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

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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.

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Authors and Affiliations

  1. Department of Molecular and Comparative Pathobiology, Johns Hopkins University, Baltimore, MD, 21205, USA

    Sarah E. Beck, Suzanne E. Queen, Darius Johnson, Robert J. Adams & Joseph L. Mankowski

  2. Department of Pediatrics, Johns Hopkins University, Baltimore, MD, 21205, USA

    Raphael Viscidi

  3. Department of Microbiology and Immunology, University of Melbourne, Victoria, 3000, Australia

    Stephen J. Kent

  4. Division of Biostatistics and Epidemiology, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, USA

    Patrick M. Tarwater

Authors
  1. Sarah E. Beck
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  2. Suzanne E. Queen
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  3. Raphael Viscidi
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  4. Darius Johnson
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  5. Stephen J. Kent
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  6. Robert J. Adams
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  7. Patrick M. Tarwater
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  8. Joseph L. Mankowski
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Corresponding author

Correspondence to Joseph L. Mankowski.

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Compliance with ethical standards

These studies were approved by the Johns Hopkins University Institutional Animal Care and Use Committee.

Financial support

This work was supported by the NIH grants R01 NS089482, R01 NS077869, P01 MH070306, P40 OD013117, and T32 OD011089.

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The authors declare that they have no conflict of interest.

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Beck, S.E., Queen, S.E., Viscidi, R. et al. Central nervous system-specific consequences of simian immunodeficiency virus Gag escape from major histocompatibility complex class I-mediated control. J. Neurovirol. 22, 498–507 (2016). https://doi.org/10.1007/s13365-015-0420-5

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  • DOI: https://doi.org/10.1007/s13365-015-0420-5

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