# Defining a common mechanism of SAMHD1 function in cancer, HIV, and AGS

> **NIH NIH F31** · EMORY UNIVERSITY · 2022 · $40,164

## Abstract

Project Summary
As of 2019 there were 38.0 million individuals living with HIV globally. This number continues to rise yearly
despite advances in HIV treatment. A significant challenge to developing a cure for HIV continues to be the
reservoir of latently infected cells. Current antiretrovirals cannot target this subset of non-dividing cells that harbor
transcriptionally inactive provirus. It is well established that HIV infection in non-dividing cells has different
properties than HIV infection in dividing cells. For example, non-dividing cells harbor dNTP concentrations below
the Km of reverse transcriptase which significantly slows the kinetics of viral replication. SAM and HD domain
containing protein 1 (SAMHD1) is the host dNTPase responsible for this restriction. A thorough understanding
of the contribution of SAMHD1 to the unique environment of HIV-1 infection in non-dividing reservoir cells has
the potential to inform novel therapeutics to target this reservoir. To this effect, I propose to characterize a novel
series of SAMHD1 mutations that have been implicated in several cancers and use these mutants as tools to
further probe the role of SAMHD1 in HIV-1 restriction. I have identified a leukemia and colon cancer associated
SAMHD1 mutant, R366C/H, that retains protein stability but loses dNTPase activity. Interactions with cell cycle
proteins and involvement in double strand DNA break repair, dNTPase independent functions of SAMHD1, are
preserved in this mutant. Interestingly, SAMHD1 mutations that result in impaired dNTPase activity were first
reported in Aicardi Goutières Syndrome (AGS), a rare inherited encephalopathy characterized by aberrant type
1 interferon production. Many of these AGS mutants are unable to restrict HIV-1 infection in macrophages due
to their inability to deplete cellular dNTPs. Given that the dNTP concentration in cancer cells is 6-11 fold higher
than in normal cells and that SAMHD1 knock-out results in cancer cell phenotypes such as increased proliferation
and reduced apoptosis, it is likely that the role of SAMHD1 as a dNTPase also involves the enzyme in cancer.
Therefore, I hypothesize that the dNTPase deficiency of the R366C/H SAMHD1 cancer mutant contributes
to cancer cell phenotypes and abrogates both HIV-1 restriction in non-dividing cells and innate immune
response suppression. In Aim 1, I will complete my functional characterization of the R366C/H cancer mutant
and determine the impact of these functional deficits on cancer cell phenotypes using biochemical and cell
biology techniques. Subsequently in Aim 2, I will use virology, cell biology, and immunology approaches to
analyze the effect of the R366C/H cancer mutation on HIV-1 restriction and innate immune suppression, thus
using this cancer mutation to probe more traditionally studied SAMHD1 disease phenotypes . Collectively, these
complimentary aims will highlight the role of SAMHD1 dNTPase activity in cancer and mechanistically link the
involvement...

## Key facts

- **NIH application ID:** 10480762
- **Project number:** 5F31AI157884-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Nicole Eileen Bowen
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $40,164
- **Award type:** 5
- **Project period:** 2021-09-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10480762

## Citation

> US National Institutes of Health, RePORTER application 10480762, Defining a common mechanism of SAMHD1 function in cancer, HIV, and AGS (5F31AI157884-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10480762. Licensed CC0.

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