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Journal of Virology, August 1999, p. 6361-6369, Vol. 73, No. 8
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Reconstitution of Human Thymic Implants Is Limited by Human Immunodeficiency Virus Breakthrough during Antiretroviral Therapy

Rafael G. Amado,1 Beth D. Jamieson,1 Ruth Cortado,1 Steve W. Cole,1 and Jerome A. Zack1,2,*

Division of Hematology/Oncology, Department of Medicine,1 and Department of Microbiology & Molecular Genetics,2 UCLA School of Medicine and Jonsson Comprehensive Cancer Center, Los Angeles, California 90095-1678

Received 16 March 1999/Accepted 10 May 1999

Human immunodeficiency virus type 1 (HIV-1)-infected SCID-hu thymic implants depleted of CD4+ cells can support renewed thymopoiesis derived from both endogenous and exogenous T-cell progenitors after combination antiretroviral therapy. However, successful production of new thymocytes occurs transiently. Possible explanations for the temporary nature of this thymic reconstitution include cessation of the thymic stromal support function, exhaustion of T-cell progenitors, and viral resurgence. Distinguishing between these processes is important for the development of therapeutic strategies aimed at reconstituting the CD4+ T-cell compartment in HIV-1 infection. Using an HIV-1 strain engineered to express the murine HSA heat-stable antigen surface marker, we explored the relationship between HIV-1 expression and CD4+ cell resurgence kinetics in HIV-1-depleted SCID-hu implants following drug therapy. Antiviral therapy significantly suppressed HIV-1 expression in double-positive (DP) CD4/CD8 thymocytes, and the eventual secondary decline of DP thymocytes following therapy was associated with renewed viral expression in this cell subset. Thymocytes derived from exogenous T-cell progenitors induced to differentiate in HIV-1-depleted, drug-treated thymic implants also became infected. These results indicate that in this model, suppression of viral replication occurs transiently and that, in spite of drug therapy, virus resurgence contributes to the transient nature of the renewed thymic function.

* Corresponding author. Mailing address: Division of Hematology/Oncology, Department of Medicine, UCLA School of Medicine, UCLA AIDS Institute and Jonsson Comprehensive Cancer Center, Los Angeles, CA 90095-1678. Phone: (310) 825-0876. Fax: (310) 825-6192. E-mail: jzack{at}ucla.edu.

Journal of Virology, August 1999, p. 6361-6369, Vol. 73, No. 8
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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