ABSTRACT
Inhibitors of HIV protease have been shown to have antiapoptotic effects in vitro, yet whether these effects are seen in vivo remains controversial. In this study, we have evaluated the impact of the HIV protease inhibitor (PI) nelfinavir, boosted with ritonavir, in models of nonviral disease associated with excessive apoptosis. In mice with Fas-induced fatal hepatitis, Staphylococcal enterotoxin B-induced shock, and middle cerebral artery occlusion-induced stroke, we demonstrate that PIs significantly reduce apoptosis and improve histology, function, and/or behavioral recovery in each of these models. Further, we demonstrate that both in vitro and in vivo, PIs block apoptosis through the preservation of mitochondrial integrity and that in vitro PIs act to prevent pore function of the adenine nucleotide translocator (ANT) subunit of the mitochondrial permeability transition pore complex.
Subject(s)
Apoptosis/drug effects , HIV Protease Inhibitors/pharmacology , Mitochondrial ADP, ATP Translocases/antagonists & inhibitors , Animals , Antibodies/administration & dosage , Disease Models, Animal , Female , Hepatitis/drug therapy , Hepatitis/pathology , Humans , Jurkat Cells , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mitochondrial ADP, ATP Translocases/chemistry , Models, Molecular , Nelfinavir/pharmacology , Ritonavir/pharmacology , Shock, Septic/drug therapy , Shock, Septic/pathology , Signal Transduction/drug effects , Stroke/drug therapy , Stroke/pathologyABSTRACT
HIV infection is inexorably linked with disordered regulation of apoptosis, and consequent alterations in mitochondrial homeostasis, resulting in CD4 T cell death and enhanced susceptibility to opportunistic infections and malignancies. Effective treatment of HIV reverses the changes in mitochondrial homeostasis and apoptosis, and enhances immunocompetence. This review will summarize current knowledge of: i) the associations of apoptosis with HIV disease progression; ii) mechanisms of enhanced apoptosis in HIV infection; iii) putative role of apoptosis in HIV complications; iv) direct effects of HIV therapies on mitochondria and apoptosis; and finally v) treatment strategies for HIV based upon modifying the apoptotic response.