Lymphocyte mitochondrial depolarization and apoptosis in HIV-1-infected HAART patients.
BACKGROUND
Efavirenz (EFV) and nevirapine (NVP), unlike nucleoside reverse transcriptase inhibitor drugs, do not inhibit mitochondrial (mt) polymerase gamma (Pol-gamma), although EFV has been shown to induce mt depolarization (Deltapsim) in vitro at supratherapeutic concentrations. However, the capacity of nonnucleoside reverse transcriptase inhibitor drugs to induce mt toxicity in vivo remains undetermined.


OBJECTIVE
To determine the influence of EFV and NVP on peripheral lymphocyte mt transmembrane potential (Deltapsim) and apoptosis in HIV-1-infected patients treated with these nonnucleoside reverse transcriptase inhibitors.


METHODS
Thirty-two HIV-1-infected patients on highly active antiretroviral therapy (HAART) between 4 and 24 months (12 on EFV, 20 on NVP) and 16 HAART-naive HIV-1-infected patients were enrolled into this study. All participants were black South African patients. Spontaneous peripheral lymphocyte apoptosis and Deltapsim were measured ex vivo by flow cytometry for all patients.


RESULTS
: CD4 T-helper apoptosis for the EFV and NVP cohorts was 19.38% +/- 2.62% and 23.35% +/- 1.51% (mean +/- SEM), respectively, whereas total lymphocyte Deltapsim was 27.25% +/- 5.05% and 17.04% +/- 2.98%, respectively. Both parameters for each cohort were significantly lower (P < 0.05) than that of the HAART-naive patients. The NVP cohort exhibited both a significant time-dependent increase in peripheral lymphocyte Deltapsim (P = 0.038) and correlation between T-helper apoptosis and Deltapsim (P = 0.0005). These trends were not observed in the EFV cohort.


CONCLUSIONS
This study provides evidence that both EFV and NVP induce peripheral lymphocyte Deltapsim in HIV-1-infected patients on nonnucleoside reverse transcriptase inhibitor-based HAART, which in the case of NVP is sufficient to induce the apoptosis cascade.
Karamchand
Leshern
L
Department of Medical Biochemistry, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
Dawood
Halima
H
Chuturgoon
Anil A
AA
D000480:Alkynes; D023241:Antiretroviral Therapy, Highly Active; D017209:Apoptosis; D048588:Benzoxazines / Q000009:adverse effects* / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology* / Q000648:ultrastructure; D015331:Cohort Studies; D003521:Cyclopropanes; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000473:pathology; D015497:HIV-1; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000139:chemically induced* / Q000276:immunology; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D019829:Nevirapine / Q000009:adverse effects* / Q000627:therapeutic use; D010865:Pilot Projects; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D016176:T-Lymphocyte Subsets / Q000502:physiology* / Q000648:ultrastructure; D006377:T-Lymphocytes, Helper-Inducer / Q000502:physiology*
D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine; C098320:efavirenz