in ART-suppressed, SIVmac239-infected rhesus macaques
We expect that this work will identify novel agents that will reduce the pool of infected cells that persist on ART. The work will provide the pre-clinical data needed to move these agents, either alone or in combination, into clinical trials in PWH on ART.