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Communicated by Anthony S. Fauci, National Institutes of Health, Bethesda, MD (received for review December 1, 1999)
Abstract
A unique cohort of HIV-1-infected long term nonprogressors (LTNP) with normal CD4+ T cell counts and <50 copies/ml of plasma were prospectively recruited for study. HLA typing revealed a dramatic association between the HLA B*5701 class I allele and nonprogressive infection [85% (11 of 13) vs. 9.5% (19 of 200) in progressors; P < 0.001]. Antigen-specific CD8+ T cells were enumerated by flow cytometric detection of intracellular IFN-γ in response to HIV antigens and HLA B*57-gag tetramer staining. No quantitative differences in the total HIV-specific CD8+ T cell responses were observed between B*57+ LTNP and five B*57+ progressors (P = 0.4). Although similar frequencies of peptide specific CD8+ T cells were also found, the gag-specific CD8+ T cell response in the LTNP group was highly focused on peptides previously shown to be B*57-restricted. These findings indicate that, within this phenotypically and genotypically distinct cohort, a host immune factor is highly associated with restriction of virus replication and nonprogressive disease. They also strongly suggest a mechanism of virus specific immunity that directly operates through the B*5701 molecule. Further characterization of qualitative differences in the virus-specific responses that distinguish HLA B*57+ LTNP from progressors may ultimately define mechanisms of effective immune mediated restriction of virus replication.
Footnotes
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↵‡‡ To whom reprint requests should be addressed at: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10, Room 11B-09, 10 Center Drive MSC 1876, Bethesda, MD 20892-1876. E-mail: mconnors{at}niaid.nih.gov.
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Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.050567397.
-
Article and publication date are at www.pnas.org/cgi/doi/10.1073/pnas.050567397
Abbreviations
- LTNP,
- long term nonprogressor;
- PBMC,
- peripheral blood mononuclear cell
- Received December 1, 1999.
- Accepted December 22, 1999.
- Copyright © 2000, The National Academy of Sciences
- Stephen A. Migueles†,
- M. Shirin Sabbaghian†,
- W. Lesley Shupert†,
- Maria P. Bettinotti‡,
- Francesco M. Marincola§,
- Lisa Martino†,
- Clair W. Hallahan†,
- Sara M. Selig†,
- David Schwartz¶,
- John Sullivan‖, and
- Mark Connors†‡‡
- †Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, ‡Department of Transfusion Medicine, Clinical Center, and §Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; ¶Department of Molecular Microbiology and Immunology, School of Hygiene and Public Health, Johns Hopkins University, Baltimore MD 21205; and ‖Australian Red Cross Blood Service-NSW, Sydney, New South Wales 2000, Australia
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Communicated by Anthony S. Fauci, National Institutes of Health, Bethesda, MD (received for review December 1, 1999)
Abstract
A unique cohort of HIV-1-infected long term nonprogressors (LTNP) with normal CD4+ T cell counts and <50 copies/ml of plasma were prospectively recruited for study. HLA typing revealed a dramatic association between the HLA B*5701 class I allele and nonprogressive infection [85% (11 of 13) vs. 9.5% (19 of 200) in progressors; P < 0.001]. Antigen-specific CD8+ T cells were enumerated by flow cytometric detection of intracellular IFN-γ in response to HIV antigens and HLA B*57-gag tetramer staining. No quantitative differences in the total HIV-specific CD8+ T cell responses were observed between B*57+ LTNP and five B*57+ progressors (P = 0.4). Although similar frequencies of peptide specific CD8+ T cells were also found, the gag-specific CD8+ T cell response in the LTNP group was highly focused on peptides previously shown to be B*57-restricted. These findings indicate that, within this phenotypically and genotypically distinct cohort, a host immune factor is highly associated with restriction of virus replication and nonprogressive disease. They also strongly suggest a mechanism of virus specific immunity that directly operates through the B*5701 molecule. Further characterization of qualitative differences in the virus-specific responses that distinguish HLA B*57+ LTNP from progressors may ultimately define mechanisms of effective immune mediated restriction of virus replication.
Footnotes
-
↵‡‡ To whom reprint requests should be addressed at: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10, Room 11B-09, 10 Center Drive MSC 1876, Bethesda, MD 20892-1876. E-mail: mconnors{at}niaid.nih.gov.
-
Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.050567397.
-
Article and publication date are at www.pnas.org/cgi/doi/10.1073/pnas.050567397
Abbreviations
- LTNP,
- long term nonprogressor;
- PBMC,
- peripheral blood mononuclear cell
- Received December 1, 1999.
- Accepted December 22, 1999.
- Copyright © 2000, The National Academy of Sciences
HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long term nonprogressors
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