HIV protease inhibitors restore impaired T-cell proliferative response in vivo and in vitro: a viral-suppression–independent mechanism

In 99 adults infected with human immunodeficiency virus type 1 (HIV-1) who received highly active antiretroviral therapy (HAART) (including 2 nucleoside analogues and 1 or 2 protease inhibitors) for 1 year, CD4+ and CD8+ T cells (including memory and naive subsets) increased similarly among patients with sustained plasma viral load decrease, transient decrease, or no decrease. A linear correlation was observed between the decrease in serum β2-microglobulin concentration (an independent surrogate marker of HIV disease) and the increase in peripheral blood T-cells (CD4+ and CD8+) counts. In vitro, HIV protease inhibitors indinavir and saquinavir (but not nucleoside analogues) enhanced the survival of patients' peripheral blood T cells at doses that are at least 30-fold lower than those required for achieving 90% viral inhibition in the same cultures. This enhanced T-cell survival (which is similar for CD4 and CD8 cells) was associated with a restoration of T-cell proliferative response to immune stimuli. However, neither TCR/CD3-ligation– nor Fas-ligation–triggered apoptosis was affected by either of the 2 protease inhibitors. A reduction in apoptosis observed after prolonged culture of patient T cells in the presence of the protease inhibitors could result from restored T-cell proliferation. These findings explain the discrepancies between virologic and immunologic responses that are increasingly reported in patients receiving HAART, and may provide insights into the pathogenesis of HIV infection.