The analysis identified two models; the antiretroviral regimen alone explained 32.8% of the variance in the change selleckchem in the mitochondrial-to-nuclear DNA ratio (P = 0.02; R = 0.573; R 2 = 0.328; F = 6.833) and after adjusting for the baseline expression of Bax the predictive value

of the therapeutic regimen increased to 61.6% (P = 0.002; R = 0.785; R 2 = 0.616; F = 10.444). The correlation analysis showed a strong association of inter-group differences in changes in the mitochondrial-to-nuclear DNA ratio with Annexin V+/7-AAD– (per cent of total CD4 T cells), the lactate-to-pyruvate ratio, Bcl-2 mRNA, Bcl-2 protein, Bax mRNA, the Bcl-2-to-Bax mRNA ratio and the activity of caspase 9. Until now, long-term data on the antiapoptotic effects of PIs in a real-life longitudinal clinical setting have been missing. In our study, we compared the effects of a PI-based regimen with those of an NNRTI-based regimen on apoptosis in patients before and 7 years after initiation of antiretroviral therapy. The CD4 T-cell increase was comparable between the treatment groups, but, compared with NNRTI-based regimens, PI-based regimens resulted in significantly better improvements in overall and intrinsic apoptosis markers, an

important underlying mechanism of immune recovery [16]. Detailed analysis of extrinsic apoptosis (caspase 8 activity, TRAIL mRNA and FasL mRNA) revealed no differences between the two treatment groups. At least five distinct mechanisms have been proposed to account Oligomycin A chemical structure for the antiapoptotic effects of PIs: decreased expression of apoptosis regulatory molecules, caspase inhibition, altered proliferation, calpain inhibition and inhibited mitochondrial function. Over the past decade, the role of mitochondria in apoptosis has become more clearly defined, and it is now generally agreed that mitochondria serve as central regulators that co-ordinate the initiation phase with the executionary phases of apoptosis [17]. Thus, we chose the mitochondrial-to-nuclear DNA ratio, as a previously well-defined measure of mitochondrial integrity, as the primary outcome learn more parameter [11]. To ensure that the observed effects on apoptosis were drug-induced and not influenced by

the existence of latent, undetectable, ongoing basal viral replication, we included viral and proinflammatory parameters triggered by viral replication in our analysis [4, 18]. Nef was chosen as a viral marker, as this is one of the most abundantly expressed viral proteins which targets CD4 T-cells for apoptosis [19]. Furthermore, we analysed IFN-α and its downstream gene product MxA. Emerging evidence from experimental studies [20] suggests that peripheral lymphocyte-derived IFN-α, induced by HIV, plays a central role in induction of extrinsic apoptosis by mediating up-regulation of the death receptor ligands TRAIL and FasL, which are involved in signalling to induce caspase-8 activation. Analysis revealed no inter-group differences in changes in Nef, IFN-α or MxA.