Clonal dynamics of HIV-infected and uninfected T cells.

Abstract

The HIV reservoir was once considered to be transcriptionally silent. Evidence is emerging that a substantial portion of the reservoir is transcriptionally active. We explore the consequences of transcriptionally active proviruses on the infected T cell by longitudinally monitoring the fate of proviral clones. We analysed proviral dynamics by monitoring ∼4000 HIV proviral sequences and ∼13,000 integration site sequences along with ∼2 million T cell receptor (TCR) sequences in up to 9 people living with HIV over time. This analysis includes 7 chronically treated and 2 elite controller participants, with paired TCR sequencing in 6 individuals. We also analysed 9 participants from published cohorts. Our analysis used a Morisita metric to capture contraction and expansion of proviral clones. The role of HIV expression was also investigated by studying the effect of integration site and orientation indirectly in vivo and directly in a cell line model. We focus on cell-intrinsic forces and provide evidence that proviral clones contract and expand more in individuals treated during chronic infection compared to elite controllers. Moreover, proviral clones change more than TCR clones suggesting a subset of infected cells may turnover more than uninfected cells. We also provide evidence of two opposing forces, both initiated by HIV expression within the cell, likely contributing to proviral dynamics. These forces could explain the increased changes in proviral clones in a subset of infected cells. Evidence of an expansion force includes an enrichment of sense-oriented proviruses in growth-related genes among large clones. At the same time, there is depletion of sense-oriented proviruses in highly expressed genes, leading to an overall enrichment of antisense. Our longitudinal analysis of HIV sequences suggests that a subset of HIV-infected cells may divide and die faster than uninfected T cells, contributing to a dynamic reservoir. This work was funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, United States (R01AI176952, R01AI165368, and R37AI150556).