PROJECT SUMMARY/ABSTRACTThe mission of the DARE Collaboratory is to harness the power of the adaptive immune system to reduce thesize of the reservoir during antiretroviral therapy (ART) and to control any residual virus after ART isinterrupted. Our overall hypothesis is that that durable remission of HIV infection will require a robust immuneresponse that is persistent and functional. Moreover, these responses need to be in the right place at the righttime. We propose four highly linked research foci aimed at reaching these goals. We will define the role ofputative immune-privileged sanctuaries that enable SIV/HIV to persist during ART and use the monkey modelto develop therapies to breach these sanctuaries (Initial Research Foci 1, IRF1). We will characterize thedistribution on replication-competent virus in lymphoid tissues of ART-suppressed adults and develop PETimaging modalities to quantify this reservoir (IRF2). We will define the role of immune checkpoints (PD-1,others) and their blockade on T cell function in monkeys and people (IRF3). Finally, we will define the safety,immunogenicity, and anti-HIV effectiveness of a human CMV (HCMV) vectored HIV vaccine in HIV-infectedadults on ART (IRF4). All four initial research foci are linked by their shared goal to understand how best toquantify, reduce, and control HIV in the human lymphoid system. We anticipate meeting the followingmilestones and deliverables: (1) definition of the replication-competent reservoir in lymphoid tissues from SIV-infected monkeys and HIV-infected humans on suppressive ART, (2) determination of whether B follicles serveas a immunologic sanctuary for infected CD4+ TFH and, if so, whether B follicular depletion reduces the size ofthe reservoir, (3) determination of the characteristics of virus-specific CD8+ T cell responses that have optimalactivity for reservoir reduction and/or post-ART viral control, (4) determination if the tissue reservoir can bemeasured by radiolabeled tracers and PET scanning, (5) identification of the optimal combination of immunecheckpoint blockers that enhance T-cell function and/or reverse HIV latency, (6) definition of the safety andimmunogenicity of immune checkpoint blockers in treated SIV and HIV disease, (7) determination of the safetyand immunogenicity of the HCMV/HIV vaccine in treated HIV disease, and (8) determination if B cell disruptionand/or immune checkpoint blockade might be necessary for this vaccine (or other comparable interventions) toachieve reservoir reduction and/or durable remission. Our work will set the stage for a future proof-of-conceptclinical trial of the HCMV/HIV vector in antiretroviral-treated individuals, either alone or in combination with Bcell follicle disruption and/or immune checkpoint blockade.
|Effective start/end date||7/14/16 → 6/30/21|
- National Institutes of Health: $5,547,114.00