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Vaccine-induced CD8+ T cells control AIDS virus replication

Abstract

Developing a vaccine for human immunodeficiency virus (HIV) may be aided by a complete understanding of those rare cases in which some HIV-infected individuals control replication of the virus1,2,3. Most of these elite controllers express the histocompatibility alleles HLA-B*57 or HLA-B*27 (ref. 3). These alleles remain by far the most robust associations with low concentrations of plasma virus4,5, yet the mechanism of control in these individuals is not entirely clear. Here we vaccinate Indian rhesus macaques that express Mamu-B*08, an animal model for HLA-B*27-mediated elite control6, with three Mamu-B*08-restricted CD8+ T-cell epitopes, and demonstrate that these vaccinated animals control replication of the highly pathogenic clonal simian immunodeficiency virus (SIV) mac239 virus. High frequencies of CD8+ T cells against these Vif and Nef epitopes in the blood, lymph nodes and colon were associated with viral control. Moreover, the frequency of the CD8+ T-cell response against the Nef RL10 epitope (Nef amino acids 137–146) correlated significantly with reduced acute phase viraemia. Finally, two of the eight vaccinees lost control of viral replication in the chronic phase, concomitant with escape in all three targeted epitopes, further implicating these three CD8+ T-cell responses in the control of viral replication. Our findings indicate that narrowly targeted vaccine-induced virus-specific CD8+ T-cell responses can control replication of the AIDS virus.

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Figure 1: Experimental design.
Figure 2: In vivo viral replication.
Figure 3: CD8 + T-cell responses in vaccinated animals after SIVmac239 infection.

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Sequence Read Archive

Data deposits

The sequence data for this study are available at the NCBI Sequence Read Archive (http://www.ncbi.nlm.nih.gov/Traces/sra) under accession number SRA055739.

References

  1. Deeks, S. G. & Walker, B. D. Human immunodeficiency virus controllers: mechanisms of durable virus control in the absence of antiretroviral therapy. Immunity 27, 406–416 (2007)

    CAS  Google Scholar 

  2. Goulder, P. J. & Watkins, D. I. HIV and SIV CTL escape: implications for vaccine design. Nature Rev. Immunol. 4, 630–640 (2004)

    CAS  Article  Google Scholar 

  3. Migueles, S. A. & Connors, M. Long-term nonprogressive disease among untreated HIV-infected individuals: clinical implications of understanding immune control of HIV. J. Am. Med. Assoc. 304, 194–201 (2010)

    CAS  Article  Google Scholar 

  4. Fellay, J. et al. A whole-genome association study of major determinants for host control of HIV-1. Science 317, 944–947 (2007)

    ADS  CAS  Article  Google Scholar 

  5. The International HIV Controllers Study. The major genetic determinants of HIV-1 control affect HLA class I peptide presentation. Science 330, 1551–1557 (2010)

  6. Loffredo, J. T. et al. Two MHC class I molecules associated with elite control of immunodeficiency virus replication, Mamu-B*08 and HLA-B*2705, bind peptides with sequence similarity. J. Immunol. 182, 7763–7775 (2009)

    CAS  Article  Google Scholar 

  7. Johnston, M. I. & Fauci, A. S. An HIV vaccine–challenges and prospects. N. Engl. J. Med. 359, 888–890 (2008)

    CAS  Article  Google Scholar 

  8. Mudd, P. A. & Watkins, D. I. Understanding animal models of elite control: windows on effective immune responses against immunodeficiency viruses. Curr. Opin. HIV AIDS 6, 197–201 (2011)

    Article  Google Scholar 

  9. Loffredo, J. T. et al. Mamu-B*08-positive macaques control simian immunodeficiency virus replication. J. Virol. 81, 8827–8832 (2007)

    CAS  Article  Google Scholar 

  10. Valentine, L. E. et al. Infection with “escaped” virus variants impairs control of simian immunodeficiency virus SIVmac239 replication in Mamu-B*08-positive macaques. J. Virol. 83, 11514–11527 (2009)

    CAS  Article  Google Scholar 

  11. Dang, Q. & Hirsch, V. M. Rapid disease progression to AIDS due to Simian immunodeficiency virus infection of macaques: host and viral factors. Adv. Pharmacol. 56, 369–398 (2008)

    CAS  Article  Google Scholar 

  12. Loffredo, J. T. et al. Patterns of CD8+ immunodominance may influence the ability of Mamu-B*08-positive macaques to naturally control simian immunodeficiency virus SIVmac239 replication. J. Virol. 82, 1723–1738 (2008)

