Central nervous system-specific consequences of simian immunodeficiency virus Gag escape from major histocompatibility complex class I-mediated control

Sarah E. Beck, Suzanne E. Queen, Raphael Viscidi, Darius Johnson, Stephen J. Kent, Robert J. Adams, Patrick M. Tarwater, Joseph L. Mankowski

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)498-507
Number of pages10
JournalJournal of neurovirology
Volume22
Issue number4
DOIs
StatePublished - Aug 1 2016

Keywords

  • CNS
  • Escape
  • MHC class I
  • SIV
  • Viral compartmentalization

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience
  • Virology

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