Loss of a tyrosine-dependent trafficking motif in the simian immunodeficiency virus envelope cytoplasmic tail spares mucosal CD4 cells but does not prevent disease progression

Matthew W. Breed, Andrea P O Jordan, Pyone P. Aye, Cornelis F. Lichtveld, Cecily C. Midkiff, Faith R. Schiro, Beth S. Haggarty, Chie Sugimoto, Xavier Alvarez, Netanya G. Sandler, Daniel C. Douek, Marcelo J. Kuroda, Bapi Pahar, Michael Piatak, Jeffrey D. Lifson, Brandon F. Keele, James A. Hoxie, Andrew A. Lackner

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

A hallmark of pathogenic simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) infections is the rapid and near-complete depletion of mucosal CD4+ T lymphocytes from the gastrointestinal tract. Loss of these cells and disruption of epithelial barrier function are associated with microbial translocation, which has been proposed to drive chronic systemic immune activation and disease progression. Here, we evaluate in rhesus macaques a novel attenuated variant of pathogenic SIVmac239, termed δGY, which contains a deletion of a Tyr and a proximal Gly from a highly conserved Yxxø trafficking motif in the envelope cytoplasmic tail. Compared to SIVmac239, δGY established a comparable acute peak of viremia but only transiently infected lamina propria and caused little or no acute depletion of mucosal CD4+ T cells and no detectable microbial translocation. Nonetheless, these animals developed T-cell activation and declining peripheral blood CD4+ T cells and ultimately progressed with clinical or pathological features of AIDS. δGY-infected animals also showed no infection of macrophages or central nervous system tissues even in late-stage disease. Although the δGY mutation persisted, novel mutations evolved, including the formation of new Yxxø motifs in two of four animals. These findings indicate that disruption of this trafficking motif by the δGY mutation leads to a striking alteration in anatomic distribution of virus with sparing of lamina propria and a lack of microbial translocation. Because these animals exhibited wild-type levels of acute viremia and immune activation, our findings indicate that these pathological events are dissociable and that immune activation unrelated to gut damage can be sufficient for the development of AIDS.

Original languageEnglish (US)
Pages (from-to)1528-1543
Number of pages16
JournalJournal of Virology
Volume87
Issue number3
DOIs
StatePublished - Feb 2013
Externally publishedYes

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Simian immunodeficiency virus
Simian Immunodeficiency Virus
disease course
Tyrosine
tyrosine
Disease Progression
Tail
tail
T-lymphocytes
T-Lymphocytes
Viremia
viremia
laminae (animals)
mutation
Mutation
Mucous Membrane
Acquired Immunodeficiency Syndrome
cells
Nerve Tissue
animals

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Loss of a tyrosine-dependent trafficking motif in the simian immunodeficiency virus envelope cytoplasmic tail spares mucosal CD4 cells but does not prevent disease progression. / Breed, Matthew W.; Jordan, Andrea P O; Aye, Pyone P.; Lichtveld, Cornelis F.; Midkiff, Cecily C.; Schiro, Faith R.; Haggarty, Beth S.; Sugimoto, Chie; Alvarez, Xavier; Sandler, Netanya G.; Douek, Daniel C.; Kuroda, Marcelo J.; Pahar, Bapi; Piatak, Michael; Lifson, Jeffrey D.; Keele, Brandon F.; Hoxie, James A.; Lackner, Andrew A.

In: Journal of Virology, Vol. 87, No. 3, 02.2013, p. 1528-1543.

