HIV-1 Infection Regulates Gene Expression by Altering Alternative Polyadenylation Through CPSF6 and CPSF5 Delocalization

Diaz-Griffero, F.; Luchsinger, C.; Dai, A. Z.; Yalamanchili, H.; Balakrishnan, A.; Huang, K.-L.; Bertelli, C.; Cui, B.; Wagner, E. J.; Lorenzo-Redondo, R.

doi:10.1101/2025.08.07.669137

bioRxiv · 10.1101/2025.08.07.669137

HIV-1 Infection Regulates Gene Expression by Altering Alternative Polyadenylation Through CPSF6 and CPSF5 Delocalization

Diaz-Griffero, F.·Luchsinger, C.·Dai, A. Z.·Yalamanchili, H.·Balakrishnan, A.·Huang, K.-L.·Bertelli, C.·Cui, B.·Wagner, E. J.·Lorenzo-Redondo, R.

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Abstract

HIV-1 viral core transport to the nucleus, an early infection event, triggers cleavage and polyadenylation specificity factor (CPSF)5 and CPSF6 to translocate from paraspeckles to nuclear speckles, forming puncta-like structures. CPSF5 and CPSF6 regulate alternative polyadenylation (APA), which governs approximately 70% of gene expression. APA alters the lengths of mRNA 3-untranslated regions (3-UTRs), which contain regulatory signals influencing RNA stability, localization, and function. We investigated whether HIV-1 infection-induced changes in CPSF5 and CPSF6 subcellular localization are accompanied by changes in cellular function. Using two independent methodologies to assess APA in human primary CD4+ T cells and cell lines, we found that HIV-1 infection regulates APA, dependent on the interaction of CPSF6 with the viral capsid, recapitulating the APA phenotype observed in CPSF6 knockout cells. Our study demonstrates that HIV-1 infection leverages the interaction between the viral capsid and CPSF6 to co-opt cellular processes, alter gene expression, and drive pathogenesis.

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Diaz-Griffero, F., Luchsinger, C., Dai, A. Z., Yalamanchili, H., Balakrishnan, A., Huang, K.-L., Bertelli, C., Cui, B., Wagner, E. J., Lorenzo-Redondo, R.. 2025-08-07. HIV-1 Infection Regulates Gene Expression by Altering Alternative Polyadenylation Through CPSF6 and CPSF5 Delocalization. https://doi.org/10.1101/2025.08.07.669137

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