# HIV-1 infection regulates gene expression by altering alternative polyadenylation correlated with CPSF6 and CPSF5 redistribution

## TL;DR

HIV-1 infection changes how genes are expressed by altering a process called alternative polyadenylation, which is linked to the redistribution of CPSF6 and CPSF5 proteins.

## Contribution

The study reveals a novel mechanism by which HIV-1 modulates gene expression through CPSF6 interaction and disruption of alternative polyadenylation.

## Key findings

- HIV-1 infection causes CPSF5 and CPSF6 to redistribute to nuclear speckles, forming puncta-like structures.
- HIV-1 regulates gene expression by altering alternative polyadenylation, mimicking the effect of CPSF6 knockout.
- The virus exploits CPSF6 to modulate cellular processes, potentially contributing to its pathogenesis.

## Abstract

HIV-1 viral core transport to the nucleus, an early infection event, triggers the redistribution of cleavage and polyadenylation specificity factors (CPSF) 5 and CPSF6 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 APA changes. Using two independent methodologies to assess APA in human cell lines and primary CD4+ T cells, we found that HIV-1 infection regulates APA, shaped by 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 potentially contribute to viral pathogenesis.

The interaction between HIV-1 and the cellular protein CPSF6 has been known for over 15 years; however, depletion of CPSF6 does not impair productive infection. An alternative possibility is that the virus exploits this protein to modulate cellular processes. This study demonstrates that HIV-1 infection alters the cellular function of CPSF6, an essential regulator of alternative polyadenylation—a mechanism that controls 70% of gene expression. Here, we show that HIV-1 regulates gene expression by disrupting the alternative polyadenylation function of CPSF6 through direct interaction. Overall, this reveals a novel strategy employed by the virus to modulate cellular gene expression.