BackgroundViral 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.
MethodsWe 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-a (IFN-a) and myxovirus resistance protein A (MxA)] were measured.
ResultsDemographic 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-a 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.
ConclusionsOur 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.Keywords: immune cells, intrinsic apoptosis, long-term study, nonnucleoside reverse transcriptase inhibitor, protease inhibitor
IntroductionProgressive loss of CD4 T cells is the hallmark of HIV infection and the causative factor for AIDS development as well as for serious non-AIDS events [1,2] , there is some evidence that protease inhibitors (PIs) inhibit T-cell apoptosis, which may have beneficial effects on immune reconstitution that are independent of their antiretroviral effects. Several mechanisms have been proposed, including preventing adenine nucleotide translocator pore function, which consequently prevents loss of mitochondrial transmembrane potential [7].Moreover, in clinical studies, PI regimens have been suggested to produce a better immunological response than nonnucleoside reverse transcriptase inhibitor (NNRTI) regimens [8][9][10], which has been attributed to intrinsic antiapoptotic effects of PIs [7].To date, a comparative study of the long-term effects of PI-vs. NNRTI-based regimens with regard to apopto...