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CTL-Mediated Selective Pressure Influences Dynamic Evolution and Pathogenic Functions of HIV-1 Nef¹

Takamasa Ueno^2,*, Chihiro Motozono^*, Sachi Dohki^*, Philip Mwimanzi^*, Susanne Rauch, Oliver T. Fackler, Shinichi Oka and Masafumi Takiguchi^*

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

HIV-1 Nef plays multiple roles in modulating immune responses, even though it is a dominant CTL target itself. How Nef accomplishes the balance between such conflicting selective pressures remains elusive. By genetic and functional studies, we found that Arg⁷⁵Thr and Tyr⁸⁵Phe mutations, located in a well-conserved proline-rich region in Nef, were differently associated with escape from CTL responses specific for two overlapping HLA-B35-restricted epitopes. CTLs specific for an epitope, that selected Tyr⁸⁵Phe, were elicited earlier and had more potent functional avidities than did those that selected Arg⁷⁵Thr. Although the double mutant could escape from both CTLs, the mutations are rarely observed in combination naturally. Introduction of both mutations reduced Nef’s HLA class I down-regulation activity and increased the susceptibility of virus-infected cells to recognition by CTLs targeting other epitopes. Moreover, the mutant Nef was impaired in the association with activated cellular kinases and in the enhancement of viral replication. These results highlight CTL immunosurveillance as important modulators of Nef’s biological activity in the infected host.

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 work 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-in-Aid for AIDS Research from the Ministry of Health, Labor, and Welfare of Japan (to T.U., S.O., and M.T.), and by Deutsche Forschungsgemeinschaft Grant SFB 638 (Project A11, to O.T.F.).

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: MHC-I, MHC class I; SH3, Src homology 3; 7-AAD, 7-aminoactinomycin D; wt, wild type; IVKA, in vitro kinase assay.

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