# Biochemistry of SAMHD1-mediated innate immunity responses

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2021 · $469,052

## Abstract

ABSTRACT
 SAMHD1, a mammalian member of the HD-domain hydrolase family of enzymes, catalyzes hydrolysis of
deoxynucleotides triphosphates (dNTPs) to triphosphate and unphosphorylated nucleosides, which is thought
to be the main pathway for controlled depletion of cellular dNTPs. Discoveries that SAMHD1 is an immune
factor that restricts retroviral replication in non-cycling immune cells and regulates interferon signaling revealed
that dNTP depletion may act as a defense mechanism of innate antiviral immunity. Existence of such
mechanism implies that the enzymatic activity of SAMHD1 must be controlled by pathways of innate immune
sensing and response, and that cellular regulation of SAMHD1 is key to understanding the functional
relationship between antiviral immunity and dNTP metabolism. In the studies described here we will use
unique experimental tools developed by my laboratory to elucidate how biochemical regulation of SAMHD1
determines its immune function. This project will explore two novel regulatory mechanisms that have emerged
from our preliminary work and establish their contribution to the SAMHD1-mediated anti-retroviral state in non-
cycling immune cells. The studies will shed light on how and possibly why different molecular clues and cellular
signaling pathways alter susceptibility of myeloid and resting T cells to HIV infection, and thus elucidate the
biological significance of SAMHD1 function at the interface of dNTP metabolism and antiviral defense. In a
continued collaboration with the laboratory of Dr. Diaz-Griffero we will pursue two major specific aims. In Aim 1
we will explore the role of nucleic acid binding in the immune function of SAMHD1, elucidate structural and
biochemical determinants of high-affinity interaction of SAMHD1 with oligonucleotides and determine what
nucleic acid species regulate SAMHD1 activity and why. Our preliminary data suggest that phosphorothioate
linkages in nucleic acids may act as a danger-associated molecular pattern or a second messenger in antiviral
immunity. In Aim 2 we will elucidate the mechanism linking redox transformations of SAMHD1 to the enzymatic
activity and the immune function of the protein. Our preliminary studies suggest that redox regulation of
SAMHD1 may offer insight into the emerging role of reactive oxygen species (ROS) in modulating innate
antiviral immunity. We will determine what redox states are sampled by the redox-active cysteines of SAMHD1,
how these transformations alter the biochemical properties of the protein and explore whether SAMHD1
activity is controlled by specific sources of ROS and signaling pathways in the cell.

## Key facts

- **NIH application ID:** 10212922
- **Project number:** 5R01AI136697-03
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** DMITRI N IVANOV
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $469,052
- **Award type:** 5
- **Project period:** 2019-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10212922

## Citation

> US National Institutes of Health, RePORTER application 10212922, Biochemistry of SAMHD1-mediated innate immunity responses (5R01AI136697-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10212922. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*