    CAS  Article  Google Scholar 

  13. Mudd, P. A. et al. Escape from CD8+ T cell responses in Mamu-B*00801+ macaques differentiates progressors from elite controllers. J. Immunol. 188, 3364–3370 (2012)

    CAS  Article  Google Scholar 

  14. Li, Q. et al. Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells. Nature 434, 1148–1152 (2005)

    ADS  CAS  Article  Google Scholar 

  15. Li, Q. et al. Glycerol monolaurate prevents mucosal SIV transmission. Nature 458, 1034–1038 (2009)

    ADS  CAS  Article  Google Scholar 

  16. Hansen, S. G. et al. Effector memory T cell responses are associated with protection of rhesus monkeys from mucosal simian immunodeficiency virus challenge. Nature Med. 15, 293–299 (2009)

    CAS  Article  Google Scholar 

  17. Hansen, S. G. et al. Profound early control of highly pathogenic SIV by an effector memory T-cell vaccine. Nature 473, 523–527 (2011)

    ADS  CAS  Article  Google Scholar 

  18. Kawada, M. et al. Gag-specific cytotoxic T-lymphocyte-based control of primary simian immunodeficiency virus replication in a vaccine trial. J. Virol. 82, 10199–10206 (2008)

    CAS  Article  Google Scholar 

  19. Tsukamoto, T. et al. Impact of cytotoxic-T-lymphocyte memory induction without virus-specific CD4+ T-cell help on control of a simian immunodeficiency virus challenge in rhesus macaques. J. Virol. 83, 9339–9346 (2009)

    CAS  Article  Google Scholar 

  20. Cline, A. N., Bess, J. W., Piatak, M. J. & Lifson, J. D. Highly sensitive SIV plasma viral load assay: practical considerations, realistic performance expectations, and application to reverse engineering of vaccines for AIDS. J. Med. Primatol. 34, 303–312 (2005)

    CAS  Article  Google Scholar 

  21. Henn, M. R. et al. Whole genome deep sequencing of HIV-1 reveals the impact of early minor variants upon immune recognition during acute infection. PLoS Pathog. 8, e1002529 (2012)

    CAS  Article  Google Scholar 

  22. Macalalad, A. R. et al. Highly sensitive and specific detection of rare variants in mixed viral populations from massively parallel sequence data. PLOS Comput. Biol. 8, e1002417 (2012)

    CAS  Article  Google Scholar 

  23. Bonaldo, M. C. et al. Recombinant yellow fever vaccine virus 17D expressing simian immunodeficiency virus SIVmac239 gag induces SIV-specific CD8+ T-cell responses in rhesus macaques. J. Virol. 84, 3699–3706 (2010)

    CAS  Article  Google Scholar 

  24. Bonaldo, M. C. et al. Construction and characterization of recombinant flaviviruses bearing insertions between E and NS1 genes. Virol. J. 4, 115 (2007)

    Article  Google Scholar 

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Acknowledgements

We would like to thank M. Stevenson, M. Reynolds, N. Maness and J. Sacha for discussions and suggestions. We also thank D. Evans, L. Heyer and Z. R. Bergman for facilitating the experiments. This work was funded in part by National Institutes of Health (NIH) grants R37 AI052056, RO1 AI076114, RR015371, contract number HHSN261200800001E and FAPERJ, INCTV, CNPq, MCT and FIOCRUZ.

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D.I.W., T.M.A. and P.A.M. conceived of and designed the experiments. P.A.M., A.J.E., M.A.M., K.A.P., A.S., A.D.G., A.T.B., S.M.P., L.D., K.L.W., J.R.F., S.C., M.P., A.T.H. and J.D.L. performed the experiments. P.A.M., M.A.M., N.A.W., E.R., M.P., A.T.H., J.D.L., D.C.T., T.M.A. and D.I.W. compiled and analysed the data. Y.K. and D.B.A. oversaw statistical analysis of the data and aided in interpretation. M.G.V., M.C.B. and R.G. designed and manufactured the rYF17D vectors used in these studies. P.A.M., A.T.H., J.D.L., T.M.A. and D.I.W. wrote the manuscript.

Corresponding author

Correspondence to David I. Watkins.

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Competing interests

D.B.A. has, anticipates, or has had financial interests with the Frontiers Foundation; Vivus, Inc: Kraft Foods; University of Wisconsin; University of Arizona; University of Miami; Paul, Weiss, Wharton & Garrison LLP; and Sage Publications.

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Mudd, P., Martins, M., Ericsen, A. et al. Vaccine-induced CD8+ T cells control AIDS virus replication. Nature 491, 129–133 (2012). https://doi.org/10.1038/nature11443

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