Hydroxyurea exerts a cytostatic but not immunosuppressive effect on T lymphocytes.
OBJECTIVE
To demonstrate that, despite a dose-dependent cytostatic effect, hydroxyurea (HU) does not have immunosuppressive effects.


METHODS
The effects of HU on T lymphocyte proliferation parameters, activation phenotype and cytokine production were examined in vitro after exposure to clinically relevant concentrations of HU (10, 50, and 100 micromol/l). The effects of HU in vivo on CD4 T cell counts, viral load, activation phenotype and virus-specific response were examined in 17 Rhesus macaques infected with SIV(mac251) and randomized into three groups: untreated controls; treated with (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) and didanosine (ddI) only; and treated with PMPA, didanosine, and HU.


RESULTS
The in vitro inhibition of T lymphocyte proliferation confirmed the cytostatic effect of HU, with a linear dose-dependent effect; however, no relevant differences were found in the expression of activation markers between treated and untreated controls. Both T helper type 1 and type 2 cytokine production were enhanced by HU. Consistent with the in vitro results, a blunted increase of peripheral CD4 T cells was observed in vivo in the HU group, without relevant effects on the expression of activation markers, and SIV-specific T cell responses were not affected by HU.


CONCLUSIONS
Hyper-proliferation of T-lymphocytes is a major factor contributing to HIV pathogenesis. HU exerts a cytostatic effect on T lymphocytes, without altering their activation and apparently without having an immunosuppressive effect. The increase in cytokine production at the single cell level might compensate for the decrease in the percentage of activated CD4 T lymphocytes, without overall impairment of HIV-specific immune responses.
Lova
Luca
L
Research Institute for Genetic and Human Therapy at IRCCS Policlinico S. Matteo, Pavia, Italy.
Groff
Antonella
A
Ravot
Elisabetta
E
Comolli
Giuditta
G
Xu
Jianqing
J
Whitman
Lucia
L
Lewis
Mark
M
Foli
Andrea
A
Lisziewicz
Julianna
J
Lori
Franco
F
D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D008253:Macaca mulatta; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects*
D015703:Antigens, CD; D000970:Antineoplastic Agents; D016207:Cytokines; D007166:Immunosuppressive Agents; D007371:Interferon-gamma; D006918:Hydroxyurea