Transcription of HIV-1 is heterogenous among authentic latent CD4⁺ T cell clones

Antiretroviral therapy suppresses HIV-1 infection but fails to eliminate a reservoir of intact latent proviruses that reside primarily in CD4⁺ T cells. The lack of precise understanding of the latent compartment has made it challenging to develop curative strategies for HIV-1 infection. Here we report on the properties of CD4⁺ T cell clones carrying intact latent proviruses, expanded in vitro from single cells obtained from the reservoir of people living with HIV-1. The latent proviruses in the clones were integrated into ZNF genes, nongenic satellite, and centromeric regions, frequently associated with latency. Despite their descent from single cells, only a fraction of the cells (0.4–14%) expressed relatively low levels of HIV-1 that did not measurably alter host gene transcriptome. Latency-reversing agents (LRAs) variably increased expression, but the effects were modest and clone and LRA specific. The results suggest that pharmacologic and immunologic approaches to clear the reservoir should be optimized to accommodate intra- and inter-clonal diversity.