# Deciphering the Role of CPSF6 in HIV Infection

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2023 · $395,200

## Abstract

PROJECT SUMMARY
Cleavage and polyadenylation specificity factor 6 (CPSF6) is an HIV host factor recruited to incoming viral cores
during the early stage of the lifecycle. The interaction between HIV capsid (CA) and CPSF6 is known to dictate
the cellular determinants of nuclear translocation and influence integration site preference, but its impact on
overall viral infectivity is unclear. While overexpression of cytoplasmic CPSF6 has been shown to restrict viral
replication, knock-down of CPSF6 or disruption of the CA-CPSF6 interaction has been reported to have a broad
range of infectivity phenotypes. Recently, our lab found that knock-out of CPSF6 in primary CD4+ T cells
dramatically increases HIV replication with minimal impact on cell viability. This increase in replication correlates
with decreased induction of interferon-stimulated genes, contrary to prior reports that suggest CPSF6 acts to
shield the virus from immune recognition. In this proposal, we are testing the overall hypothesis that CPSF6
plays a critical role in regulating the innate immune response to HIV infection and that the virus recruits CPSF6
in part to circumvent this response. This hypothesis will be tested in three aims that broadly seek to understand
the mechanism by which loss of CPSF6 dampens the immune response to infection, the impact of HIV infection
on CPSF6 function, and the potential role of CPSF6 regulatory pathways in controlling infection. In Aim 1, we
will test the hypothesis that loss of CPSF6 acts to dampen the immune response directly by induction of
alternative polyadenylation (APA) or indirectly by allowing enhanced recruitment of Cyclophilin A (CYPA) to
protect the core from restriction by the antiviral factor TRIM5. CPSF6 normally acts as a member of the CFIm
cleavage factor complex to direct polyadenylation to distal sites of the 3' untranslated region (UTR). Inhibition of
CFIm activity triggers APA, which has been previously implicated in the regulation of the innate immune
response, and could explain the observed phenotype. Alternatively, there is evidence to suggest that CPSF6
and CYPA compete for core binding and loss of CYPA binding has been previously linked to enhanced restriction
and innate sensing. In Aim 2, we will test the hypothesis that CPSF6 recruitment by incoming viral cores can
alter overall CFIm function and induce APA. Regardless if this is linked to dampening of the immune response
above, it is well established that other viruses hijack the APA pathway to enhance their replication, though this
hasn't been explored during HIV infection. Finally, in Aim 3, we will test the hypothesis that perturbation of the
CPSF6 regulatory network can control viral infectivity and the immune response to infection. CPSF6 activity is
regulated by post-translational modification and nuclear-cytoplasmic shuttling. Truncation mutants of CPSF6 that
force cytoplasmic localization have been shown to restrict HIV infection, and we will test if we can mimic ...

## Key facts

- **NIH application ID:** 10646402
- **Project number:** 5R01AI165236-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Judd F Hultquist
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $395,200
- **Award type:** 5
- **Project period:** 2021-07-13 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10646402

## Citation

> US National Institutes of Health, RePORTER application 10646402, Deciphering the Role of CPSF6 in HIV Infection (5R01AI165236-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10646402. Licensed CC0.

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