Nef-Mediated CD3-TCR Downmodulation Dampens Acute Inflammation and Promotes SIV Immune Evasion

Cell Rep. 2020 Feb 18;30(7):2261-2274.e7. doi: 10.1016/j.celrep.2020.01.069.

Abstract

The inability of Nef to downmodulate the CD3-T cell receptor (TCR) complex distinguishes HIV-1 from other primate lentiviruses and may contribute to its high virulence. However, the role of this Nef function in virus-mediated immune activation and pathogenicity remains speculative. Here, we selectively disrupted this Nef activity in SIVmac239 and analyzed the consequences for the virological, immunological, and clinical outcome of infection in rhesus macaques. The inability to downmodulate CD3-TCR does not impair viral replication during acute infection but is associated with increased immune activation and antiviral gene expression. Subsequent early reversion in three of six animals suggests strong selective pressure for this Nef function and is associated with high viral loads and progression to simian AIDS. In the absence of reversions, however, viral replication and the clinical course of infection are attenuated. Thus, Nef-mediated downmodulation of CD3 dampens the inflammatory response to simian immunodeficiency virus (SIV) infection and seems critical for efficient viral immune evasion.

Keywords: AIDS; CD3-TCR signaling; Nef function; SIV/macaque model; inflammation; viral immune evasion.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • Gene Products, nef
  • Immune Evasion / immunology*
  • Inflammation / immunology
  • Inflammation / pathology
  • Macaca mulatta
  • Male
  • Receptor-CD3 Complex, Antigen, T-Cell / immunology*
  • Receptor-CD3 Complex, Antigen, T-Cell / metabolism
  • Simian Immunodeficiency Virus / immunology
  • Viral Regulatory and Accessory Proteins / metabolism*

Substances

  • Gene Products, nef
  • Receptor-CD3 Complex, Antigen, T-Cell
  • Viral Regulatory and Accessory Proteins