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Our research is focused on three principal areas, summarized below,
focused on achieving HIV remission and eradication.
Research Focus - Basic Research.
Characterization of the mechanisms responsible for the cytolytic and pro-latency CD8 T cell functions that influence the establishment and maintenance of latency; impact the size of the persistent reservoir; and mediate the control of virus rebound after ATI. RF1 has been designed to identify the molecular and cellular mechanisms underlying the two distinct antiviral activities of CD8 T cells: the MHC-restricted, Ag- specific cytolytic response that directly eliminates virus-infected cells, and the non-MHC restricted, non-cytolytic silencing of HIV transcription that may paradoxically promote latency. As such, we are anticipating that RF1 will provide the conceptual basis for the strategies tested in RF2 and RF3.
Research Focus. - Control of Viral Rebound
Immune-based strategies to induce host immune responses able to control the rebounding virus. RF2 will use SHIV-infected RMs and HIV-infected humanized (hu)-mouse models of ART- treated infection to (i) restore CD8T and NK cell function with a combined aIL-10 and IL-15 super agonist (N- 803) strategy; (ii) target rebounding virus by using a CD4-mimetic compound (CD4mc) to enhance antibody recognition of Env-expressing cells and their elimination by ADCC; and (iii) determine if improving CD8 T and NK cell function via aIL-10 and N-803 synergizes with a CD4mc to clear infected cells. As such, we expect that RF2 will allow us to identify the most effective strategy for HIV remission after ATI; furthermore, it will provide ex vivo specimens to RF1 for further defining the mechanisms of viral control and inform the final studies of RF3.
Research Focus – Eradication
Modulation of the CD8 T cell-mediated pro-latency activity to effectively reactivate and eradicate the latent reservoir. RF3 will determine if suppression of the latency-promoting activity of CD8 T cells, coupled with N-803 and interventions to promote apoptosis (Bcl-2 inhibitors) or immune-mediated removal (CD4mc) of cells that have reactivated virus, will reduce the reservoir size. As such, RF3 will identify the most effective eradication strategy and provide ex vivo specimens to RF1 for further defining mechanisms of viral eradication. Finally, we will leverage the synergy between the mechanistic data of RF1 and the interventions tested and characterized in RF2 and RF3 to inform the final studies of ERASE HIV aimed at validating a novel, community-supported therapeutic strategy that potently limits both HIV persistence during ART and HIV recrudescence after ATI. We believe ERASE HIV will advance our understanding of the biology of HIV persistence, while generating pre-clinical data on novel therapeutic strategies aimed at curing HIV infection with an excellent potential for translation into human clinical studies.
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