Persistent survival of prevalent clonotypes within an immunodominant HIV gag-specific CD8+ T cell response.
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-7Rα) and Bcl-2. Of note, we also found evidence that promiscuous TCR α-chain pairing associated with alterations in fine specificity for KK10 variants could contribute to TCR β-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.
St. Vincent's Centre for Applied Medical Research, University of New South Wales, Sydney, New South Wales, Australia. d.vanbockel@cfi.unsw.edu.au
David J
DJ
van Bockel
David A
DA
Price
Mee Ling
ML
Munier
Vanessa
V
Venturi
Tedi E
TE
Asher
Kristin
K
Ladell
Hui Yee
HY
Greenaway
John
J
Zaunders
Daniel C
DC
Douek
David A
DA
Cooper
Miles P
MP
Davenport
Anthony D
AD
Kelleher
D000595:Amino Acid Sequence; D017951:Antigen Presentation / Q000276:immunology; D000940:Antigenic Variation / Q000276:immunology; D017209:Apoptosis / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D002469:Cell Separation; D002470:Cell Survival / Q000276:immunology; D002999:Clone Cells; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D015658:HIV Infections / Q000276:immunology / Q000473:pathology / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D057131:Immune Evasion / Q000276:immunology; D016056:Immunodominant Epitopes / Q000276:immunology*; D008969:Molecular Sequence Data; D010641:Phenotype; D015995:Prevalence; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D054301:gag Gene Products, Human Immunodeficiency Virus