title: Enhanced antagonism of BST-2 by a neurovirulent SIV envelope.
abstract: Current antiretroviral therapy (ART) is not sufficient to completely suppress disease progression in the CNS, as indicated by the rising incidence of HIV-1-associated neurocognitive disorders (HAND) among infected individuals on ART. It is not clear why some HIV-1-infected patients develop HAND, despite effective repression of viral replication in the circulation. SIV-infected nonhuman primate models are widely used to dissect the mechanisms of viral pathogenesis in the CNS. Here, we identified 4 amino acid substitutions in the cytoplasmic tail of viral envelope glycoprotein gp41 of the neurovirulent virus SIVsm804E that enhance replication in macrophages and associate with enhanced antagonism of the host restriction factor BM stromal cell antigen 2 (BST-2). Rhesus macaques were inoculated with a variant of the parental virus SIVsmE543-3 that had been engineered to contain the 4 amino acid substitutions present in gp41 of SIVsm804E. Compared with WT virus-infected controls, animals infected with mutant virus exhibited higher viral load in cerebrospinal fluid. Together, these results are consistent with a potential role for BST-2 in the CNS microenvironment and suggest that BST-2 antagonists may serve as a possible target for countermeasures against HAND.
authors.forename: Kenta
authors.initials: K
authors.lastname: Matsuda
authors.forename: Chia-Yen
authors.initials: CY
authors.lastname: Chen
authors.forename: Sonya
authors.initials: S
authors.lastname: Whitted
authors.forename: Elena
authors.initials: E
authors.lastname: Chertova
authors.forename: David J
authors.initials: DJ
authors.lastname: Roser
authors.forename: Fan
authors.initials: F
authors.lastname: Wu
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Plishka
authors.forename: Ilnour
authors.initials: I
authors.lastname: Ourmanov
authors.forename: Alicia
authors.initials: A
authors.lastname: Buckler-White
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Lifson
authors.forename: Klaus
authors.initials: K
authors.lastname: Strebel
authors.forename: Vanessa M
authors.initials: VM
authors.lastname: Hirsch
mesh_terms: D015526:AIDS Dementia Complex / Q000209:etiology; D019943:Amino Acid Substitution; D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D004195:Disease Models, Animal; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D015497:HIV-1; D054884:Host-Pathogen Interactions; D006801:Humans; D008253:Macaca mulatta; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology; D012191:Retroviridae Proteins / Q000235:genetics / Q000502:physiology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D019562:Viral Load; D014774:Virulence / Q000235:genetics; D014779:Virus Replication / Q000235:genetics; D000074010:Bone Marrow Stromal Antigen 2
chemical_list: D015703:Antigens, CD; D058851:GPI-Linked Proteins; D008562:Membrane Glycoproteins; D012191:Retroviridae Proteins; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2; C082614:SIV envelope protein gp41