AEGiS-15IAC: Qualitative characterization of HIV-specific CD8+ T cells associated with immunologic restriction of HIV replication.

15th International AIDS Conference

Bangkok, Thailand - July 11-16, 2004

Qualitative characterization of HIV-specific CD8+ T cells associated with immunologic restriction of HIV replication.

Int Conf AIDS 2004 Jul 11-16; 15:(abstract no. MoOrA1052)

Connors M, Migueles SA, Royce C, Ambrozak DR, Price DA, Douek DC, Imamichi T, Berg S
Laboratory of Immunoregulation, National Institute of Allergy and infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States

BACKGROUND: High frequencies of HIV-specific CD8+ T cells remain detectable in patients with or without immunologic control over HIV replication. To better understand the qualitative features of an effective HIV-specific CD8+ T cell response, we examined the surface phenotype and TCR clonal composition of immunodominant HLA B57-Gag tetramer+ CD8+ T cells in two patient groups, long-term nonprogressors (LTNPs) and progressors.

METHODS: PBMCs were labeled with tetramers, stained for markers of activation (CD25, HLA DR), co-stimulation (CD27, CD28), memory (CD45RO), replicative history (CD57), lymphocyte homing receptors (CD62L, CCR7) and Interleukin-7 receptor (CD127) expression and analyzed by flow cytometry. The TCR clonotype of sorted tetramer+ CD8+ T cells was analyzed by spectratyping, anchored (RT)-PCR and sequencing.

RESULTS: In 9 LTNPs and 8 progressors, the phenotype of the tetramer+ CD8+ T cells was CD25-CD27+CD45RO+CCR7-, with more variable expression of the other mark ers. CD127 expression was modestly increased on the HIV-specific CD8+ T cells of LTNPs (medians, 52.9 [LTNPs] vs. 32.5 [progressors]; p=0.03). No significant differences were observed in other surface markers between the two patient groups (median percentage hi, p>=0.26). TCR clonotypic analysis demonstrated generally oligoclonal responses to dominant Gag epitopes in both patient groups; however, there was a greater tendency towards monoclonal epitope-specific CD8+ T cell responses in LTNPs.

CONCLUSIONS: Except for a modest, yet significant, difference in CD127 expression, CD8+ T cells that recognize highly conserved, immunodominant Gag epitopes are similar in surface phenotypic marker expression and clonal diversity in both LTNPs and progressors. A trend towards greater heterogeneity in the clonality of the epitope-specific CD8+ T cell responses, in the absence of escape mutations at these positions in progressors, indicates that highly diverse clonotypes may be recruited in the setting of a hig her plasma HIV RNA levels during chronic infection.

Keywords: AEGIS, HIV, Acquired Immunodeficiency Syndrome, HIV Seropositivity, Antigens, CD8, CD8-Positive T-Lymphocytes, Virus Replication, HIV Infections, Antigens, CD28, HIV Long-Term Survivors, Antigens, CD27, HIV Antigens, HIV Core Protein p24, Antigens, CD57, HLA-B Antigens, HLA-B57, Humans, immunology, virology

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MoOrA1052