Reservoir features associated with time-to-rebound during analytical treatment interruption

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Project Summary/Abstract (Project 3) Combination antiretroviral therapy (ART) can suppress HIV replication and lead to decreased mortality in HIV-infected individuals. However, ART does not eliminate the reservoir of HIV-infected cells, and upon treatment interruption or cessation, virus typically rebounds from this reservoir within several weeks. Although the viral reservoir has long been recognized as the main barrier to curing HIV, the basic mechanisms underlying viral rebound, and the nature of the rebound-competent reservoir cells, remain poorly understood. In this Project, we hypothesize that both viral transcriptionally activity and immune states of reservoir cells are key determinants of the time it takes for virus to rebound when ART is stopped, and that these features will define the early targets of infection at the time of rebound. To test this hypothesis, we will implement a variety of high-dimensional single- cell analysis techniques to define the HIV transcriptional state and phenotypic features of HIV reservoir cells in people living with HIV (PLWH) undergoing analytical treatment interruption (ATI) as part of ongoing trials. These include individuals who initiated treatment early after diagnosis (Fiebigs I-V of acute infection) and those who initiated treatment during the chronic phase of infection. In Aim 1, ddPCR- and viral sequencing-based approaches will be used to characterize the intactness and HIV transcriptional activity of reservoir cells, while novel single-cell methods will be used to interrogate the phenotypes of transcriptionally-active and inducible reservoir cells. This information will then be associated with the time it takes virus to rebound from these individuals. These same individuals will be extensively sampled over the course of treatment interruption in order to better understand the early events occurring at the time of rebound, which will be extensively characterized in Aim 2. Finally, Aim 3 will use similar techniques to characterize two additional cohorts of individuals undergoing ATI, but in the context of cure-based interventions aimed at achieving a functional cure through immune modulation. Overall, this study will establish an in-depth view of the viral and host cell features of rebound- competent reservoir cells, and will relate this knowledge to the time it takes for viral rebound during ART interruption, in the context of ongoing non-interventional and interventional cure-based clinical trials.