The interaction between HIV-1 Nef and adaptor protein-2 reduces Nef-mediated CD4+ T cell apoptosis

Virology. 2017 Sep:509:1-10. doi: 10.1016/j.virol.2017.05.018. Epub 2017 Jun 1.

Abstract

Acquired Immune Deficiency Syndrome is characterized by a decline in CD4+ T cells. Here, we elucidated the mechanism underlying apoptosis in Human Immunodeficiency Virus-1 (HIV-1) infection by examining host apoptotic pathways hijacked by the HIV-1 Nef protein in the CD4+ T-cell line Sup-T1. Using a panel of Nef mutants unable to bind specific host proteins we uncovered that Nef generates pro- and anti-apoptotic signals. Apoptosis increased upon mutating the motifs involved in the interaction of Nef:AP-1 (NefM20A or NefEEEE62-65AAAA) or Nef:AP-2 (NefLL164/165AA), implying these interactions limit Nef-mediated apoptosis. In contrast, disrupting the Nef:PAK2 interaction motifs (NefH89A or NefF191A) reduced apoptosis. To validate further, apoptosis was measured after short-hairpin RNA knock-down of AP-1, AP-2 and PAK2. AP-2α depletion enhanced apoptosis, demonstrating that disrupting the Nef:AP-2α interaction limits Nef-mediated apoptosis. Collectively, we describe a mechanism by which HIV-1 regulates cell survival and demonstrate the consequence of interfering with Nef:host protein interactions.

Keywords: AP-1; AP-2; Apoptosis; CD4(+) T cells; Caspase-3; HIV-1 Nef; Membrane trafficking.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Protein Complex 2 / metabolism*
  • Apoptosis*
  • CD4-Positive T-Lymphocytes / physiology*
  • CD4-Positive T-Lymphocytes / virology*
  • Cell Line
  • DNA Mutational Analysis
  • HIV-1 / pathogenicity*
  • Host-Pathogen Interactions*
  • Humans
  • nef Gene Products, Human Immunodeficiency Virus / genetics
  • nef Gene Products, Human Immunodeficiency Virus / metabolism*

Substances

  • Adaptor Protein Complex 2
  • nef Gene Products, Human Immunodeficiency Virus
  • nef protein, Human immunodeficiency virus 1

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