SAMHD1 enhances HIV-1-induced apoptosis in monocytic cells via the mitochondrial pathway
Year: 2025
Type: article
Abstract: Sterile alpha motif (SAM) and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) inhibits HIV-1 replication in non-dividing cells by reducing the intracellular dNTP pool. While SAMHD1 is known to promote spontaneous apoptosis, its role in HIV-1-induced apoptosis and the underlying mechanisms remain unclear. In this study, we identify a novel mechanism by which SAMHD1 enhances HIV-1-induced apoptosis in monocytic cells via the mitochondrial pathway. We demonstrate that SAMHD1 enhances apoptosis induced by HIV-1 infection in dividing monocytic THP-1 and U937 cell lines, but not in differentiated macrophage-like cells. Mechanistically, SAMHD1 expression reduces mitochondrial membrane potential and promotes cytochrome c release in HIV-1-infected THP-1 cells, thereby augmenting the mitochondrial apoptotic pathway. Furthermore, SAMHD1-enhanced apoptosis is linked to elevated levels of the pro-apoptotic protein BCL-2-interacting killer (BIK) in cells, which contributes to enhanced apoptosis during HIV-1 infection. These findings reveal a previously unrecognized regulatory role of SAMHD1 in amplifying HIV-1-induced apoptosis in monocytic cells, highlighting its involvement in the mitochondrial apoptotic pathway.IMPORTANCESterile alpha motif (SAM) and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1), a dNTP triphosphohydrolase, lowers intracellular dNTP levels and restricts HIV-1 replication in non-dividing cells. HIV-1 infection induces cell death mainly through apoptosis. While we have shown that endogenous SAMHD1 enhances spontaneous apoptosis in monocytic cells, its role in HIV-1-induced apoptosis and the underlying mechanisms remain unknown. In this study, we aim to bridge this knowledge gap by investigating the functional significance of SAMHD1 in regulating apoptosis during HIV-1 infection of immune cells. Our findings reveal a novel mechanism whereby SAMHD1 enhances HIV-1-induced apoptosis in monocytic cells through the mitochondrial pathway. This suggests a previously unrecognized role of SAMHD1 in modulating cellular responses to HIV-1 infection.
Source: mBio
Authors: Hua Yang, Pak-Hin Hinson Cheung, Li Wu
Institution: University of Iowa
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,900
Awards: G1835645643, Targeting HIV-1 RNA modifications in latently infected CD4+ T cells for therapeutic development, G3760990340, G4400893249, SAMHD1-mediated regulation of HIV-1 innate immunity and viral gene expression, HIV-1-induced upregulation of m6A modifications of cellular RNA in CD4+ T-cells, G630064964, G9000088747, G9000189621, SAMHD1-mediated regulation of innate immunity during SARS-CoV-2 infection
OpenAlex ID: W4410823776