SERINC3 and SERINC5 restrict HIV-1 infectivity and are counteracted by Nef

Nature. 2015 Oct 8;526(7572):218-23. doi: 10.1038/nature15400. Epub 2015 Sep 30.

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

  • Research Support, N.I.H., Extramural

MeSH terms

  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Line
  • Down-Regulation
  • Gene Deletion
  • Gene Products, gag / metabolism
  • HIV Infections / drug therapy
  • HIV Infections / virology
  • HIV-1 / chemistry*
  • HIV-1 / drug effects
  • HIV-1 / growth & development
  • HIV-1 / physiology*
  • Host-Pathogen Interactions / drug effects
  • Humans
  • Leukemia Virus, Murine / chemistry
  • Membrane Glycoproteins
  • Membrane Proteins / antagonists & inhibitors*
  • Membrane Proteins / deficiency
  • Membrane Proteins / metabolism*
  • Membrane Proteins / pharmacology
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / deficiency
  • Neoplasm Proteins / metabolism*
  • Neoplasm Proteins / pharmacology
  • Protein Transport
  • Receptors, Cell Surface / antagonists & inhibitors*
  • Receptors, Cell Surface / deficiency
  • Receptors, Cell Surface / metabolism*
  • Virion / chemistry
  • Virion / drug effects
  • Virion / growth & development
  • Virion / physiology
  • Virus Replication / drug effects
  • nef Gene Products, Human Immunodeficiency Virus / deficiency
  • nef Gene Products, Human Immunodeficiency Virus / metabolism*

Substances

  • Gene Products, gag
  • Membrane Glycoproteins
  • Membrane Proteins
  • Neoplasm Proteins
  • Receptors, Cell Surface
  • SERINC3 protein, human
  • SERINC5 protein, human
  • nef Gene Products, Human Immunodeficiency Virus