Link between Primate Lentiviral Coreceptor Usage and Nef Function

• Type of Material: Article
• Authors: Jan Schmoekel, University of Ulm; Hui Li, University of Pennsylvania; Asma Shabir, University of Ulm; Hangxing Yu, University of Ulm; Matthias Geyer, Center of Advanced European Studies and Research (CAESAR); Guido Silvestri, Emory University; Donald L. Sodora, Seattle Biomedical Research Institute; Beatrice H. Hahn, University of Pennsylvania; Frank Kirchhoff, University of Ulm
• Language: English
• Date: 2013-11-01
• Publisher: Elsevier
• Publication Version: Final Published Version
• Copyright Statement: © 2013 The Authors. Published by Elsevier Inc.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1016/j.celrep.2013.10.028
• Title of Journal or Parent Work: Cell Reports
• ISSN: 2211-1247
• Volume: 5
• Issue: 4
• Start Page: 997
• End Page: 1009
• Grant/Funding Information: TZM-bl cells were obtained through the NIH AIDS Research and Reference Reagent Program.; This work was supported in part by the NIH (P01 AI 088564, R01 AI 050529, and R01 AI 066998) and the Deutsche Forschungsgemeinschaft (Leibniz award to F.K.).
• Keywords: ACTIVATION; CELL BIOLOGY; HOSTS; Science & Technology; AIDS PATHOGENESIS; CCR5; Life Sciences & Biomedicine; CD4(+) T-CELLS; SIV INFECTION; INDUCTION; SOOTY MANGABEYS; HIV-1; SIMIAN IMMUNODEFICIENCY VIRUS; Cell Biology
• Research Categories: Biology, Virology; Biology, Microbiology

Abstract

Simian immunodeficiency virus (SIVsmm) infection of sooty mangabeys (Cercocebus atys) is characterized by stable CD4 + Tcell counts despite high plasma levels of CCR5-tropic viruses. However, in rare instances, SIVsmm acquires CXCR4 coreceptor tropism and causes severe CD4 + Tcell depletion, albeit without clinical signs of immunodeficiency. Here, we show that CXCR4-tropic SIVsmm strains lost their ability to downmodulate TCR-CD3 by evolving unusual Nef mutations that initially reduced (I132V) and subsequently disrupted (I123L and L146F) interaction with the CD3 ζ chain. This coevolution of Env and Nef function suggests that CD3 downmodulation is advantageous for viral replication in activated CCR5 + memory Tcells, but not in resting naive CXCR4 + Tcells that have not yet undergone TCR-CD3-mediated stimulation. This may explain why HIV-1, which generally lacks the CD3 downmodulation function, commonly switches to CXCR4 usage, whereas this is extremely rare for SIV strains that have retained this Nef activity.