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Altering Effects of Antigenic Variations in HIV-1 on Antiviral Effectiveness of HIV-Specific CTLs¹

Takamasa Ueno^2,*, Yuka Idegami^*, Chihiro Motozono^*, Shinichi Oka^, and Masafumi Takiguchi^*

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

The mutational escape of HIV-1 from established CTL responses is becoming evident. However, it is not yet clear whether antigenic variations of HIV-1 may have an additional effect on the differential antiviral effectiveness of HIV-specific CTLs. Herein, we characterized HIV-specific CTL responses toward Pol, Env, and Nef optimal epitopes presented by HLA-B*35 during a chronic phase of HIV-1 infection. We found CTL escape variants within Pol and Nef epitopes that affected recognition by TCRs, although there was no mutation within the Env epitope. An analysis of peptide-HLA tetrameric complexes revealed that CD8 T cells exclusively specific for the Nef variant were generated following domination by the variant viruses. The variant-specific cells were capable of killing target cells and producing antiviral cytokines but showed impaired Ag-specific proliferation ex vivo, whereas wild-type specific cells had potent activities. Moreover, clonotypic CD8 T cells specific for the Pol variant showed diminished proliferation, whereas Env-specific ones had no functional heterogeneity. Taken together, our data indicate that antigenic variations that abolished TCR recognition not only resulted in escape from established CTL responses but also eventually generated another subset of variant-specific CTLs having decreased antiviral activity, causing an additional negative effect on antiviral immune responses during a chronic HIV infection.

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 by grants-in-aid for scientific research from the Ministry of Education, Science, Sports and Culture of Japan.

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, Japan. E-mail address: uenotaka{at}kumamoto-u.ac.jp

³ Abbreviations used in this paper: Pt, patient; 7-AAD, 7-aminoactinomycin D; PD-1, programmed death 1.

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