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Vaccine-induced CD8+ T cells control AIDS virus replication

Nature volume 491, pages 129–133 (2012)Cite this article

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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.

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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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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, 53711, Wisconsin, USA

    Philip A. Mudd, Adam J. Ericsen, Alex T. Bean, Shari M. Piaskowski, Kim L. Weisgrau, Jessica R. Furlott & Nancy A. Wilson

  2. Medical Scientist Training Program, University of Wisconsin-Madison, Madison, 53705, Wisconsin, USA

    Philip A. Mudd

  3. Department of Pathology, University of Miami Miller School of Medicine, Miami, 33136, Florida, USA

    Mauricio A. Martins & David I. Watkins

  4. Ragon Institute of MGH, MIT and Harvard, Boston, 02129, Massachusetts, USA

    Damien C. Tully, Karen A. Power, Aaron Seese, Adrianne D. Gladden & Todd M. Allen

  5. Department of Microbiology, University of Minnesota, Minneapolis, 55455, Minnesota, USA

    Lijie Duan & Ashley T. Haase

  6. Department of Medicine, Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, 35294, Alabama, USA

    Young-il Kim

  7. Laboratório de Biologia Molecular de Flavivírus, Instituto Oswaldo Cruz—FIOCRUZ, Rio de Janeiro, Brazil,

    Marlon G. Veloso de Santana & Myrna C. Bonaldo

  8. Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, 53711, Wisconsin, USA

    Eva Rakasz, Saverio Capuano III & Nancy A. Wilson

  9. Instituto de Tecnologia em Imunobiológicos, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil,

    Ricardo Galler

  10. Department of Biostatistics, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, 35294, Alabama, USA

    David B. Allison

  11. AIDS and Cancer Virus Program, SAIC Frederick, Inc., National Cancer Institute, Frederick, 21702, Maryland, USA

    Michael Piatak Jr & Jeffrey D. Lifson

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  1. Philip A. Mudd
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Contributions

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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