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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.

Publication ,  Journal Article
Breed, MW; Elser, SE; Torben, W; Jordan, APO; Aye, PP; Midkiff, C; Schiro, F; Sugimoto, C; Alvarez-Hernandez, X; Blair, RV; Somasunderam, A ...
Published in: J Virol
October 2015

UNLABELLED: 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. IMPORTANCE: 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.

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Published In

J Virol

DOI

EISSN

1098-5514

Publication Date

October 2015

Volume

89

Issue

20

Start / End Page

10156 / 10175

Location

United States

Related Subject Headings

  • Virus Replication
  • Virology
  • Viremia
  • Viral Load
  • Viral Envelope Proteins
  • Species Specificity
  • Simian immunodeficiency virus
  • Simian Immunodeficiency Virus
  • Simian Acquired Immunodeficiency Syndrome
  • Sequence Deletion
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Breed, M. W., Elser, S. E., Torben, W., Jordan, A. P. O., Aye, P. P., Midkiff, C., … Hoxie, J. A. (2015). 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. J Virol, 89(20), 10156–10175. https://doi.org/10.1128/JVI.01134-15
Breed, Matthew W., Samra E. Elser, Workineh Torben, Andrea P. O. Jordan, Pyone P. Aye, Cecily Midkiff, Faith Schiro, et al. “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.J Virol 89, no. 20 (October 2015): 10156–75. https://doi.org/10.1128/JVI.01134-15.
Breed, Matthew W., et al. “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.J Virol, vol. 89, no. 20, Oct. 2015, pp. 10156–75. Pubmed, doi:10.1128/JVI.01134-15.
Breed MW, Elser SE, Torben W, Jordan APO, Aye PP, Midkiff C, Schiro F, Sugimoto C, Alvarez-Hernandez X, Blair RV, Somasunderam A, Utay NS, Kuroda MJ, Pahar B, Wiseman RW, O’Connor DH, LaBranche CC, Montefiori DC, Marsh M, Li Y, Piatak M, Lifson JD, Keele BF, Fultz PN, Lackner AA, Hoxie JA. 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. J Virol. 2015 Oct;89(20):10156–10175.

Published In

J Virol

DOI

EISSN

1098-5514

Publication Date

October 2015

Volume

89

Issue

20

Start / End Page

10156 / 10175

Location

United States

Related Subject Headings

  • Virus Replication
  • Virology
  • Viremia
  • Viral Load
  • Viral Envelope Proteins
  • Species Specificity
  • Simian immunodeficiency virus
  • Simian Immunodeficiency Virus
  • Simian Acquired Immunodeficiency Syndrome
  • Sequence Deletion