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 in vivo, clonal expansion and the establishment of latency occurred in subsets of engrafted infected cells. Clonal expansion in vivo was driven by T-cell receptor identity, but not by proviral insertional mutagenesis. The integration sites of proviruses that became latent in vivo 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.