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Journal of Virology, January 2008, p. 805-816, Vol. 82, No. 2
0022-538X/08/$08.00+0     doi:10.1128/JVI.01038-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Clonal Focusing of Epitope-Specific CD8+ T Lymphocytes in Rhesus Monkeys following Vaccination and Simian-Human Immunodeficiency Virus Challenge{triangledown}

Pritha Sen, William A. Charini, Ramu A. Subbramanian,{dagger} Edwin R. Manuel, Marcelo J. Kuroda,{ddagger} Patrick A. Autissier, and Norman L. Letvin*

Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215

Received 13 May 2007/ Accepted 22 October 2007

To afford the greatest possible immune protection, candidate human immunodeficiency virus (HIV) vaccines must generate diverse and long-lasting CD8+ T lymphocyte responses. In the present study, we evaluate T-cell receptor Vβ (variable region beta) gene usage and a CDR3 (complementarity-determining region 3) sequence to assess the clonality of epitope-specific CD8+ T lymphocytes generated in rhesus monkeys following vaccination and simian-human immunodeficiency virus (SHIV) challenge. We found that vaccine-elicited epitope-specific CD8+ T lymphocytes have a clonal diversity comparable to those cells generated in response to SHIV infection. Moreover, we show that the clonal diversity of vaccine-elicited CD8+ T-lymphocyte responses is dictated by the epitope sequence and is not affected by the mode of antigen delivery to the immune system. Clonal CD8+ T-lymphocyte populations persisted following boosting with different vectors, and these clonal cell populations could be detected for as long as 4 years after SHIV challenge. Finally, we show that the breadth of these epitope-specific T lymphocytes transiently focuses in response to intense SHIV replication. These observations demonstrate the importance of the initial immune response to SHIV, induced by vaccination or generated during primary infection, in determining the clonal diversity of cell-mediated immune responses and highlight the focusing of this clonal diversity in the setting of high viral loads. Circumventing this restricted CD8+ T-lymphocyte clonal diversity may present a significant challenge in the development of an effective HIV vaccine strategy.

* Corresponding author. Mailing address: Beth Israel Deaconess Medical Center, Division of Viral Pathogenesis, 330 Brookline Ave., Boston, MA 02215. Phone: (617) 667-2766. Fax: (617) 667-8210. E-mail: nletvin{at}bidmc.harvard.edu

{triangledown} Published ahead of print on 31 October 2007.

{dagger} Present address: Cincinnati Children's Hospital Medical Center, College of Medicine, University of Cincinnati, 3333 Burnet Avenue, Cincinnati, OH 45229.

{ddagger} Present address: Division of Immunology, Tulane National Primate Research Center, Tulane University Health Sciences Center, 18703 Three Rivers Road, Covington, LA 70433.

Journal of Virology, January 2008, p. 805-816, Vol. 82, No. 2
0022-538X/08/$08.00+0     doi:10.1128/JVI.01038-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Hulot, S. L., Seaman, M. S., Sen, P., Autissier, P. A., Manuel, E. R., Letvin, N. L. (2009). Diverse Cross-Reactive Potential and V{beta} Gene Usage of an Epitope-Specific Cytotoxic T-Lymphocyte Population in Monkeys Immunized with Diverse Human Immunodeficiency Virus Type 1 Env Immunogens. J. Virol. 83: 9803-9812 [Abstract] [Full Text]  
  • Manuel, E. R., Yeh, W. W., Seaman, M. S., Furr, K., Lifton, M. A., Hulot, S. L., Autissier, P., Letvin, N. L. (2009). Dominant CD8+ T-Lymphocyte Responses Suppress Expansion of Vaccine-Elicited Subdominant T Lymphocytes in Rhesus Monkeys Challenged with Pathogenic Simian-Human Immunodeficiency Virus. J. Virol. 83: 10028-10035 [Abstract] [Full Text]  
  • Smith, M. Z., Asher, T. E., Venturi, V., Davenport, M. P., Douek, D. C., Price, D. A., Kent, S. J. (2008). Limited Maintenance of Vaccine-Induced Simian Immunodeficiency Virus-Specific CD8 T-Cell Receptor Clonotypes after Virus Challenge. J. Virol. 82: 7357-7368 [Abstract] [Full Text]  


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