Human splice factors contribute to latent HIV infection in primary cell models and blood CD4+ T cells from ART-treated individuals

It is unclear what mechanisms govern latent HIV infection in vivo or in primary cell models. To investigate these questions, we compared the HIV and cellular transcription profile in three primary cell models and peripheral CD4(+) T cells from HIV-infected ART-suppressed individuals using RT-ddPCR and RNA-seq. All primary cell models recapitulated the block to HIV multiple splicing seen in cells from ART-suppressed individuals, suggesting that this may be a key feature of HIV latency in primary CD4(+) T cells. Blocks to HIV transcriptional initiation and elongation were observed more variably among models. A common set of 234 cellular genes, including members of the minor spliceosome pathway, was differentially expressed between unstimulated and activated cells from primary cell models and ART-suppressed individuals, suggesting these genes may play a role in the blocks to HIV transcription and splicing underlying latent infection. These genes may represent new targets for therapies designed to reactivate or silence latently-infected cells. Author summary The ability of HIV to establish a reversibly silent (latent) infection in CD4+ T cells is widely regarded as the main barrier to curing HIV, but it is unclear what mechanisms govern latent HIV infection. To investigate these questions, we compared the HIV and cellular transcription profile in three primary cell models of HIV latency and cells from the blood of HIV-infected individuals. A reversible block to HIV RNA splicing was common to all primary cell models and cells from HIV-infected individuals, suggesting that this may be a key mechanism of latent HIV infection. Blocks at other stages of HIV transcription were observed more variably among models. Differential expression of 234 human genes, including members of the minor spliceosome pathway, distinguished latently-infected from reactivated (non-latently infected) CD4+ T cells in primary cell models and HIV-infected individuals. These genes may play a role in the blocks to HIV transcription and splicing underlying latent infection and may represent new targets for therapies aimed at curing HIV.