Immune restoration by combination of a cytostatic drug (hydroxyurea) and anti-HIV drugs (didanosine and indinavir).
Cell activation is essential for HIV infection. CD4+ T lymphocyte activation allows virus replication and CD8+ T lymphocyte activation may contribute to pathogenesis. We combined hydroxyurea, a cytostatic drug that inhibits cell activation and proliferation, with two drugs that inhibit HIV (didanosine and indinavir), to block the "cell activation-virus production-pathogenesis" cycle. HIV was strongly suppressed in treated patients, and the average CD4 count increased to 224/mm3. Compared with a matched group of patients who had declined antiretroviral treatment, treated patients had a significantly lower proportion of activated CD8+ T lymphocytes and a significantly higher number of naive CD8+ and CD4+ T lymphocytes. The proliferative responses to allogeneic and influenza virus antigens were increased in treated patients, and a defect in CD3-zeta expression, the signaling chain of the T cell receptor complex, was reversed. The use of a cytostatic drug was not detrimental to the immune system; on the contrary, the combination of antiviral and cytostatic treatment improved all of the immune parameters tested.
Lori
F
F
Research Institute for Genetic and Human Therapy, Washington, DC 20007, USA.
Jessen
H
H
Lieberman
J
J
Clerici
M
M
Tinelli
C
C
Lisziewicz
J
J
D019380:Anti-HIV Agents / Q000627:therapeutic use*; D017252:CD3 Complex / Q000378:metabolism; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016049:Didanosine / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology*; D017320:HIV Protease Inhibitors / Q000627:therapeutic use; D006801:Humans; D006918:Hydroxyurea / Q000627:therapeutic use*; D019469:Indinavir / Q000627:therapeutic use*; D008213:Lymphocyte Activation; D019384:Nucleic Acid Synthesis Inhibitors / Q000627:therapeutic use*; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D014766:Viremia
D019380:Anti-HIV Agents; D017252:CD3 Complex; D017320:HIV Protease Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D018894:Reverse Transcriptase Inhibitors; D019469:Indinavir; D016049:Didanosine; D006918:Hydroxyurea