Human SAMHD1: An Ally and Adversary for Viral Replication

Abstract:

The human SAMHD1 is a 65-kDA protein comprising of 626 amino acid residues and an N-terminal SAM domain, as well as a C-terminal HD domain. It primarily functions as a dNTP triphosphohydrolase (dNTPase) which degrades host cellular dNTPs. As a result of its dNTPase activity, SAMHD1 is a well-established HIV-1 restriction factor, especially within the low dNTP environment of primary monocyte-derived macrophages. However, other lentiviruses which express the viral protein X (Vpx) such as HIV-2 and certain strains of SIV do not succumb to SAMHD1’s restriction effect, as SAMHD1 is targeted by Vpx for proteosomal degradation. Interestingly, Vpx is also implicated in the mutagenesis of HIV-1 due to the resulting higher incorporation rate of the non-canonical rNTPs during viral reverse transcription within the SAMHD1-mediated low dNTP level environment of macrophages.

On the other hand, SAMHD1 has been characterized for its role as a negative regulator of the host innate immunity. This is evident from previously reported findings that mutation of SAMHD1 is one of the nine genes associated with the development of Aicardi Goutieres Syndrome, a rare neuroimmunological genetic disorder that induces constant activation of cellular innate immunity even in the absence of any pathogen infections. Suppression of replication and viral yield of RNA viruses such as Zika virus as well as the SARS-CoV-2 have been reported in SAMHD1 knockdown or knockout cells, whereas several pathways including the JAK/STAT, NF-κB and IRF-3 pathways are shown to be targeted for downregulation by SAMHD1. Overall, the human SAMHD1 is an interesting host factor which warrants further in-depth studies for its broad-spectrum roles in regulating viral infections as well as other important human diseases.

Speaker's Profile:

Dr Adrian Oo is a Research Fellow at the Department of Microbiology and Immunology in National University of Singapore (NUS). Following the completion of his PhD in Universiti Malaya, he has performed his postdoctoral trainings at Emory University in Atlanta, GA, USA, before joining the NUS in 2023. Over the years in collaboration with various research institutes and the pharmaceutical industry, his research focus has primarily been on infectious diseases involving viruses such as human immunodeficiency virus, dengue virus, chikungunya virus, zika virus, influenza A virus, as well as the recent severe acute respiratory syndrome coronavirus 2.

His expertise on molecular and biochemical virology has enabled him to identify antivirals and prophylactic vaccines for different types of viruses, as well as epigenetically decipher specific underlying host and viral factors involved in viral mutagenesis and replication.