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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.02755-25","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T13:00:47Z","timestamp":1763989247000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":3,"title":["HIV-1 transcription dominates over host gene activity at the HIV-1 integration site"],"prefix":"10.1128","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4377-1094","authenticated-orcid":false,"given":"Samuel","family":"Weissman","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03v76x132","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbial Pathogenesis, Yale University School of Medicine","place":["New Haven, 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