title: Central nervous system-specific consequences of simian immunodeficiency virus Gag escape from major histocompatibility complex class I-mediated control.
abstract: In the fourth decade of the HIV epidemic, the relationship between host immunity and HIV central nervous system (CNS) disease remains incompletely understood. Using a simian immunodeficiency virus (SIV)/macaque model, we examined CNS outcomes in pigtailed macaques expressing the MHC class I allele Mane-A1*084:01 which confers resistance to SIV-induced CNS disease and induces the prototypic viral escape mutation Gag K165R. Insertion of gag K165R into the neurovirulent clone SIV/17E-Fr reduced viral replication in vitro compared to SIV/17E-Fr. We also found lower cerebrospinal fluid (CSF), but not plasma, viral loads in macaques inoculated with SIV/17E-Fr K165R versus those inoculated with wildtype. Although escape mutation K165R was genotypically stable in plasma, it rapidly reverted to wildtype Gag KP9 in both CSF and in microglia cultures. We induced robust Gag KP9-specific CTL tetramer responses by vaccinating Mane-A*084:01-positive pigtailed macaques with a Gag KP9 virus-like particle (VLP) vaccine. Upon SIV/17E-Fr challenge, vaccinated animals had lower SIV RNA in CSF compared to unvaccinated controls, but showed no difference in plasma viral loads. These data clearly demonstrate that viral fitness in the CNS is distinct from the periphery and underscores the necessity of understanding the consequences of viral escape in CNS disease with the advent of new therapeutic vaccination strategies.
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University, Baltimore, MD, 21205, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Beck
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University, Baltimore, MD, 21205, USA.
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Queen
authors.affiliation: Department of Pediatrics, Johns Hopkins University, Baltimore, MD, 21205, USA.
authors.forename: Raphael
authors.initials: R
authors.lastname: Viscidi
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University, Baltimore, MD, 21205, USA.
authors.forename: Darius
authors.initials: D
authors.lastname: Johnson
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, Victoria, 3000, Australia.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kent
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University, Baltimore, MD, 21205, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Adams
authors.affiliation: Division of Biostatistics and Epidemiology, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, USA.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Tarwater
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University, Baltimore, MD, 21205, USA. jmankows@jhmi.edu.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Mankowski
mesh_terms: D000483:Alleles; D000818:Animals; D002490:Central Nervous System / Q000276:immunology / Q000821:virology; D015870:Gene Expression; D015683:Gene Products, gag / Q000235:genetics / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology*; D057131:Immune Evasion / Q000235:genetics; D008254:Macaca nemestrina / Q000276:immunology / Q000821:virology; D008297:Male; D017628:Microglia / Q000276:immunology / Q000821:virology; D009154:Mutation; D061251:Primary Cell Culture; D012367:RNA, Viral / Q000097:blood / Q000134:cerebrospinal fluid*; D018449:SAIDS Vaccines / Q000008:administration & dosage*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects / Q000276:immunology / Q000472:pathogenicity; D014611:Vaccination; D058425:Vaccines, Virus-Like Particle / Q000008:administration & dosage*; D019562:Viral Load / Q000276:immunology; D014779:Virus Replication / Q000276:immunology
chemical_list: D015683:Gene Products, gag; D015395:Histocompatibility Antigens Class I; D012367:RNA, Viral; D018449:SAIDS Vaccines; D058425:Vaccines, Virus-Like Particle
keywords: CNS; Escape; MHC class I; SIV; Viral compartmentalization