Long‐term beneficial effect of protease inhibitors on the intrinsic apoptosis of peripheral blood mononuclear cells in HIV‐infected patients

Abstract

Viral suppression by antiretroviral therapy (ART) inhibits HIV-induced apoptosis and CD4 T-cell loss. It has been suggested that protease inhibitors (PIs) have nonviral antiapoptotic effects by maintaining mitochondrial integrity. Long-term clinical effects of PI-based ART on mitochondrial toxicity and lymphocyte apoptosis beyond viral suppression have not been exploited to date. We conducted a 7-year study on HIV-1-infected patients from the Cologne HIV cohort with sufficient viral suppression under either a PI-based or nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen. Eight patients on PI and eight on NNRTI were eligible for inclusion in the analysis. The primary outcome measure was defined as a change in the mitochondrial-to-nuclear DNA ratio in PBMCs. Further key molecules involved in extrinsic [tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), Fas ligand (FasL) and caspase 8], intrinsic [B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), caspase 9 and lactate-to-pyruvate ratio] and overall apoptosis [Annexin+/7-aminoactinomycin D (7-AAD)- and caspase 3/7] and viral activity [negative regulatory factor (Nef), interferon-α (IFN-α) and myxovirus resistance protein A (MxA)] were measured. Demographic and baseline clinical parameters were similar in the two groups, except that patients in the PI group had a higher mean age. After 7 years of treatment, CD4 T-cell count increased and the expression of genes encoding the proapoptotic viral protein Nef and HIV-induced cytokine IFN-α and its downstream effector MxA decreased in both groups. Focusing on the different pathways of apoptosis, only in the PI group intrinsic apoptosis decreased significant and in the inter-group comparison the decrease was significantly higher than in the NNRTI group. Our study provides evidence that long-term therapy with a PI-based regimen may be superior to that with a NNRTI-based regimen with regard to its intrinsic antiapoptotic effect.