HIV-1 Integrase Variants Retarget Viral Integration and Are Associated with Disease Progression in a Chronic Infection Cohort

• S119 and R231 of HIV-1 integrase (IN) directly contact target DNA (tDNA) bases
• Altering tDNA-contacting IN residues retargets viral integration without altering fitness
• IN polymorphisms exhibit distinct local and global integration preferences
• INS119G and INR231G are linked to disease progression in chronic HIV-1/AIDS patients

SummaryDistinct integration patterns of different retroviruses, including HIV-1, have puzzled virologists for over 20 years. A tetramer of the viral integrase (IN) assembles on the two viral cDNA ends, docks onto the target DNA (tDNA), and catalyzes viral genome insertion into the host chromatin. We identified the amino acids in HIV-1 IN that directly contact tDNA bases and affect local integration site sequence selection. These residues also determine the propensity of the virus to integrate into flexible tDNA sequences. Remarkably, natural polymorphisms INS119G and INR231G retarget viral integration away from gene-dense regions. Precisely these variants were associated with rapid disease progression in a chronic HIV-1 subtype C infection cohort. These findings link integration site selection to virulence and viral evolution, but also to the host immune response and antiretroviral therapy, since HIV-1 IN119 is under selection by HLA alleles and integrase inhibitors.

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