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However, its significance in HIV-1 infection remains unclear because IL-32 inhibits and stimulates viral production in monocyte-derived macrophages (MDMs) and CD4+ T cells, respectively. In this study, we initially found that the inhibitory effect on human MDMs depends on SAMHD1, a dNTP triphosphohydrolase that inhibits viral reverse transcription. IL-32 increased the unphosphorylated active form of SAMHD1, which was consistent with the reduced expression of the upstream cyclin-dependent kinases. Indeed, IL-32 lost its anti\u2013HIV-1 activity in MDMs when SAMHD1 was depleted. These results explain why IL-32 inhibits HIV-1 in MDMs but not CD4+ T cells, because SAMHD1 restricts HIV-1 in noncycling MDMs but not in cycling CD4+ T cells. Another unique feature of IL-32 is the induction of the immunosuppressive molecule IDO1, which is beneficial for HIV-1 infection. In this study, we found that IL-32 also upregulates other immunosuppressive molecules, including PD-L1, in MDMs. Moreover, IL-32 promoted the motility of MDMs, which potentially facilitates intercellular HIV-1 transmission. Our findings indicate that IL-32 has both the direct inhibitory effect on HIV-1 production in MDMs and the indirect stimulatory effects through phenotypic modulation of MDMs, and they suggest that the stimulatory effects may outweigh the inhibitory effect because the window for IL-32 to inhibit HIV-1 is relatively confined to SAMHD1-mediated reverse transcription suppression in the viral life cycle.<\/jats:p>","DOI":"10.4049\/jimmunol.2200087","type":"journal-article","created":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T13:21:30Z","timestamp":1666272090000},"page":"970-978","source":"Crossref","is-referenced-by-count":11,"title":["Inhibitory and Stimulatory Effects of IL-32 on HIV-1 Infection"],"prefix":"10.1093","volume":"209","author":[{"given":"Hesham","family":"Nasser","sequence":"first","affiliation":[{"name":"Joint Research Center for Human Retrovirus Infection, Kumamoto University , Kumamoto,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naofumi","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Joint Research Center for Human Retrovirus Infection, Kumamoto University , Kumamoto,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5398-4205","authenticated-orcid":false,"given":"Youssef M","family":"Eltalkhawy","sequence":"additional","affiliation":[{"name":"Joint Research Center for Human Retrovirus Infection, Kumamoto University , Kumamoto,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1260-0527","authenticated-orcid":false,"given":"Omnia","family":"Reda","sequence":"additional","affiliation":[{"name":"Joint Research Center for Human Retrovirus Infection, Kumamoto University , Kumamoto,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7627-2430","authenticated-orcid":false,"given":"Sameh","family":"Lotfi","sequence":"additional","affiliation":[{"name":"Joint Research Center for Human Retrovirus Infection, Kumamoto University , Kumamoto,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanako","family":"Nasu","sequence":"additional","affiliation":[{"name":"Joint Research Center for Human Retrovirus Infection, Kumamoto University , Kumamoto,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1877-4680","authenticated-orcid":false,"given":"Jun-ichi","family":"Sakuragi","sequence":"additional","affiliation":[{"name":"Division of Microbiology, Kanagawa Prefectural Institute of Public Health , Kanagawa,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2531-4770","authenticated-orcid":false,"given":"Shinya","family":"Suzu","sequence":"additional","affiliation":[{"name":"Joint Research Center for Human Retrovirus Infection, Kumamoto University , Kumamoto,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,9,1]]},"reference":[{"key":"2025021008280385800_r1","first-page":"131","article-title":"Interleukin-32: a cytokine and inducer of TNF\u03b1","volume":"22","author":"Kim","year":"2005","journal-title":"Immunity"},{"key":"2025021008280385800_r2","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.smim.2018.03.004","article-title":"Insights into the role of IL-32 in cancer","volume":"38","author":"Sloot","year":"2018","journal-title":"Semin. 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