Abstract
SUMMARYThe 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.
Highlights
T cell receptor (TCR) signaling in response to antigen recognition plays a key role in the immune response and is modulated by numerous viral pathogens (Jerome, 2008)
Specific Disruption of the CD3 Downmodulation Function of SIVmac239 Nef Given that primate lentiviral Nef proteins differ fundamentally in their ability to downmodulate CD3-TCR cell surface expression, it seemed paradoxical that this function maps to the highly conserved core region of otherwise highly variable primate lentiviral Nef proteins (Iafrate et al, 1997; Schaefer et al, 2002)
These findings suggested that specific amino acid changes located at the rim of the hydrophobic pocket in the core region of Nef affect CD3-TCR downmodulation
Summary
T cell receptor (TCR) signaling in response to antigen recognition plays a key role in the immune response and is modulated by numerous viral pathogens (Jerome, 2008). HIV-1 and its SIV precursors infecting chimpanzees and gorillas (SIVcpz and SIVgor) entirely lost the CD3-TCR downmodulation function of Nef (Schindler et al, 2006) These viruses boost rather than prevent the responsiveness of infected CD4+ T cells to CD3-TCR-mediated stimulation by APCs (Arhel et al, 2009; Fenard et al, 2005; Fortin et al, 2004). The loss of this Nef function in the primate lentiviral lineage that gave rise to HIV-1 was most likely facilitated by the acquisition of a vpu gene (Heusinger and Kirchhoff, 2017; Kirchhoff, 2009), because Vpu and Nef-mediated downmodulation of CD3 both suppress nuclear factor kB (NF-kB)-driven antiviral gene expression (Hotter et al, 2017; Langer et al, 2019; Sauter et al, 2015)
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