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

HIV-1 persists as an integrated provirus in infected cells. Antiretroviral therapy (ART) does not inhibit HIV-1 promoter activity. Therefore, despite effective ART, HIV-1 promoter continues to drive HIV-1 antigen expression and induce chronic immune activation. HIV-1 eradication relies on either effective HIV-1 latency reversal (the shock-and-kill strategy) or permanent HIV-1 silencing (the block-and-lock strategy). Therefore, understanding the transcriptional regulation of HIV-1 expression is key to HIV cure. Presumably, HIV-1 transcription passively follows host gene activity at the HIV-1 integration site. Using a CRISPR-mediated host gene activation and inhibition, we found that host gene activation does not increase HIV-1 transcription, while host gene repression does not inhibit HIV-1 transcription. HIV-1 drives aberrant host RNA expression even when HIV-1 is integrated into a non-genic region. Overall, HIV-1 dominates over host gene activity at the HIV-1 integration site. Despite ART, additional strategies silencing HIV-1 promoter activity are required to halt HIV-1-induced chronic immune activation.