HIV-1 Reservoir and Host Cell Dynamics Over Twenty Years on ART: Reservoir Kinetics, Antigen-Specific T Cell Dynamics, and Model-Building

About This Grant

PROJECT SUMMARY/ABSTRACT Despite the success of antiretroviral therapy (ART) in suppressing viral replication, no cure for HIV has been found. This is because HIV persists in a reservoir comprised of intact, inducible HIV proviruses in CD4+ T cells and, to a lesser degree, myeloid cells. A deeper, more quantitative understanding of the forces that sustain the reservoir will allow us to engineer more effective HIV cure therapeutics. We know that the HIV reservoir decays in the first ~7 years after ART initiation, but reservoir dynamics in the second decade and beyond are not well characterized. Of the few individuals studied longitudinally out to 20 years, some experience continued reservoir decay while others show signs of reservoir expansion. In this work, we will conduct a large, multi-decade, multi- platform study of the dynamics of latently infected cells and host CD4+ T cells. We will use this data to estimate the relative contributions of the biological factors that sustain the reservoir at different points in time after ART initiation. We will test the hypothesis that the reservoir initially decays due to immune selection, after which the reservoir’s persistence is largely driven by the kinetics of the most highly-expanded, infected clones. In the first aim, we will characterize 20-year HIV reservoir trajectories using the intact proviral DNA assay in dozens of people living with HIV (PWH) on ART and identify biological factors that differ between those with continued decay and those with expansion in the second decade on ART. Biological factors examined include expansion rates of underlying HIV-infected CD4s and uninfected memory CD4s, CMV serostatus, and sex. In the second aim, we will quantify the contribution of antigen-specific clonal proliferation to overall memory (m)CD4+ T cell persistence in a subset of PWH on long-term ART. To do this, we will first use the ViraFEST assay to identify T- cell receptor (TCR)β sequences of mCD4+ T cells that proliferate in response to one of four viral antigens. Then we will obtain longitudinal resting mCD4+ TCRβ and paired TCRαβ repertoires from the same individuals and track each antigen-specific clone’s proliferative kinetics over 20 years on ART. We will model these thousands of antigen-specific clone trajectories to provide insight into how antigen exposure shapes long-term persistence of memory CD4+ T cells. In the third aim, we will refine, validate, and extend our stochastic model of HIV reservoir dynamics to incorporate 20 years of ART data. First, we will generate empiric data on clone kinetics of CD4s harboring intact and defective proviruses and uninfected mCD4s by performing near-full length sequencing and mCD4+ TCR repertoire sequencing on longitudinal samples. We will use this data to refine and validate our current model and extend its applicability to the first twenty years on ART, thus providing a comprehensive framework to estimate the relative contributions of various forces, such as immune selection and antigen-driven proliferation, in driving reservoir dynamics at different times after ART initiation. Our study will yield quantitative insight that will be immediately applicable to HIV cure efforts and will generate a freely available, advanced mathematical model of the reservoir that can provide predictions to optimize the design of future HIV cure trials.