IMMUNE SELECTION IN THE CNS: CONSEQUENCES OF SIV GAG ESCAPE FROM MHC CLASS I-MEDIATED CONTROL
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Date
2014-03-21
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Johns Hopkins University
Abstract
Immune pressure exerted by host factors including MHC class I-mediated cytotoxic T cell control affects HIV disease progression and drives the development of viral escape mutations; nonetheless, the relationship between host immunity and HIV central nervous system (CNS) disease remains poorly understood. The simian immunodeficiency virus (SIV) macaque model recapitulates key features of HIV infection including development of AIDS and CNS disease. To investigate host factors regulating SIV CNS disease progression, we compared the incidence of SIV encephalitis and the effects of MHC class I allele expression on the development of CNS disease in pigtailed macaques versus rhesus macaques. Species-specific differences in susceptibility to SIV disease demonstrated that host factors are critical to SIV CNS disease progression. We extended these studies by examining CNS pathogenesis in pigtailed macaques expressing the MHC-I allele Mane-A1*084:01:01, which confers resistance to SIV-induced CNS disease in pigtailed macaques and induces viral development of prototypic escape (K165R) in the immunodominant SIV Gag KP9 epitope. Insertion of the Gag K165R escape mutation into molecularly cloned SIV/17E-Fr resulted in reduced viral replication compared to wildtype SIV/17E-Fr in vitro. To investigate viral fitness in vivo, we inoculated six Mane-A1*084:01:01 expressing macaques: three with SIV/17E-Fr K165R, and three with wildtype, parental SIV/17E-Fr. We found lower CSF, but not plasma, viral loads in animals inoculated with SIV/17E-Fr K165R versus those inoculated with wildtype, and although the escape mutation K165R was genotypically stable in the plasma, it rapidly reverted to wildtype Gag KP9 in both CSF and in microglia. To induce Gag KP9-specific CTL immune pressure, we vaccinated two Mane-A*084:01:01 expressing pigtailed macaques with Gag KP9 peptide loaded onto a virus-like particle (VLP) vaccine. Both animals developed robust KP9-specific tetramer responses to vaccination, and upon challenge with SIV/17E-Fr, developed lower viral replication in the CSF but not the plasma. These data clearly demonstrate that viral fitness in the CNS is distinct from the periphery. As therapeutic vaccination strategies to enhance CTL responses against HIV Gag could promote HIV escape, it is vital that we understand the consequences of viral escape on CNS disease.
Thesis Advisor: Joseph L. Mankowski, D.V.M., Ph.D., D.A.C.V.P. (jmankows@jhmi.edu)
Thesis Reader: Joel M. Blankson, M.D., Ph.D. (committee chair, jblanks@jhmi.edu)
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SIV, MHC class I, encephalitis