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Journal of Virology, October 2005, p. 12952-12960, Vol. 79, No. 20
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.20.12952-12960.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

De Novo Generation of Escape Variant-Specific CD8+ T-Cell Responses following Cytotoxic T-Lymphocyte Escape in Chronic Human Immunodeficiency Virus Type 1 Infection

Todd M. Allen,1,{dagger} Xu G. Yu,1,{dagger} Elizabeth T. Kalife,1 Laura L. Reyor,1 Mathias Lichterfeld,1 Mina John,3 Michael Cheng,1 Rachel L. Allgaier,1 Stanley Mui,1 Nicole Frahm,1 Galit Alter,1 Nancy V. Brown,1 Mary N. Johnston,1 Eric S. Rosenberg,1 Simon A. Mallal,3 Christian Brander,1 Bruce D. Walker,1,2 and Marcus Altfeld1*

Partners AIDS Research Center and Infectious Diseases Unit, Massachusetts General Hospital, and Division of AIDS, Harvard Medical School, Boston, Massachusetts 02129,1 Howard Hughes Medical Institute Chevy Chase, Maryland 20815,2 Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital, Perth, Western Australia 6000, Australia3

Received 1 April 2005/ Accepted 22 July 2005

Human immunodeficiency virus type 1 (HIV-1) evades CD8+ T-cell responses through mutations within targeted epitopes, but little is known regarding its ability to generate de novo CD8+ T-cell responses to such mutants. Here we examined gamma interferon-positive, HIV-1-specific CD8+ T-cell responses and autologous viral sequences in an HIV-1-infected individual for more than 6 years following acute infection. Fourteen optimal HIV-1 T-cell epitopes were targeted by CD8+ T cells, four of which underwent mutation associated with dramatic loss of the original CD8+ response. However, following the G357S escape in the HLA-A11-restricted Gag349-359 epitope and the decline of wild-type-specific CD8+ T-cell responses, a novel CD8+ T-cell response equal in magnitude to the original response was generated against the variant epitope. CD8+ T cells targeting the variant epitope did not exhibit cross-reactivity against the wild-type epitope but rather utilized a distinct T-cell receptor Vß repertoire. Additional studies of chronically HIV-1-infected individuals expressing HLA-A11 demonstrated that the majority of the subjects targeted the G357S escape variant of the Gag349-359 epitope, while the wild-type consensus sequence was significantly less frequently recognized. These data demonstrate that de novo responses against escape variants of CD8+ T-cell epitopes can be generated in chronic HIV-1 infection and provide the rationale for developing vaccines to induce CD8+ T-cell responses directed against both the wild-type and variant forms of CD8 epitopes to prevent the emergence of cytotoxic T-lymphocyte escape variants.

* Corresponding author. Mailing address: Partners AIDS Research Center, Massachusetts General Hospital, 149 13th Street, Boston, MA 02129. Phone: (617) 724-2461. Fax: (617) 724-8586. E-mail: maltfeld{at}partners.org.

{dagger} T.M.A. and X.G.Y. contributed equally to this study.

Journal of Virology, October 2005, p. 12952-12960, Vol. 79, No. 20
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.20.12952-12960.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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