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Journal of Virology, February 2004, p. 1324-1332, Vol. 78, No. 3
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.3.1324-1332.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Impaired Processing and Presentation of Cytotoxic-T-Lymphocyte (CTL) Epitopes Are Major Escape Mechanisms from CTL Immune Pressure in Human Immunodeficiency Virus Type 1 Infection

Yoshiyuki Yokomaku,¹ Hideka Miura,¹ Hiroko Tomiyama,² Ai Kawana-Tachikawa,³ Masafumi Takiguchi,² Asato Kojima,⁴ Yoshiyuki Nagai ,^1, Aikichi Iwamoto,³ Zene Matsuda,¹ and Koya Ariyoshi^1*

AIDS Research Center,¹ Department of Pathology, National Institute of Infectious Diseases,⁴ Department of Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo,³ Center for AIDS Research, Kumamoto University, Kumamoto, Japan²

Received 21 April 2003/ Accepted 7 October 2003

Investigating escape mechanisms of human immunodeficiency virus type 1 (HIV-1) from cytotoxic T lymphocytes (CTLs) is essential for understanding the pathogenesis of HIV-1 infection and developing effective vaccines. To study the processing and presentation of known CTL epitopes, we prepared Epstein-Barr virus-transformed B cells that endogenously express the gag gene of six field isolates by adopting an env/nef-deletion HIV-1 vector pseudotyped with vesicular stomatitis virus G protein and then tested them for the recognition by Gag epitope-specific CTL lines or clones. We observed that two field variants, SLFNTVAVL and SVYNTVATL, of an A*0201-restricted Gag CTL epitope SLYNTVATL, and three field variants, KYRLKHLVW, QYRLKHIVW, and RYRLKHLVW, of an A24-restricted Gag CTL epitope KYKLKHIVW escaped from being killed by the CTL lines, despite the fact that they were recognized when the synthetic peptides corresponding to these variant sequences were exogenously loaded onto the target cells. Thus, their escape is likely due to the changes that occur during the processing and presentation of epitopes in the infected cells. Mutations responsible for this mode of escape were located within the epitope regions rather than the flanking regions, and such mutations did not influence the virus replication. The results suggest that the impaired antigen processing and presentation often occur in HIV-1 field isolates and thus are one of the major mechanisms that enable HIV-1 to escape from CTL recognition. We emphasize the importance of testing HIV-1 variants in an endogenous expression system.

Present address: Toyama Institute of Health, Toyama, 939-0363 Japan

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