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Journal of Virology, July 2002, p. 6929-6943, Vol. 76, No. 14
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.14.6929-6943.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Impact of Cytokines on Replication in the Thymus of Primary Human Immunodeficiency Virus Type 1 Isolates from Infants

Livia Pedroza-Martins,1 W. John Boscardin,2 Deborah J. Anisman-Posner,1 Dominique Schols,3 Yvonne J. Bryson,4,5 and Christel H. Uittenbogaart1,4,5*

Departments of Microbiology, Immunology, and Molecular Genetics,1 Biostatistics, and,2 Pediatrics, UCLA AIDS Institute,4 Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California,5 Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium3

Received 1 November 2001/ Accepted 10 April 2002

Early infection of the thymus with the human immunodeficiency virus (HIV) may explain the more rapid disease progression among children infected in utero than in children infected intrapartum. Therefore, we analyzed infection of thymocytes in vitro by HIV type 1 primary isolates, obtained at or near birth, from 10 children with different disease outcomes. HIV isolates able to replicate in the thymus and impact thymopoiesis were present in all infants, regardless of the timing of viral transmission and the rate of disease progression. Isolates from newborns utilized CCR5, CXCR4, or both chemokine receptors to enter thymocytes. Viral expression was observed in discrete thymocyte subsets postinfection with HIV isolates using CXCR4 (X4) and isolates using CCR5 (R5), despite the wider distribution of CXCR4 in the thymus. In contrast to previous findings, the X4 primary isolates were not more cytopathic for thymocytes than were the R5 isolates. The cytokines interleukin-2 (IL-2), IL-4, and IL-7 increased HIV replication in the thymus by inducing differentiation and expansion of mature CD27+ thymocytes expressing CXCR4 or CCR5. IL-2 and IL-4 together increased expression of CXCR4 and CCR5 in this population, whereas IL-4 and IL-7 increased CXCR4 but not CCR5 expression. IL-2 plus IL-4 increased the viral production of all pediatric isolates, but IL-4 and IL-7 had a significantly higher impact on the replication of X4 isolates compared to R5 isolates. Our studies suggest that coreceptor use by HIV primary isolates is important but is not the sole determinant of HIV pathogenesis in the thymus.

* Corresponding author. Mailing address: Department of Microbiology, Immunology, and Molecular Genetics, UCLA School of Medicine, Los Angeles, CA 90095-1747. Phone: (310) 825-1982. Fax: (310) 206-1318. E-mail: uittenbo{at}ucla.edu.

Journal of Virology, July 2002, p. 6929-6943, Vol. 76, No. 14
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.14.6929-6943.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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