Reconstitution of human thymic implants is limited by human immunodeficiency virus breakthrough during antiretroviral therapy.
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.
Division of Hematology/Oncology, Department of Medicine, UCLA School of Medicine and Jonsson Comprehensive Cancer Center, Los Angeles, California 90095-1678, USA.
R G
RG
Amado
B D
BD
Jamieson
R
R
Cortado
S W
SW
Cole
J A
JA
Zack
D000818:Animals; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016049:Didanosine / Q000627:therapeutic use; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000628:therapy*; D017320:HIV Protease Inhibitors / Q000627:therapeutic use; D015497:HIV-1 / Q000276:immunology* / Q000502:physiology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D019469:Indinavir / Q000627:therapeutic use; D007700:Kinetics; D008212:Lymphocyte Depletion; D051379:Mice; D016513:Mice, SCID; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*; D015215:Zidovudine / Q000627:therapeutic use
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D019469:Indinavir; D016049:Didanosine