# SAMHD1-mediated regulation of HIV-1 innate immunity and viral gene expression

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2022 · $472,357

## Abstract

Project Summary/Abstract
A critical barrier to developing a cure for HIV-1 infection is the long-lived viral reservoir in cells due to
viral latency. Many host proteins regulate HIV-1 gene expression and viral latency. By reducing
intracellular dNTP levels, the host protein SAMHD1 inhibits HIV-1 replication in myeloid cells and resting
CD4+ T-cells, cell types that are important for HIV-1 latency. Patients with homozygous SAMHD1
mutations experience autoimmune diseases, but the functions and mechanisms of SAMHD1 in
modulating inflammation and immunity remain unclear. Despite extensive studies of the mechanisms
underlying SAMHD1-mediated restriction of virus replication, it is unknown whether and how SAMHD1
regulates antiviral innate immune responses. Here, we aim to address two key questions: (a) What are
the mechanisms of SAMHD1 in modulating the innate immune response to HIV-1 infection? (b) How
does SAMHD1 affect HIV-1 gene expression?
Our new findings demonstrated that SAMHD1 suppresses innate immune responses to viral infections
and inflammatory stimuli by inhibiting nuclear factor-kappa B (NF-κB) activation and type I interferon
(IFN-I) induction through distinct mechanisms. We discovered that SAMHD1 interacts with key proteins
in the NF-κB and IFN-I pathways, allowing it to act as a multifaceted repressor of innate immune
signaling. We also found that SAMHD1 impairs HIV-1 gene expression and reactivation of viral latency in
primary CD4+ T-cells. NF-κB is critical for HIV-1 gene transcription and transcriptional inhibition of viral
gene expression is the main mechanism of HIV-1 latency. Our central hypothesis is that SAMHD1
modulates HIV-1 antiviral immunity and viral gene expression by suppressing NF-κB activation, IFN-I
induction, and viral transcription. We designed three specific aims to test this hypothesis. Aim 1.
Elucidate the mechanisms by which SAMHD1 suppresses NF-κB activation in HIV-1 infection; Aim 2.
Define the mechanisms by which SAMHD1 suppresses IFN-I induction during HIV-1 infection; Aim 3.
Investigate the mechanisms by which SAMHD1 impairs reactivation of HIV-1 gene expression.
Overall impact. These studies will reveal novel physiological functions of SAMHD1 during HIV-1
infection of primary target cells, which are beyond its known function in restricting virus replication.
Furthermore, our interdisciplinary studies will yield new results to fundamentally enhance our mechanistic
understanding of SAMHD1 in regulating HIV-1 infection, viral gene expression, and anti-HIV innate
immune responses.

## Key facts

- **NIH application ID:** 10337184
- **Project number:** 5R01AI141495-04
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Li Wu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $472,357
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10337184

## Citation

> US National Institutes of Health, RePORTER application 10337184, SAMHD1-mediated regulation of HIV-1 innate immunity and viral gene expression (5R01AI141495-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10337184. Licensed CC0.

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