Species-specific host factors rather than virus-intrinsic virulence determine primate lentiviral pathogenicity

• Type of Material: Article
• Authors: Simone Joas, Ulm University; Erica H. Parrish, University of Pennsylvania; Clement W. Gnanadurai, Ulm University; Edina Lump, Ulm University; Christina M. Stuerzel, Ulm University; Nicholas F. Parrish, University of Pennsylvania; Gerald H. Learn, University of Pennsylvania; Urike Sauermann, German Primate Centre; Berit Neumann, German Primate Centre; Kerstin Matz Rensing, German Primate Centre; Dietmar Fuchs, Biocenter Innsbruck Medical University; James M. Billingsley, Emory University; Steven Bosinger, Emory University; Guido Silvestri, Emory University; Cristian Apetrei, University of Pittsburgh; Nicolas Huot, Unité HIV; Thalia Garcia-Tellez, Unité HIV; Michaela Mueller-Trutwin, Unité HIV; Dominik Hotter, Ulm University; Daniel Sauter, Ulm University; Chritiane Stahl-Hennig, German Primate Centre; Beatrice H. Hahn, University of Pennsylvania; Frank Kirchhoff, Ulm University
• Language: English
• Date: 2018-04-10
• Publisher: Nature Publishing Group: Nature Communications
• Publication Version: Final Published Version
• Copyright Statement: © 2018 The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-018-03762-3
• Title of Journal or Parent Work: Nature Communications
• ISSN: 2041-1723
• Volume: 9
• Issue: 1
• Start Page: 1371
• End Page: 1371
• Grant/Funding Information: This work was supported by NIH grants to B.H.H. (R37 AI50529, R01 AI 120810, R01 AI 114266), G.S. (R37 AI66998), and YYY (R01 AI 120860), and the BEAT-HIV Delaney Consortium (UM1 AI 126620), DFG CRC 1279 and SPP 1923, an Advanced ERC investigator grant to F.K., and a grant from Sidaction to M.M.-T. N.H. was supported by VRI (Créteil, France) and T.G.-T. by the Pasteur-Paris University PhD program.; We thank the IDMIT center for access to the stellar Imaging platform and acknowledge the Imagopole France–BioImaging infrastructure, supported by the French ANR (10-INSB-04-01, Investments for the Future), for advice and access to the CV1000 system. S.J. and E.L. were part of IGradU Ulm and S.J. was supported by the DFG RTG CEMMA.
• Keywords: INFECTED SOOTY MANGABEYS; SIMIAN-IMMUNODEFICIENCY-VIRUS; IN-VIVO; CD4 DOWN-REGULATION; T-CELL-ACTIVATION; SIV INFECTION; LYMPHOCYTE-ACTIVATION; NF-KAPPA-B; Science & Technology; HIV-1 VPU INTERFERENCE; Science & Technology - Other Topics; AFRICAN-GREEN MONKEYS; Multidisciplinary Sciences
• Research Categories: Biology, Microbiology; Biology, Virology; Chemistry, Biochemistry

Abstract

HIV-1 causes chronic inflammation and AIDS in humans, whereas related simian immunodeficiency viruses (SIVs) replicate efficiently in their natural hosts without causing disease. It is currently unknown to what extent virus-specific properties are responsible for these different clinical outcomes. Here, we incorporate two putative HIV-1 virulence determinants, i.e., a Vpu protein that antagonizes tetherin and blocks NF-κB activation and a Nef protein that fails to suppress T cell activation via downmodulation of CD3, into a non-pathogenic SIVagm strain and test their impact on viral replication and pathogenicity in African green monkeys. Despite sustained high-level viremia over more than 4 years, moderately increased immune activation and transcriptional signatures of inflammation, the HIV-1-like SIVagm does not cause immunodeficiency or any other disease. These data indicate that species-specific host factors rather than intrinsic viral virulence factors determine the pathogenicity of primate lentiviruses.