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Functionally Impaired HIV-Specific CD8 T Cells Show High Affinity TCR-Ligand Interactions¹

Takamasa Ueno^*, Hiroko Tomiyama^*, Mamoru Fujiwara^*, Shinichi Oka and Masafumi Takiguchi^2,*

^* Division of Viral Immunology, Center for AIDS Research, Kumamoto University, Kumamoto, Japan; and AIDS Clinical Center, International Medical Center of Japan, Tokyo, Japan

We eventually isolated two different clonotypic CD8 T cell subsets recognizing an HIV Pol-derived epitope peptide (IPLTEEAEL) in association with HLA-B35 from a chronic HIV-infected patient. By kinetic analysis experiments, the subsets showed a >3-fold difference in half-lives for the HLA tetramer in complex with the Pol peptide. In functional assays in vitro and ex vivo, both subsets showed substantial functional avidity toward peptide-loaded cells. However, the high affinity subset did not show cytolytic activity, cytokine production, or proliferation activity toward HIV-infected cells, whereas the moderate affinity one showed potent activities. Furthermore, using ectopic expression of each of the TCR genes into primary human CD8 T cells, the CD8 T cells transduced with the high affinity TCR showed greater binding activity toward the tetramer and impaired cytotoxic activity toward HIV-infected cells, corroborating the results obtained with parental CD8 T cells. Taken together, these data indicate that impaired responsiveness of T cells toward HIV-infected cells can occur at the level of TCR-ligand interactions, providing us further insight into the immune evasion mechanisms by HIV.

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