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Impact of Intrinsic Cooperative Thermodynamics of Peptide-MHC Complexes on Antiviral Activity of HIV-Specific CTL¹

Chihiro Motozono^*, Saeko Yanaka, Kouhei Tsumoto, Masafumi Takiguchi^* and Takamasa Ueno^2,*

^* Division of Viral Immunology, Center for AIDS Research, Kumamoto University, Kumamoto, Japan, and Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan

The antiviral activity of HIV-specific CTL is not equally potent but rather is dependent on their specificity. But what characteristic of targeted peptides influences CTL antiviral activity remains elusive. We addressed this issue based on HLA-B35-restricted CTLs specific for two overlapping immunodominant Nef epitopes, VY8 (VPLRPMTY) and RY11 (RPQVPLRPMTY). VY8-specific CTLs were more potently cytotoxic toward HIV-infected primary CD4⁺ cells than RY11-specific CTLs. Reconstruction of their TCR revealed no substantial difference in their functional avidity toward cognate Ags. Instead, the decay analysis of the peptide-MHC complex (pMHC) revealed that the VY8/HLA-B35 complex could maintain its capacity to sensitize T cells much longer than its RY11 counterpart. Corroboratively, the introduction of a mutation in the epitopes that substantially delayed pMHC decay rendered Nef-expressing target cells more susceptible to CTL killing. Moreover, by using differential scanning calorimetry and circular dichroism analyses, we found that the susceptible pMHC ligands for CTL killing showed interdependent and cooperative, rather than separate or sequential, transitions within their heterotrimer components under the thermally induced unfolding process. Collectively, our results highlight the significant effects of intrinsic peptide factors that support cooperative thermodynamics within pMHC on the efficient CTL killing of HIV-infected cells, thus providing us better insight into vaccine design.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported in part by a grant-in-aid for scientific research from the Ministry of Education, Science, Sports, and Culture of Japan (to T.U.), by a grant from Human Science Foundation (to T.U.), and by a grant-in-aid for AIDS research from the Ministry of Health, Labor, and Welfare of Japan (to T.U. and M.T.).

² Address correspondence and reprint requests to Dr. Takamasa Ueno, Division of Viral Immunology, Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto, 860-0811, Japan. E-mail address: uenotaka{at}kumamoto-u.ac.jp

³ Abbreviations used in this paper: pMHC, peptide-MHC class I complex; DSC, differential scanning calorimetry; CD, circular dichroism; β₂m, β₂-microglobulin.