Infection with "escaped" virus variants impairs control of simian immunodeficiency virus SIVmac239 replication in Mamu-B*08-positive macaques

Laura E. Valentine, John T. Loffredo, Alex T. Bean, Enrique J. Leon, Caitlin E. MacNair, Dominic R. Beal, Shari M. Piaskowski, Yann C. Klimentidis, Simon M. Lank, Roger W. Wiseman, Jason T. Weinfurter, Gemma E. May, Eva G. Rakasz, Nancy A. Wilson, Thomas C. Friedrich, David H. O'Connor, David B. Allison, David Watkins

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

An understanding of the mechanism(s) by which some individuals spontaneously control human immuno-deficiency virus (HIV)/simian immunodeficiency virus replication may aid vaccine design. Approximately 50% of Indian rhesus macaques that express the major histocompatibility complex (MHC) class I allele Mamu-B*08 become elite controllers after infection with simian immunodeficiency virus SIVmac239. Mamu-B*08 has a binding motif that is very similar to that of HLA-B27, a human MHC class I allele associated with the elite control of HIV, suggesting that SIVmac239-infected Mamu-B*08-positive (Mamu-B*08+) animals may be a good model for the elite control of HIV. The association with MHC class I alleles implicates CD8+ T cells and/or natural killer cells in the control of viral replication. We therefore introduced point mutations into eight Mamu-B*08-restricted CD8+ T-cell epitopes to investigate the contribution of epitope-specific CD8+ T-cell responses to the development of the control of viral replication. Ten Mamu-B*08+ macaques were infected with this mutant virus, 8X-SIVmac239. We compared immune responses and viral loads of these animals to those of wild-type SIVmac239-infected Mamu-B*08+ macaques. The five most immunodominant Mamu-B*08-restricted CD8+ T-cell responses were barely detectable in 8X-SIVmac239-infected animals. By 48 weeks postinfection, 2 of 10 8X-SIVmac239-infected Mamu-B*08+ animals controlled viral replication to <20,000 viral RNA (vRNA) copy equivalents (eq)/ml plasma, while 10 of 15 wild-type-infected Mamu-B*08+ animals had viral loads of <20,000 vRNA copy eq/ml (P = 0.04). Our results suggest that these epitope-specific CD8+ T-cell responses may play a role in establishing the control of viral replication in Mamu-B*08+ macaques.

Original languageEnglish
Pages (from-to)11514-11527
Number of pages14
JournalJournal of Virology
Volume83
Issue number22
DOIs
StatePublished - Nov 1 2009
Externally publishedYes

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ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Valentine, L. E., Loffredo, J. T., Bean, A. T., Leon, E. J., MacNair, C. E., Beal, D. R., Piaskowski, S. M., Klimentidis, Y. C., Lank, S. M., Wiseman, R. W., Weinfurter, J. T., May, G. E., Rakasz, E. G., Wilson, N. A., Friedrich, T. C., O'Connor, D. H., Allison, D. B., & Watkins, D. (2009). Infection with "escaped" virus variants impairs control of simian immunodeficiency virus SIVmac239 replication in Mamu-B*08-positive macaques. Journal of Virology, 83(22), 11514-11527. https://doi.org/10.1128/JVI.01298-09