title: 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.
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.
authors.affiliation: Tulane National Primate Research Center, Covington, Louisiana, USA.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Breed
authors.forename: Andrea P O
authors.initials: AP
authors.lastname: Jordan
authors.forename: Pyone P
authors.initials: PP
authors.lastname: Aye
authors.forename: Cornelis F
authors.initials: CF
authors.lastname: Lichtveld
authors.forename: Cecily C
authors.initials: CC
authors.lastname: Midkiff
authors.forename: Faith R
authors.initials: FR
authors.lastname: Schiro
authors.forename: Beth S
authors.initials: BS
authors.lastname: Haggarty
authors.forename: Chie
authors.initials: C
authors.lastname: Sugimoto
authors.forename: Xavier
authors.initials: X
authors.lastname: Alvarez
authors.forename: Netanya G
authors.initials: NG
authors.lastname: Sandler
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.forename: Marcelo J
authors.initials: MJ
authors.lastname: Kuroda
authors.forename: Bapi
authors.initials: B
authors.lastname: Pahar
authors.forename: Michael
authors.initials: M
authors.lastname: Piatak
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Lifson
authors.forename: Brandon F
authors.initials: BF
authors.lastname: Keele
authors.forename: James A
authors.initials: JA
authors.lastname: Hoxie
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Lackner
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D002490:Central Nervous System / Q000821:virology; D018450:Disease Progression; D005260:Female; D041981:Gastrointestinal Tract / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology; D008253:Macaca mulatta; D008264:Macrophages / Q000821:virology; D008297:Male; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D012367:RNA, Viral / Q000235:genetics; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000472:pathogenicity*; D014759:Viral Envelope Proteins / Q000235:genetics / Q000378:metabolism*; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D050505:Mutant Proteins; D012367:RNA, Viral; D014759:Viral Envelope Proteins; D037521:Virulence Factors