Tuesday, July 1, 2025 7/1/2025

Biochemistry of SAMHD1-mediated innate immunity responses

Award Number: R37AI136697
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/25/2024
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Biochemistry of SAMHD1-mediated innate immunity responses - ABSTRACT SAMHD1 is a human immune factor that impedes infection of myeloid cells and resting T lymphocytes by HIV- 1. SAMHD1 is a deoxynucleotide triphosphate hydrolase (dNTPase), and the discovery of its anti-retroviral activity brought to light a novel antiviral mechanism that depends on the enzymatically controlled depletion of cellular dNTP pools. The ability of immune cells to use dNTP depletion for antiviral defense is puzzling, because even quiescent and terminally differentiated cells require deoxynucleotides for DNA repair and mitochondrial biogenesis. SAMHD1 is a key regulator of dNTP concentrations in nonproliferating cells and better understanding of its enzymatic properties may shed light on the tantalizing relationship between dNTP metabolism and antiviral immunity. Our recent work revealed that the 'facilitated dNTP depletion' function of SAMHD1 arises from its allosteric activation mechanism, a two-step process involving tetramer assembly and subsequent activation. Facilitated dNTP depletion enables regulatory crosstalk between biosynthesis and depletion of different dNTPs and manifests as more robust depletion of some nucleotides when biosynthesis of certain others is elevated. We hypothesize that the allosteric regulation of SAMHD1 is a key component to the cellular decision-making mechanism that controls the switching between multiple discrete states of cellular dNTP metabolism in nonproliferating immune cells and thus determines whether and when these cells become non-permissive to HIV infection. In this project we seek to advance our understanding of how allosteric and posttranslational regulation of SAMHD1 enables distinct states of dNTP metabolism by pursuing two specific aims. In Aim 1 we will delineate how enzymatic properties of SAMHD1 give rise to the antiviral modalities of dNTP homeostasis and enable immune and metabolic decision-making. We also seek to establish mechanistic relationships between the distinct states of cellular dNTP metabolism and the susceptibility to HIV infection. In Aim 2 we will elucidate the structural basis of allosteric and posttranslational regulation of SAMHD1. Our recent findings reveal that SAMHD1 activation by dNTP substrates involves an inactive tetrameric intermediate with partial dNTP occupancy of the allosteric sites. Here we will further elucidate the conformational repertoire of SAMHD1 activation and how it is modulated by posttranslational modifications, nucleic acid ligands and pathogenic mutations.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $736,678 )
2025	2025	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	001	6	5/14/2025	NON-COMPETING CONTINUATION	$556,253
2025	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	000	5	2/25/2025	COMPETING CONTINUATION	$180,425
														Subtotal = $736,678

Issue Date FY: 2024 ( Subtotal = $570,845 )
2024	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	001	5	7/31/2024	COMPETING CONTINUATION	$0
2024	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	000	5	6/25/2024	COMPETING CONTINUATION	$515,198
2024	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	002	5	9/5/2024	COMPETING CONTINUATION	$55,647
														Subtotal = $570,845

Grand Total All Awards = $1,307,523

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Biochemistry of SAMHD1-mediated innate immunity responses

Award Number: R37AI136697

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/25/2024

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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