title: Long-term beneficial effect of protease inhibitors on the intrinsic apoptosis of peripheral blood mononuclear cells in HIV-infected patients.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  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, 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.
  
  
  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.
authors.affiliation: First Department of Internal Medicine, Medical Hospital of the University of Cologne, Cologne, Germany. norma.jung@uni-koeln.de
authors.forename: N
authors.initials: N
authors.lastname: Jung
authors.forename: C
authors.initials: C
authors.lastname: Lehmann
authors.forename: M
authors.initials: M
authors.lastname: Knispel
authors.forename: E K
authors.initials: EK
authors.lastname: Meuer
authors.forename: J
authors.initials: J
authors.lastname: Fischer
authors.forename: G
authors.initials: G
authors.lastname: Fätkenheuer
authors.forename: P
authors.initials: P
authors.lastname: Hartmann
authors.forename: D
authors.initials: D
authors.lastname: Taubert
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D015415:Biomarkers / Q000032:analysis; D002467:Cell Nucleus / Q000235:genetics; D015331:Cohort Studies; D004272:DNA, Mitochondrial / Q000032:analysis; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D011480:Protease Inhibitors / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D012044:Regression Analysis
chemical_list: D015415:Biomarkers; D004272:DNA, Mitochondrial; D011480:Protease Inhibitors; D012333:RNA, Messenger