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Journal of Virology, April 2009, p. 3138-3149, Vol. 83, No. 7
0022-538X/09/$08.00+0     doi:10.1128/JVI.02073-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Differential Neutralization of Human Immunodeficiency Virus (HIV) Replication in Autologous CD4 T Cells by HIV-Specific Cytotoxic T Lymphocytes{triangledown}

Huabiao Chen,1,2 Alicja Piechocka-Trocha,1,2 Toshiyuki Miura,1,2 Mark A. Brockman,1,2 Boris D. Julg,1 Brett M. Baker,1 Alissa C. Rothchild,1 Brian L. Block,1 Arne Schneidewind,1 Tomohiko Koibuchi,1 Florencia Pereyra,1 Todd M. Allen,1 and Bruce D. Walker1,2*

Ragon Institute of MGH, MIT, and Harvard, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129,1 Howard Hughes Medical Institute, Chevy Chase, Maryland 208152

Received 2 October 2008/ Accepted 13 January 2009

Defining the antiviral efficacy of CD8 T cells is important for immunogen design, and yet most current assays do not measure the ability of responses to neutralize infectious virus. Here we show that human immunodeficiency virus (HIV)-specific cytotoxic T-lymphocyte (CTL) clones and cell lines derived from infected persons and targeting diverse epitopes differ by over 1,000-fold in their ability to retard infectious virus replication in autologous CD4 T cells during a 7-day period in vitro, despite comparable activity as assessed by gamma interferon (IFN-{gamma}) enzyme-linked immunospot (ELISPOT) assay. Cell lines derived from peripheral blood mononuclear cells stimulated in vitro with peptides representing targeted Gag epitopes consistently neutralized HIV better than Env-specific lines from the same person, although ineffective inhibition of virus replication is not a universal characteristic of Env-specific responses at the clonal level. Gag-specific cell lines were of higher avidity than Env-specific lines, although avidity did not correlate with the ability of Gag- or Env-specific lines to contain HIV replication. The greatest inhibition was observed with cell lines restricted by the protective HLA alleles B*27 and B*57, but stimulation with targeted Gag epitopes resulted in greater inhibition than did stimulation with targeted Env epitopes even in non-B*27/B*57 subjects. These results assessing functional virus neutralization by HIV-specific CD8 T cells indicate that there are marked epitope- and allele-specific differences in virus neutralization by in vitro-expanded CD8 T cells, a finding not revealed by standard IFN-{gamma} ELISPOT assay currently in use in vaccine trials, which may be of critical importance in immunogen design and testing of candidate AIDS vaccines.

* Corresponding author. Mailing address: Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, 149 13th St., Charlestown, MA 02129. Phone: (617) 724-8332. Fax: (617) 726-4691. E-mail: bwalker{at}partners.org

{triangledown} Published ahead of print on 21 January 2009.

Journal of Virology, April 2009, p. 3138-3149, Vol. 83, No. 7
0022-538X/09/$08.00+0     doi:10.1128/JVI.02073-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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  • Saez-Cirion, A., Sinet, M., Shin, S. Y., Urrutia, A., Versmisse, P., Lacabaratz, C., Boufassa, F., Avettand-Fenoel, V., Rouzioux, C., Delfraissy, J.-F., Barre-Sinoussi, F., Lambotte, O., Venet, A., Pancino, G., for the ANRS EP36 HIV Controllers Study Group, (2009). Heterogeneity in HIV Suppression by CD8 T Cells from HIV Controllers: Association with Gag-Specific CD8 T Cell Responses. J. Immunol. 182: 7828-7837 [Abstract] [Full Text]  
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