title: SERINC3 and SERINC5 restrict HIV-1 infectivity and are counteracted by Nef.
abstract: HIV-1 Nef and the unrelated mouse leukaemia virus glycosylated Gag (glycoGag) strongly enhance the infectivity of HIV-1 virions produced in certain cell types in a clathrin-dependent manner. Here we show that Nef and glycoGag prevent the incorporation of the multipass transmembrane proteins serine incorporator 3 (SERINC3) and SERINC5 into HIV-1 virions to an extent that correlates with infectivity enhancement. Silencing of both SERINC3 and SERINC5 precisely phenocopied the effects of Nef and glycoGag on HIV-1 infectivity. The infectivity of nef-deficient virions increased more than 100-fold when produced in double-knockout human CD4(+) T cells that lack both SERINC3 and SERINC5, and re-expression experiments confirmed that the absence of SERINC3 and SERINC5 accounted for the infectivity enhancement. Furthermore, SERINC3 and SERINC5 together restricted HIV-1 replication, and this restriction was evaded by Nef. SERINC3 and SERINC5 are highly expressed in primary human HIV-1 target cells, and inhibiting their downregulation by Nef is a potential strategy to combat HIV/AIDS.
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Usami
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors.forename: Yuanfei
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors.forename: Heinrich G
authors.initials: HG
authors.lastname: Göttlinger
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002460:Cell Line; D015536:Down-Regulation; D017353:Gene Deletion; D015683:Gene Products, gag / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D015497:HIV-1 / Q000737:chemistry* / Q000187:drug effects / Q000254:growth & development / Q000502:physiology*; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D009052:Leukemia Virus, Murine / Q000737:chemistry; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism* / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism* / Q000494:pharmacology; D021381:Protein Transport; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism*; D014771:Virion / Q000737:chemistry / Q000187:drug effects / Q000254:growth & development / Q000502:physiology; D014779:Virus Replication / Q000187:drug effects; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000172:deficiency / Q000378:metabolism*
chemical_list: D015683:Gene Products, gag; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D011956:Receptors, Cell Surface; C103949:SERINC3 protein, human; C000602387:SERINC5 protein, human; D054311:nef Gene Products, Human Immunodeficiency Virus