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* Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom;
Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and
Vaccine and Gene Therapy Institute, Departments of Pathology and Molecular Microbiology and Immunology, and Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006
CMV infection induces robust CD4+ T cell responses in immunocompetent hosts that orchestrate immune control of viral replication, dissemination, and disease. In this study, we characterized the clonotypic composition of CD4+ T cell populations specific for rhesus CMV (RhCMV) in chronically infected adult rhesus macaques (RM) and in juvenile RM undergoing primary RhCMV infection and subsequent secondary challenge with RhCMV. In adult RM with established chronic infection, RhCMV-specific CD4+ T cell populations exhibited stable, pauciclonal structures with skewed hierarchies dominated by two or three clonotypes. During primary infection, in contrast, the initial RhCMV-specific CD4+ T cell populations were highly polyclonal and progressive evolution to the chronic pattern manifest in adults occurred over the ensuing 2–3 years. Clear patterns of clonal succession were observed during this maturation process, such that clonotypes present in the acute phase were largely replaced over time. However, rechallenge with RhCMV expanded virus-specific CD4+ T cell clonotypes identified solely during acute infection. These findings indicate that, during persistent viral infection, substantial selection pressures and ongoing clonotype recruitment shape the specific CD4+ T cell repertoire and that rapidly exhausted or superseded clonotypes often remain within the memory T cell pool.
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 by National Institutes of Health Grants P01-AG023644, R01-AI060392, P51-RR00163, U42-RR016025, and U24-RR018107. D.A.P. is a Medical Research Council (U.K.) Senior Clinical Fellow.
2 D.A.P. and A.D.B. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. David A. Price, Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 or Dr. Louis J. Picker, Vaccine and Gene Therapy Institute, Oregon Health and Science University, 505 NW 185th Avenue, Beaverton, OR 97006; E-mail addresses: dpricel{at}mail.nih.gov and pickerl{at}ohsu.edu
4 Abbreviations used in this paper: RhCMV, rhesus CMV; RM, rhesus macaque; BAL, bronchoalveolar lavage; qPCR, quantitative PCR.
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