Journal
JOURNAL OF IMMUNOLOGY
Volume 186, Issue 1, Pages 359-371Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1001807
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Funding
- Australian Government Department of Health and Ageing
- National Institutes of Health (Vaccine Research Centre, National Institute of Allergy and Infectious Diseases)
- Australian National Health and Medical Research Council
- Dora Lush (Biomedical) Postgraduate Research Scholarship
- Practitioner Fellowship
- Medical Research Council [G0501963] Funding Source: researchfish
- MRC [G0501963] Funding Source: UKRI
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [ZIAAI005066, ZIAAI005033, ZIAAI005031] Funding Source: NIH RePORTER
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CD8(+) T cells play a significant role in the control of HIV replication, yet the associated qualitative and quantitative factors that determine the outcome of infection remain obscure. In this study, we examined Ag-specific CD8(+) TCR repertoires longitudinally in a cohort of HLA-B*2705(+) long-term nonprogressors with chronic HIV-1 infection using a combination of molecular clonotype analysis and polychromatic flow cytometry. In each case, CD8(+) T cell populations specific for the immunodominant p24 Gag epitope KRWIILGLNK (KK10; residues 263-272) and naturally occurring variants thereof, restricted by HLA-B*2705, were studied at multiple time points; in addition, comparative data were collected for CD8(+) T cell populations specific for the CMV pp65 epitope NLVPMVATV (NV9; residues 495-503), restricted by HLA-A*0201. Dominant KK10-specific clonotypes persisted for several years and exhibited greater stability than their contemporaneous NV9-specific counterparts. Furthermore, these dominant KK10-specific clonotypes exhibited cross-reactivity with antigenic variants and expressed significantly higher levels of CD127 (IL-7R alpha) and Bcl-2. Of note, we also found evidence that promiscuous TCR alpha-chain pairing associated with alterations in fine specificity for KK10 variants could contribute to TCR beta-chain prevalence. Taken together, these data suggest that an antiapoptotic phenotype and the ability to cross-recognize variant epitopes contribute to clonotype longevity and selection within the peripheral memory T cell pool in the presence of persistent infection with a genetically unstable virus. The Journal of Immunology, 2011, 186: 359-371.
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