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Journal of Virology, May 2002, p. 4971-4986, Vol. 76, No. 10
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.10.4971-4986.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Comprehensive Screening for Human Immunodeficiency Virus Type 1 Subtype-Specific CD8 Cytotoxic T Lymphocytes and Definition of Degenerate Epitopes Restricted by HLA-A0207 and -CW0304 Alleles

Jeffrey R. Currier,1* Mark deSouza,2 Penprapa Chanbancherd,3 Wendy Bernstein,1 Deborah L. Birx,1 and Josephine H. Cox1

U.S. Military HIV Research Program, Rockville, Maryland 20850,1 Armed Forces Research Institute for Medical Sciences,2 Armed Forces Institute of Pathology, Bangkok, Thailand3

Received 19 December 2001/ Accepted 8 February 2002

For this report, the rapid identification and characterization of human immunodeficiency virus type 1 (HIV-1)-derived broadly cross-subtype-reactive CD8 cytotoxic T lymphocyte (CTL) epitopes were performed. Using a gamma interferon (IFN-{gamma}) Elispot assay-based approach and a panel of recombinant vaccinia viruses expressing gag, env, pol, and nef genes representing the seven most predominant subtypes and one circulating recombinant form of HIV-1, the subtype specificity and cross-subtype reactivity of a CD8 response were directly measured from circulating peripheral blood mononuclear cells (PBMC). Enhanced sensitivity of detection of CD8 responses from cryopreserved PBMC was achieved using autologous vaccinia virus-infected B-lymphoblastoid cell lines as supplemental antigen-presenting cells. Of eleven subjects studied, six exhibited broadly cross-subtype-reactive CD8-mediated IFN-{gamma} production (at least seven of eight subtypes recognized) to at least one major gene product from HIV-1. Screening of subjects showing broadly cross-subtype-specific responses in the vaccinia virus-based enzyme-linked immunospot (Elispot) assay using a panel of overlapping peptides resulted in the identification of cross-subtype responses down to the 20-mer peptide level in less than 3 days. Three subjects showed broad cross-subtype reactivity in both the IFN-{gamma} Elispot assay and the standard chromium release cytotoxicity assay. Fine mapping and HLA restriction analysis of the response from three subjects demonstrated that this technique can be used to define epitopes restricted by HLA-A, -B, and -C alleles. In addition, the ability of all three epitopes to be processed from multiple subtypes of their parent proteins and presented in the context of HLA class I molecules following de novo synthesis is shown. While all three minimal epitopes mapped here had previously been defined as HIV-1 epitopes, two are shown to have novel HLA restriction alleles and therefore exhibit degenerate HLA binding capacity. These findings provide biological validation of HLA supertypes in HIV-1 CTL recognition and support earlier studies of cross-subtype CTL responses during HIV-1 infection.

* Corresponding author. Mailing address: U.S. Military HIV Research Program, Suite 200, 13 Taft Court, Rockville, MD 20850. Phone: (301) 251 8311. Fax: (301) 762 4177. E-mail: jcurrier{at}hivresearch.org.

Journal of Virology, May 2002, p. 4971-4986, Vol. 76, No. 10
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.10.4971-4986.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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