HIV-1 Integration Site Determines the Transcriptional Fate and Persistence of Integrated Proviruses

The mechanisms by which latent HIV-1 reservoirs persist during antiretroviral therapy is incompletely understood. Here, we derive a model system to measure clonal expansion and viral latency in which populations of human memory CD4⁺ T cells, each bearing a single transcriptionally active HIV-1 provirus are engrafted into immunodeficient mice. Over ~2 months <i>in vivo</i>, clonal expansion and the establishment of latency occurred in subsets of engrafted infected cells. Clonal expansion <i>in vivo</i> was driven by T-cell receptor identity, but not by proviral insertional mutagenesis. The integration sites of proviruses that became latent <i>in vivo</i> were enriched on chromosome 19, in intergenic and centromeric satellite regions, and genes whose expression is atypically low. Pre-existing repressive epigenetic features were associated with latency for subsets of proviruses. Our findings suggest a confluency of genomic and epigenomic factors predispose certain genomic locations, including ZNF genes, to host proviruses that constitute the latent reservoir.