title: Immune Activation Influences SAMHD1 Expression and Vpx-mediated SAMHD1 Degradation during Chronic HIV-1 Infection.
abstract: SAMHD1 restricts human immunodeficiency virus type 1 (HIV-1) replication in myeloid cells and CD4+T cells, while Vpx can mediate SAMHD1 degradation to promote HIV-1 replication. Although the restriction mechanisms of SAMHD1 have been well-described, SAMHD1 expression and Vpx-mediated SAMHD1 degradation during chronic HIV-1 infection were poorly understood. Flow cytometric analysis was used to directly visualize ex vivo, and after in vitro SIV-Vpx treatment, SAMHD1 expression in CD4+T cells and monocytes. Here we report activated CD4+T cells without SAMHD1 expression were severely reduced, and SAMHD1 in CD4+T cells became susceptible to SIV-Vpx mediated degradation during chronic HIV-1 infection, which was absent from uninfected donors. These alterations were irreversible, even after long-term fully suppressive antiretroviral treatment. Although SAMHD1 expression in CD4+T cells and monocytes was not found to correlate with plasma viral load, Vpx-mediated SAMHD1 degradation was associated with indicators of immune activation. In vitro assays further revealed that T-cell activation and an upregulated IFN-I pathway contributed to these altered SAMHD1 properties. These findings provide insight into how immune activation during HIV-1 infection leads to irreparable aberrations in restriction factors and in subsequent viral evasion from host antiviral defenses.
authors.affiliation: Shanghai Public Health Clinical Center, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.|Key Laboratory of Medical Molecular Virology of Ministry of Education/Health at Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Weihui
authors.initials: W
authors.lastname: Fu
authors.affiliation: Shanghai Public Health Clinical Center, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.|Key Laboratory of Medical Molecular Virology of Ministry of Education/Health at Shanghai Medical College, Fudan University, Shanghai, China.|Huashan Hospital, Fudan University, Shanghai, China.|Minhang Hospital, Fudan University, Shanghai, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Qiu
authors.affiliation: Shanghai Public Health Clinical Center, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.|Key Laboratory of Medical Molecular Virology of Ministry of Education/Health at Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Mingzhe
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministry of Education/Health at Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Lingyan
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministry of Education/Health at Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministry of Education/Health at Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Chenli
authors.initials: C
authors.lastname: Qiu
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministry of Education/Health at Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Linxia
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministry of Education/Health at Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Xu
authors.affiliation: Shanghai Municipal Center for Disease Control &Prevention, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Shanghai Public Health Clinical Center, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.|Key Laboratory of Medical Molecular Virology of Ministry of Education/Health at Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Jianqing
authors.initials: J
authors.lastname: Xu
authors.affiliation: Shanghai Public Health Clinical Center, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.|Key Laboratory of Medical Molecular Virology of Ministry of Education/Health at Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000627:therapeutic use; D002460:Cell Line; D002908:Chronic Disease; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1 / Q000472:pathogenicity / Q000502:physiology; D054884:Host-Pathogen Interactions; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D059748:Proteolysis; D000076106:SAM Domain and HD Domain-Containing Protein 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019562:Viral Load; D054334:Viral Regulatory and Accessory Proteins / Q000378:metabolism* / Q000494:pharmacology; D014779:Virus Replication
chemical_list: D019380:Anti-HIV Agents; C513059:VPX protein, Simian immunodeficiency virus; D054334:Viral Regulatory and Accessory Proteins; D007371:Interferon-gamma; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human