Modulation of TCR-dependent NFAT signaling is impaired in HIV-1 Nef isolates from elite controllers

Virology. 2019 Apr:530:39-50. doi: 10.1016/j.virol.2019.02.008. Epub 2019 Feb 11.

Abstract

HIV-1 Nef modulates the activation state of CD4+ T cells by altering signaling events elicited by the T cell receptor (TCR). Primary nef sequences exhibit extensive inter-individual diversity that influences their ability to downregulate CD4 and HLA class I; however, the impact of nef variation on modulation of T cell signaling is poorly characterized. Here, we measured TCR-mediated activation of NFAT transcription factor in the presence of nef alleles isolated from 45 elite controllers (EC) and 46 chronic progressors (CP). EC Nef clones displayed lower ability to inhibit NFAT signaling (median 87 [IQR 75-93]% relative to SF2 Nef) compared to CP clones (94 [IQR 89-98]%) (p < 0.001). Polymorphisms in Nef's N-terminal domain impaired its ability to inhibit NFAT signaling. Results indicate that primary nef alleles exhibit a range of abilities to modulate TCR-dependent NFAT signaling, implicating natural variation in this function as a potential contributor to differential HIV-1 pathogenesis.

Keywords: HIV-1 controllers; NFAT; Nef; Signal transduction; T cell receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • HIV Infections / immunology*
  • HIV Infections / virology
  • HIV Long-Term Survivors*
  • Host-Pathogen Interactions*
  • Humans
  • NFATC Transcription Factors / antagonists & inhibitors*
  • Receptors, Antigen, T-Cell / metabolism*
  • Signal Transduction*
  • nef Gene Products, Human Immunodeficiency Virus / metabolism*

Substances

  • NFATC Transcription Factors
  • Receptors, Antigen, T-Cell
  • nef Gene Products, Human Immunodeficiency Virus
  • nef protein, Human immunodeficiency virus 1