Early pandemic HIV-1 integration site preferences differ across anatomical sites

BACKGROUND: HIV-1 persists in the body even when treatment suppresses viral replication. This persistence is due in part to the virus integrating into the DNA of infected cells. While it is known that HIV-1 can integrate into many different tissues, it remains unclear whether integration patterns differ across anatomical sites. This study investigated how the location and characteristics of HIV-1 integration sites vary across distinct tissues in people living with HIV-1 subtype B during the early years of the pandemic, before modern treatment was widely available. METHODS: Integration site data were obtained from matched samples from the esophagus, blood, stomach, duodenum, and colon, and from unmatched brain tissue. We evaluated how frequently the virus integrated near different genomic features, including gene regions, repetitive elements, and predicted DNA structures, and compared integration patterns across tissues and individuals. RESULTS: We show that integration site patterns differ by tissue. In brain tissue, HIV integrates less frequently into genes and more frequently into specific repetitive elements and accessible regions of DNA. We also find that integration near unusual DNA shapes varies by tissue, and that certain integration hotspots are shared while others are unique. Genes involved in HIV-1-related diseases are frequently targeted across tissues. CONCLUSIONS: This study reveals that HIV-1 integration patterns are shaped by the tissue environment. These findings suggest that the long-term persistence of HIV-1 depends in part on tissue-specific integration site features, with potential implications for disease risk and treatment strategies.