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

• Published in: Cell reports (Cambridge) Vol. 30; no. 7; pp. 2261 - 2274.e7
• Main Authors: Joas, Simone, Sauermann, Ulrike, Roshani, Berit, Klippert, Antonina, Daskalaki, Maria, Mätz-Rensing, Kerstin, Stolte-Leeb, Nicole, Heigele, Anke, Tharp, Gregory K., Gupta, Prachi Mehrotra, Nelson, Sydney, Bosinger, Steven, Parodi, Laura, Giavedoni, Luis, Silvestri, Guido, Sauter, Daniel, Stahl-Hennig, Christiane, Kirchhoff, Frank
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18-02-2020; Elsevier
• Subjects: AIDS; Animals; CD3-TCR signaling; Female; Gene Products, nef; Immune Evasion - immunology; inflammation; Inflammation - immunology; Inflammation - pathology; Macaca mulatta; Male; Nef function; Receptor-CD3 Complex, Antigen, T-Cell - immunology; Receptor-CD3 Complex, Antigen, T-Cell - metabolism; Simian Immunodeficiency Virus - immunology; SIV/macaque model; viral immune evasion; Viral Regulatory and Accessory Proteins - metabolism; AIDS; Nef function; SIV/macaque model; viral immune evasion; inflammation; CD3-TCR signaling
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.01.069

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.
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•Mutation of I123L and L146F specifically disrupts CD3 downmodulation by SIVmac Nef•Lack of CD3 modulation by Nef increases the inflammatory response to SIV infection•Increased immune activation aggravates the course of infection if SIV evades control•Nef-mediated CD3 downmodulation seems critical for effective immune evasion of SIV
HIV-1 lacks the CD3 downmodulation function of Nef that is otherwise conserved in primate lentiviruses. Joas et al. disrupted this Nef activity in SIVmac239 and show that Nef-mediated downmodulation of CD3 dampens inflammatory responses to SIV. This promotes effective immune evasion and maintenance of high viral loads in infected rhesus macaques.