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Long‐term beneficial effect of protease inhibitors on the intrinsic apoptosis of peripheral blood mononuclear cells in HIV ‐infected patients
Author(s) -
Jung N,
Lehmann C,
Knispel M,
Meuer EK,
Fischer J,
Fätkenheuer G,
Hartmann P,
Taubert D
Publication year - 2012
Publication title -
hiv medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 79
eISSN - 1468-1293
pISSN - 1464-2662
DOI - 10.1111/j.1468-1293.2012.00999.x
Subject(s) - apoptosis , medicine , peripheral blood mononuclear cell , fas ligand , viral load , immunology , tumor necrosis factor alpha , mitochondrial toxicity , caspase 3 , cytokine , programmed cell death , virology , biology , virus , human immunodeficiency virus (hiv) , in vitro , biochemistry
Background Viral suppression by antiretroviral therapy ( ART ) inhibits HIV ‐induced apoptosis and CD 4 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. Methods We conducted a 7‐year study on HIV ‐1‐infected patients from the C ologne 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 ( B cl‐2), B cl‐2‐associated X protein ( B ax), caspase 9 and lactate‐to‐pyruvate ratio] and overall apoptosis [ A nnexin+/7‐aminoactinomycin D (7‐ AAD )– and caspase 3/7] and viral activity [negative regulatory factor ( N ef), interferon‐α ( IFN ‐α) and myxovirus resistance protein A ( MxA )] were measured. Results 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, CD 4 T ‐cell count increased and the expression of genes encoding the proapoptotic viral protein N ef 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. Conclusions 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.