title: Elite Control, Gut CD4 T Cell Sparing, and Enhanced Mucosal T Cell Responses in Macaca nemestrina Infected by a Simian Immunodeficiency Virus Lacking a gp41 Trafficking Motif.
abstract: Deletion of Gly-720 and Tyr-721 from a highly conserved GYxxØ trafficking signal in the SIVmac239 envelope glycoprotein cytoplasmic domain, producing a virus termed ΔGY, leads to a striking perturbation in pathogenesis in rhesus macaques (Macaca mulatta). Infected macaques develop immune activation and progress to AIDS, but with only limited and transient infection of intestinal CD4(+) T cells and an absence of microbial translocation. Here we evaluated ΔGY in pig-tailed macaques (Macaca nemestrina), a species in which SIVmac239 infection typically leads to increased immune activation and more rapid progression to AIDS than in rhesus macaques. In pig-tailed macaques, ΔGY also replicated acutely to high peak plasma RNA levels identical to those for SIVmac239 and caused only transient infection of CD4(+) T cells in the gut lamina propria and no microbial translocation. However, in marked contrast to rhesus macaques, 19 of 21 pig-tailed macaques controlled ΔGY replication with plasma viral loads of <15 to 50 RNA copies/ml. CD4(+) T cells were preserved in blood and gut for up to 100 weeks with no immune activation or disease progression. Robust antiviral CD4(+) T cell responses were seen, particularly in the gut. Anti-CD8 antibody depletion demonstrated CD8(+) cellular control of viral replication. Two pig-tailed macaques progressed to disease with persisting viremia and possible compensatory mutations in the cytoplasmic tail. These studies demonstrate a marked perturbation in pathogenesis caused by ΔGY's ablation of the GYxxØ trafficking motif and reveal, paradoxically, that viral control is enhanced in a macaque species typically predisposed to more pathogenic manifestations of simian immunodeficiency virus (SIV) infection.
  
  
  OBJECTIVE
  The pathogenesis of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) reflects a balance between viral replication, host innate and adaptive antiviral immune responses, and sustained immune activation that in humans and Asian macaques is associated with persistent viremia, immune escape, and AIDS. Among nonhuman primates, pig-tailed macaques following SIV infection are predisposed to more rapid disease progression than are rhesus macaques. Here, we show that disruption of a conserved tyrosine-based cellular trafficking motif in the viral transmembrane envelope glycoprotein cytoplasmic tail leads in pig-tailed macaques to a unique phenotype in which high levels of acute viral replication are followed by elite control, robust cellular responses in mucosal tissues, and no disease. Paradoxically, control of this virus in rhesus macaques is only partial, and progression to AIDS occurs. This novel model should provide a powerful tool to help identify host-specific determinants for viral control with potential relevance for vaccine development.
authors.affiliation: Tulane National Primate Research Center, Covington, Louisiana, USA.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Breed
authors.affiliation: Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Samra E
authors.initials: SE
authors.lastname: Elser
authors.affiliation: Tulane National Primate Research Center, Covington, Louisiana, USA.
authors.forename: Workineh
authors.initials: W
authors.lastname: Torben
authors.affiliation: Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Andrea P O
authors.initials: AP
authors.lastname: Jordan
authors.affiliation: Tulane National Primate Research Center, Covington, Louisiana, USA.
authors.forename: Pyone P
authors.initials: PP
authors.lastname: Aye
authors.affiliation: Tulane National Primate Research Center, Covington, Louisiana, USA.
authors.forename: Cecily
authors.initials: C
authors.lastname: Midkiff
authors.affiliation: Tulane National Primate Research Center, Covington, Louisiana, USA.
authors.forename: Faith
authors.initials: F
authors.lastname: Schiro
authors.affiliation: Tulane National Primate Research Center, Covington, Louisiana, USA.
authors.forename: Chie
authors.initials: C
authors.lastname: Sugimoto
authors.affiliation: Tulane National Primate Research Center, Covington, Louisiana, USA.
authors.forename: Xavier
authors.initials: X
authors.lastname: Alvarez-Hernandez
authors.affiliation: Tulane National Primate Research Center, Covington, Louisiana, USA.
authors.forename: Robert V
authors.initials: RV
authors.lastname: Blair
authors.affiliation: Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Anoma
authors.initials: A
authors.lastname: Somasunderam
authors.affiliation: Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Netanya S
authors.initials: NS
authors.lastname: Utay
authors.affiliation: Tulane National Primate Research Center, Covington, Louisiana, USA.
authors.forename: Marcelo J
authors.initials: MJ
authors.lastname: Kuroda
authors.affiliation: Tulane National Primate Research Center, Covington, Louisiana, USA.
authors.forename: Bapi
authors.initials: B
authors.lastname: Pahar
authors.affiliation: University of Wisconsin National Primate Research Center, Madison, Wisconsin, USA.
authors.forename: Roger W
authors.initials: RW
authors.lastname: Wiseman
authors.affiliation: University of Wisconsin National Primate Research Center, Madison, Wisconsin, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: O'Connor
authors.affiliation: Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Celia C
authors.initials: CC
authors.lastname: LaBranche
authors.affiliation: Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College, London, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Marsh
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Piatak
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Lifson
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Brandon F
authors.initials: BF
authors.lastname: Keele
authors.affiliation: University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Patricia N
authors.initials: PN
authors.lastname: Fultz
authors.affiliation: Tulane National Primate Research Center, Covington, Louisiana, USA.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Lackner
authors.affiliation: Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA hoxie@mail.med.upenn.edu.
authors.forename: James A
authors.identifier: http://orcid.org/0000-0002-6257-4902
authors.initials: JA
authors.lastname: Hoxie
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D018928:Immunity, Mucosal; D007422:Intestines / Q000276:immunology / Q000821:virology; D008253:Macaca mulatta / Q000821:virology; D008254:Macaca nemestrina / Q000821:virology*; D008297:Male; D008969:Molecular Sequence Data; D009092:Mucous Membrane / Q000276:immunology / Q000821:virology; D021382:Protein Sorting Signals; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D017384:Sequence Deletion; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000473:pathology / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology; D013045:Species Specificity; D014759:Viral Envelope Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D019562:Viral Load / Q000235:genetics / Q000276:immunology; D014766:Viremia / Q000276:immunology / Q000473:pathology; D014779:Virus Replication / Q000235:genetics / Q000276:immunology
chemical_list: D021382:Protein Sorting Signals; D014759:Viral Envelope Proteins