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Journal of Virology, January 2005, p. 458-471, Vol. 79, No. 1
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.1.458-471.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

R5 Human Immunodeficiency Virus Type 1 Infection of Fetal Thymic Organ Culture Induces Cytokine and CCR5 Expression{dagger}

Shailesh K. Choudhary,1 Neelima R. Choudhary,1 Katherine C. Kimbrell,2 Jonathan Colasanti,2 Argyrios Ziogas,3 David Kwa,4 Hanneke Schuitemaker,4 and David Camerini1*

Department of Molecular Biology and Biochemistry,1 Epidemiology Division, Department of Medicine, University of California, Irvine, California,3 Department of Microbiology and Myles H. Thaler Center for AIDS Research, University of Virginia, Charlottesville, Virginia,2 Sanquin Research and Landsteiner Laboratory of the Academical Medical Center, University of Amsterdam, Amsterdam, The Netherlands4

Received 18 May 2004/ Accepted 17 August 2004

Late-stage CCR5 tropic human immunodeficiency virus type 1 (HIV-1) isolates (R5 HIV-1) can deplete nearly all CD4+ thymocytes from human thymus/liver grafts, despite the fact that fewer than 5% of these cells express CCR5. To resolve this paradox, we studied the replication and cytopathic effects (CPE) of late-stage R5 HIV-1 biological clones from two progressors and two long-term nonprogressors (LTNP) in fetal thymic organ culture (FTOC) with and without added cytokines. We found that R5 HIV-1 clones from progressors but not LTNP were cytopathic in untreated FTOC. Moreover, R5 HIV-1 clones from progressors replicated to higher levels than LTNP-derived R5 HIV-1 clones in this system. In contrast, when FTOC was maintained in the presence of interleukin 2 (IL-2), IL-4, and IL-7, both progressor and LTNP clones exhibited similar replication and CPE, which were equal to or greater than the levels achieved by progressor-derived R5 HIV-1 clones in untreated FTOC. This finding was likely due to IL-2-induced CCR5 expression on CD4+ thymocytes in FTOC. R5 HIV-1 clones showed greater pathogenesis for CCR5+ cells but also showed evidence of CPE on CCR5– cells. Furthermore, infection of FTOC by R5 HIV-1 induced IL-10 and transforming growth factor ß (TGF-ß) expression. Both IL-10 and TGF-ß in turn induced CCR5 expression in FTOC. Induction of CCR5 expression via cytokine induction by R5 HIV-1 infection of CCR5+ thymocytes likely permitted further viral replication in newly CCR5+ thymocytes. CCR5 expression, therefore, is a key determinant of pathogenesis of R5 HIV-1 in FTOC.

* Corresponding author. Mailing address: Dept. of Molecular Biology and Biochemistry, University of California, Irvine, 3213 McGaugh Hall, Irvine, CA 92697-3900. Phone: (949) 824-3381. Fax: (949) 824-8551. E-mail: dcamerin{at}uci.edu.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, January 2005, p. 458-471, Vol. 79, No. 1
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.1.458-471.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Choudhary, S. K., Vrisekoop, N., Jansen, C. A., Otto, S. A., Schuitemaker, H., Miedema, F., Camerini, D. (2007). Low Immune Activation despite High Levels of Pathogenic Human Immunodeficiency Virus Type 1 Results in Long-Term Asymptomatic Disease. J. Virol. 81: 8838-8842 [Abstract] [Full Text]  
  • Karlsson, I., Grivel, J.-C., Chen, S. S., Karlsson, A., Albert, J., Fenyo, E. M., Margolis, L. B. (2005). Differential Pathogenesis of Primary CCR5-Using Human Immunodeficiency Virus Type 1 Isolates in Ex Vivo Human Lymphoid Tissue. J. Virol. 79: 11151-11160 [Abstract] [Full Text]  


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