Immunological and clinical benefits of highly active antiretroviral therapy (HAART) do not always correlate with its efficacy in controlling HIV replication. This could be due to biological effects on the cell of retroviral agents. DESIGN: To this view we evaluated possible direct immunomodulatory effects of two HIV protease inhibitors, such as Saquinavir (SQ) and Ritonavir (RIT). METHODS: In particular we assessed the PHA- and anti-CD3-driven T cell proliferation, mixed lymphocyte reaction (MLR) and cytokine production on PBMCs from HIV-uninfected subjects incubated with increasing concentrations (2, 5, 10 and 20 microM) of SQ or RIT. RESULTS: Treatment of PBMCs with RIT resulted in a dose-dependent reduction of lymphoproliferative responses. Such an effect was also marked with SQ. MLR was significantly reduced in a concentration-dependent fashion after incubation with either drug. The percentages of stimulated PBMCs and mostly of CD4+ cells expressing TNF-alpha, IL-2 and IFN-gamma were also reduced by SQ or RIT. CONCLUSION: At therapeutic doses both SQ and RIT exhibit potent immunomodulatory activity, which may contribute to correct the HIV-driven cytokine dysregulation and account for some clinical and immunological benefits of therapy in patients with virologic failure. In view of autoreactive immunopathology occurring in AIDS, these direct biologic effects raise intriguing speculations on anti-HIV strategy.
Immunomodulatory effects of two HIV protease inhibitors, Saquinavir and Ritonavir, on lymphocytes from healthy seronegative individuals
TOVO, Pier Angelo
2007-01-01
Abstract
Immunological and clinical benefits of highly active antiretroviral therapy (HAART) do not always correlate with its efficacy in controlling HIV replication. This could be due to biological effects on the cell of retroviral agents. DESIGN: To this view we evaluated possible direct immunomodulatory effects of two HIV protease inhibitors, such as Saquinavir (SQ) and Ritonavir (RIT). METHODS: In particular we assessed the PHA- and anti-CD3-driven T cell proliferation, mixed lymphocyte reaction (MLR) and cytokine production on PBMCs from HIV-uninfected subjects incubated with increasing concentrations (2, 5, 10 and 20 microM) of SQ or RIT. RESULTS: Treatment of PBMCs with RIT resulted in a dose-dependent reduction of lymphoproliferative responses. Such an effect was also marked with SQ. MLR was significantly reduced in a concentration-dependent fashion after incubation with either drug. The percentages of stimulated PBMCs and mostly of CD4+ cells expressing TNF-alpha, IL-2 and IFN-gamma were also reduced by SQ or RIT. CONCLUSION: At therapeutic doses both SQ and RIT exhibit potent immunomodulatory activity, which may contribute to correct the HIV-driven cytokine dysregulation and account for some clinical and immunological benefits of therapy in patients with virologic failure. In view of autoreactive immunopathology occurring in AIDS, these direct biologic effects raise intriguing speculations on anti-HIV strategy.
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