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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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CD4-Positive T-Lymphocytes / metabolism
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Cell Line
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Down-Regulation
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Gene Deletion
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Gene Products, gag / metabolism
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HIV Infections / drug therapy
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HIV Infections / virology
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HIV-1 / chemistry*
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HIV-1 / drug effects
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HIV-1 / growth & development
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HIV-1 / physiology*
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Host-Pathogen Interactions / drug effects
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Humans
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Leukemia Virus, Murine / chemistry
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Membrane Glycoproteins
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Membrane Proteins / antagonists & inhibitors*
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Membrane Proteins / deficiency
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Membrane Proteins / metabolism*
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Membrane Proteins / pharmacology
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / deficiency
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Neoplasm Proteins / metabolism*
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Neoplasm Proteins / pharmacology
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Protein Transport
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Receptors, Cell Surface / antagonists & inhibitors*
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Receptors, Cell Surface / deficiency
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Receptors, Cell Surface / metabolism*
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Virion / chemistry
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Virion / drug effects
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Virion / growth & development
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Virion / physiology
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Virus Replication / drug effects
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nef Gene Products, Human Immunodeficiency Virus / deficiency
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nef Gene Products, Human Immunodeficiency Virus / metabolism*
Substances
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Gene Products, gag
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Membrane Glycoproteins
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Membrane Proteins
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Neoplasm Proteins
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Receptors, Cell Surface
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SERINC3 protein, human
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SERINC5 protein, human
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nef Gene Products, Human Immunodeficiency Virus