{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T16:07:20Z","timestamp":1786118840181,"version":"build-2736575974"},"posted":{"date-parts":[[2026,8,4]]},"group-title":"Microbiology","reference-count":66,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R01AI189220"],"award-info":[{"award-number":["R01AI189220"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  SAMHD1 is a mitochondria-associated cellular protein that restricts HIV-1 replication by depleting intracellular dNTP pools in non-dividing immune cells, such as macrophages, dendritic cells, and resting CD4\n                  <jats:sup>+<\/jats:sup>\n                  T cells; however, its role in host metabolism remains unclear. Building on our previous finding that SAMHD1 promotes mitochondrial membrane damage in HIV-1-infected monocytic cells, here we identify a new function for SAMHD1 in enhancing HIV-1-induced glycolysis through upregulation of hexokinase 2 (HK2). In monocytic THP-1 cells, but not differentiated macrophage-like cells, SAMHD1 amplifies HIV-1-triggered glucose uptake and basal glycolysis. Mechanistically, SAMHD1 increases HK2 expression and promotes its cytosolic accumulation, leading to elevated reactive oxygen species (ROS) production. This SAMHD1-dependent metabolic rewiring links antiviral restriction to glycolytic control and cellular stress responses. Our findings reveal a cell state-specific role for SAMHD1 in regulating glycolysis during HIV-1 infection, identify HK2 as a key effector, and uncover an unanticipated layer of host-virus interaction in monocytic cells.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>IMPORTANCE<\/jats:title>\n                  <jats:p>SAMHD1 is best known as a restriction factor that inhibits HIV-1 replication mainly through its dNTPase activity. However, emerging evidence suggests that SAMHD1 also regulates mitochondrial homeostasis and cellular metabolism. We previously demonstrated that SAMHD1 promotes HIV-1-induced apoptosis in monocytic cells through a mitochondrial pathway, implicating SAMHD1 in the control of mitochondrial function during infection. Because mitochondria are central regulators of cellular energy metabolism, we investigated whether SAMHD1 influences glycolytic reprogramming in HIV-1-infected monocytic cells. Our results show that SAMHD1 enhances glucose uptake, glycolysis, HK2 expression, and ROS production during HIV-1 infection. These findings reveal a previously unrecognized role for SAMHD1 in coordinating metabolic and oxidative stress responses to HIV-1 infection and provide new mechanistic insight into the interplay between antiviral factors, cellular metabolism, and HIV-1 pathogenesis. Understanding how SAMHD1 regulates glucose metabolism may uncover novel links between innate immune defenses and metabolic disease.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.08.03.742570","type":"posted-content","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T04:52:00Z","timestamp":1785905520000},"source":"Crossref","is-referenced-by-count":0,"title":["SAMHD1 enhances HIV-1-induced glycolysis in monocytic cells through hexokinase 2 upregulation"],"prefix":"10.64898","author":[{"given":"Hua","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3682-7571","authenticated-orcid":false,"given":"Pak-Hin Hinson","family":"Cheung","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5468-2487","authenticated-orcid":false,"given":"Li","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, 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