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

作者：Jacob Rajesh Abraham; Johnson Aaron L; Pawlak Emily N; Dirk Brennan S; Van Nynatten Logan R; Haeryfar S M Mansour; Dikeakos Jimmy D^*

来源：Virology, 2017, 509: 1-10.

DOI：10.1016/j.virol.2017.05.018

• HIV-1 Nef
• CD4(+)T cells
• Apoptosis
• Caspase-3
• Membrane trafficking
• AP-1
• AP-2

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-Tl. 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 (Nef(M20A) or Nef(EEEE62-65AAAA)) or Nef:AP-2 (Nef(LL164/165AA)), implying these interactions limit Nef-mediated apoptosis. In contrast, disrupting the Nef:PAK2 interaction motifs (Nef(H89A) or Nef(F191A)) reduced apoptosis. To validate further, apoptosis was measured after short-hairpin RNA knock-down of AP-1, AP-2 and PAK2. AP-2 alpha depletion enhanced apoptosis, demonstrating that disrupting the Nef:AP-2 alpha interaction limits Nef-mediated apoptosis. Collectively, we describe a mechanism by which HIV-I regulates cell survival and demonstrate the consequence of interfering with Nef:host protein interactions.

• 出版日期2017-9