HIV-1 transcription dominates over host gene activity at the HIV-1 integration site

ABSTRACT: Despite effective antiretroviral therapy (ART), HIV-1 persists as an integrated DNA provirus in the genome of infected cells. Host cells can regulate HIV-1 transcription at the HIV-1 integration site dependent on the location (actively transcribed genes vs repressive chromatin) and the orientation (in the same vs opposite orientation of the host gene transcription) of HIV-1 integration. Presumably, HIV-1 follows the host gene transcriptional activity at the HIV-1 integration site. We interrogated HIV-1-host gene transcriptional interactions at the HIV-1 integration site using CRISPR-mediated activation and inhibition of the host genes (in which HIV-1 was integrated) in seven HIV-1-infected Jurkat T cell clones with known HIV-1 integration sites in the introns of actively transcribed genes and a non-genic region. Using ATAC-seq and strand-specific RNA-seq to examine chromatin accessibility and RNA transcription levels, we found that host gene activation did not increase HIV-1 transcription, while host gene inhibition did not decrease HIV-1 transcription. HIV-1 drove high levels of aberrant host RNA transcription regardless of the HIV-1 integration orientation. HIV-1-driven aberrant host RNA transcription was inhibited by CRISPR-mediated HIV-1 inhibition but not by CRISPR-mediated host gene activation or inhibition. When HIV-1 was integrated into a non-genic region, HIV-1 increased host chromatin accessibility and drove high levels of aberrant host RNA transcription. Overall, HIV-1 LTR promoter-driven transcriptional activity dominated over the host promoter activity. HIV-1 transcription does not passively follow host gene activity. Our results highlight that despite effective ART, silencing HIV-1 promoter is required to inhibit HIV-1-driven aberrant host gene expression and chronic immune activation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE302199 | GEO | 2025/10/21

REPOSITORIES: GEO