HIV-1 Capsid Rapidly Induces Long-Lived CPSF6 Puncta in Non-Dividing Cells, but Similar Puncta Already Exist in Uninfected T-Cells

Guedán, Anabel; Burley, Megan; Caroe, Eve R.; Bishop, Kate N.

doi:10.3390/v16050670

Cited by 2 publications

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

HIV-1 usurps mixed-charge domain-dependent CPSF6 phase separation for higher-order capsid binding, nuclear entry and viral DNA integration

Jang,

Bedwell,

Singh

et al. 2024

Nucleic Acids Research

View full text Add to dashboard Cite

HIV-1 integration favors nuclear speckle (NS)-proximal chromatin and viral infection induces the formation of capsid-dependent CPSF6 condensates that colocalize with nuclear speckles (NSs). Although CPSF6 displays liquid-liquid phase separation (LLPS) activity in vitro, the contributions of its different intrinsically disordered regions, which includes a central prion-like domain (PrLD) with capsid binding FG motif and C-terminal mixed-charge domain (MCD), to LLPS activity and to HIV-1 infection remain unclear. Herein, we determined that the PrLD and MCD both contribute to CPSF6 LLPS activity in vitro. Akin to FG mutant CPSF6, infection of cells expressing MCD-deleted CPSF6 uncharacteristically arrested at the nuclear rim. While heterologous MCDs effectively substituted for CPSF6 MCD function during HIV-1 infection, Arg-Ser domains from related SR proteins were largely ineffective. While MCD-deleted and wildtype CPSF6 proteins displayed similar capsid binding affinities, the MCD imparted LLPS-dependent higher-order binding and co-aggregation with capsids in vitro and in cellulo. NS depletion reduced CPSF6 puncta formation without significantly affecting integration into NS-proximal chromatin, and appending the MCD onto a heterologous capsid binding protein partially restored virus nuclear penetration and integration targeting in CPSF6 knockout cells. We conclude that MCD-dependent CPSF6 condensation with capsids underlies post-nuclear incursion for viral DNA integration and HIV-1 pathogenesis.

show abstract

HIV-1 usurps mixed-charge domain-dependent CPSF6 phase separation for higher-order capsid binding, nuclear entry and viral DNA integration

Jang,

Bedwell,

Singh

et al. 2024

Nucleic Acids Research

View full text Add to dashboard Cite

show abstract

Disruption of CPSF6 enhances cellular permissivity to HIV-1 infection through alternative polyadenylation

Hultquist,

Cornish,

Jackson-Jones

et al. 2024

Preprint

View full text Add to dashboard Cite

Human immunodeficiency virus (HIV) relies upon a broad array of host factors in order to replicate and evade the host antiviral response1. Cleavage and polyadenylation specificity factor 6 (CPSF6) is one such host factor that is recruited by incoming HIV-1 cores to regulate trafficking2, nuclear import3-5, uncoating6, and integration site selection4,6-11. Despite these well-described roles, the impact of CPSF6 perturbation on HIV-1 infectivity varies considerably by cell type. Here, we report that CPSF6 knock-out in primary CD4+ T cells leads to increased permissivity to HIV-1 infection due to broad transcriptional reprogramming. Knock-out of CPSF6 results in widespread differential gene expression, including downregulation of genes involved in the innate immune response and enhanced expression of the HIV-1 co-receptors. Accordingly, these cells are less responsive to interferon and express lower levels of antiretroviral restriction factors, including TRIM5α. These transcriptional changes are linked to global shortening of mRNA 3’ untranslated regions (UTRs) through alternative polyadenylation (APA), which is triggered by disruption of the CPSF6-containing Cleavage Factor Im (CFIm) complex12,13. Furthermore, we find that recruitment of CPSF6 by HIV-1 cores is sufficient to perturb CPSF6 function, leading to 3’ UTR shortening and subsequent transcriptional rewiring. These results suggest a novel mechanism by which HIV-1 transcriptionally reprograms CD4+ T cells through recruitment of CPSF6 to circumvent the innate immune response and enhance permissivity to infection.

show abstract

HIV-1 Capsid Rapidly Induces Long-Lived CPSF6 Puncta in Non-Dividing Cells, but Similar Puncta Already Exist in Uninfected T-Cells

Cited by 2 publications

References 57 publications

HIV-1 usurps mixed-charge domain-dependent CPSF6 phase separation for higher-order capsid binding, nuclear entry and viral DNA integration

HIV-1 usurps mixed-charge domain-dependent CPSF6 phase separation for higher-order capsid binding, nuclear entry and viral DNA integration

Disruption of CPSF6 enhances cellular permissivity to HIV-1 infection through alternative polyadenylation

Contact Info

Product

Resources

About