Research output: Contribution to journalArticle

Breed, MW, Jordan, APO, Aye, PP, Lichtveld, CF, Midkiff, CC, Schiro, FR, Haggarty, BS, Sugimoto, C, Alvarez, X, Sandler, NG, Douek, DC, Kuroda, MJ, Pahar, B, Piatak, M, Lifson, JD, Keele, BF, Hoxie, JA & Lackner, AA 2013, 'Loss of a tyrosine-dependent trafficking motif in the simian immunodeficiency virus envelope cytoplasmic tail spares mucosal CD4 cells but does not prevent disease progression', Journal of Virology, vol. 87, no. 3, pp. 1528-1543. https://doi.org/10.1128/JVI.01928-12
Breed, Matthew W. ; Jordan, Andrea P O ; Aye, Pyone P. ; Lichtveld, Cornelis F. ; Midkiff, Cecily C. ; Schiro, Faith R. ; Haggarty, Beth S. ; Sugimoto, Chie ; Alvarez, Xavier ; Sandler, Netanya G. ; Douek, Daniel C. ; Kuroda, Marcelo J. ; Pahar, Bapi ; Piatak, Michael ; Lifson, Jeffrey D. ; Keele, Brandon F. ; Hoxie, James A. ; Lackner, Andrew A. / Loss of a tyrosine-dependent trafficking motif in the simian immunodeficiency virus envelope cytoplasmic tail spares mucosal CD4 cells but does not prevent disease progression. In: Journal of Virology. 2013 ; Vol. 87, No. 3. pp. 1528-1543.
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abstract = "A hallmark of pathogenic simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) infections is the rapid and near-complete depletion of mucosal CD4+ T lymphocytes from the gastrointestinal tract. Loss of these cells and disruption of epithelial barrier function are associated with microbial translocation, which has been proposed to drive chronic systemic immune activation and disease progression. Here, we evaluate in rhesus macaques a novel attenuated variant of pathogenic SIVmac239, termed δGY, which contains a deletion of a Tyr and a proximal Gly from a highly conserved Yxx{\o} trafficking motif in the envelope cytoplasmic tail. Compared to SIVmac239, δGY established a comparable acute peak of viremia but only transiently infected lamina propria and caused little or no acute depletion of mucosal CD4+ T cells and no detectable microbial translocation. Nonetheless, these animals developed T-cell activation and declining peripheral blood CD4+ T cells and ultimately progressed with clinical or pathological features of AIDS. δGY-infected animals also showed no infection of macrophages or central nervous system tissues even in late-stage disease. Although the δGY mutation persisted, novel mutations evolved, including the formation of new Yxx{\o} motifs in two of four animals. These findings indicate that disruption of this trafficking motif by the δGY mutation leads to a striking alteration in anatomic distribution of virus with sparing of lamina propria and a lack of microbial translocation. Because these animals exhibited wild-type levels of acute viremia and immune activation, our findings indicate that these pathological events are dissociable and that immune activation unrelated to gut damage can be sufficient for the development of AIDS.",
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AU - Breed, Matthew W.

AU - Jordan, Andrea P O

AU - Aye, Pyone P.

AU - Lichtveld, Cornelis F.

AU - Midkiff, Cecily C.

AU - Schiro, Faith R.

AU - Haggarty, Beth S.

AU - Sugimoto, Chie

AU - Alvarez, Xavier

AU - Sandler, Netanya G.

AU - Douek, Daniel C.

AU - Kuroda, Marcelo J.

AU - Pahar, Bapi

AU - Piatak, Michael

AU - Lifson, Jeffrey D.

AU - Keele, Brandon F.

AU - Hoxie, James A.

AU - Lackner, Andrew A.

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N2 - A hallmark of pathogenic simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) infections is the rapid and near-complete depletion of mucosal CD4+ T lymphocytes from the gastrointestinal tract. Loss of these cells and disruption of epithelial barrier function are associated with microbial translocation, which has been proposed to drive chronic systemic immune activation and disease progression. Here, we evaluate in rhesus macaques a novel attenuated variant of pathogenic SIVmac239, termed δGY, which contains a deletion of a Tyr and a proximal Gly from a highly conserved Yxxø trafficking motif in the envelope cytoplasmic tail. Compared to SIVmac239, δGY established a comparable acute peak of viremia but only transiently infected lamina propria and caused little or no acute depletion of mucosal CD4+ T cells and no detectable microbial translocation. Nonetheless, these animals developed T-cell activation and declining peripheral blood CD4+ T cells and ultimately progressed with clinical or pathological features of AIDS. δGY-infected animals also showed no infection of macrophages or central nervous system tissues even in late-stage disease. Although the δGY mutation persisted, novel mutations evolved, including the formation of new Yxxø motifs in two of four animals. These findings indicate that disruption of this trafficking motif by the δGY mutation leads to a striking alteration in anatomic distribution of virus with sparing of lamina propria and a lack of microbial translocation. Because these animals exhibited wild-type levels of acute viremia and immune activation, our findings indicate that these pathological events are dissociable and that immune activation unrelated to gut damage can be sufficient for the development of AIDS.

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