Project 002 - VIDI

PROJECT 2. Viral Immunology, Drugs, and Imaging (VIDI) Research Project - ABSTRACT Despite the success of antiretroviral therapy (ART) improving the lives of persons with HIV (PWH), curing HIV would be important to reduce stigma and long-term co-morbidities associated with HIV infection that occur even

during ART. Developing a successful cure will need to better identify the viral and host factors that govern HIV dynamics in its HIV Obligate MicroEnvironment (HOME) to identify reservoir vulnerabilities that can be targeted. The Viral Immunology, Drugs, and Imaging (VIDI) Research Project (RP) will focus on immune, pharmacological,

host epigenetic cellular environments, and tissue architecture that govern the continuum of HIV reservoir dynamics. This characterization by the VIDI RP alone will add considerable new knowledge to the field. In the HOME program, these assay results will be integrated with viral features of HIV reservoir dynamics characterized

by VENI RP, and all datasets will be further integrated and analyzed by VICI RP. For experimental planning, the HIV reservoir dynamic continuum is simplified as the following reservoir states: · Leaves HOME when HIV (re)activates from tissues during antiretroviral therapy (ART) (i.e., like packing its

bag and getting ready to leave) and causes rebound viremia during ART interruption. · Comes HOME when HIV (re)populates tissues during viremia off ART and through the spread of clonally expanded HIV-infected cells while on ART. (Clonal expansion is like adding family to the home.) · Stays HOME when HIV (silently) persists in blood and tissue reservoirs (on and off ART).

To optimize allocated resources, we developed a two-step Adaptive Learning Approach. During the Mapping phase, the VIDI RP will examine how cellular and soluble inflammatory milieus and ART levels are associated with each reservoir state (i.e., leaving, coming, staying). The VICI RP will assist in the integration and analysis

of these data to identify ‘samples-of-interest’ that have pre-defined reservoir states and sufficient cellular environment for deeper investigation. In the Confirmation phase, the VIDI RP will use single-cell and imaging technologies to further characterize environmental factors associated with reservoir dynamics at a deeper level.

Importantly, the feasibility of our VIDI RP is greatly enhanced by the knowledge gained from our previous P01 (AI131385) and its Last Gift Cohort, which collects pre- and post- mortem specimens from PWH who did (n=5) or did not stop ART (n=15) before death. The HOME program will allow the continuation of this cohort while

expanding the science to study HIV dynamics across the human body at the single-genome and single-cell level. In summary, the overall HOME program will provide a deep delineation of environmental factors governing HIV reservoir dynamics, which is directly responsive to the Understanding HIV Reservoir Dynamics RFA AI-21-013.

This new knowledge will inform HIV cure strategies aiming at reversing latency (“Shock and Kill”) or at silencing permanently deep reservoirs (“Block and Lock”) and provide new insights in ways to reduce local HIV-associated tissue damage, which has been implicated in inflammation-related illnesses.