TY - JOUR
T1 - Proteomic analysis identifies prohibitin down-regulation as a crucial event in the mitochondrial damage observed in HIV-infected patients
AU - Ciccosanti, Fabiola
AU - Corazzari, Marco
AU - Soldani, Fabio
AU - Matarrese, Paola
AU - Pagliarini, Vittoria
AU - Iadevaia, Valentina
AU - Tinari, Antonella
AU - Zaccarelli, Mauro
AU - Perfettini, Jean Luc
AU - Malorni, Walter
AU - Kroemer, Guido
AU - Antinori, Andrea
AU - Fimia, Gian Maria
AU - Piacentini, Mauro
PY - 2010
Y1 - 2010
N2 - Background: Highly active antiretroviral therapy (HAART) has largely reduced the occurrence of AIDS-related diseases and death in HIV-infected patients. However, HAART produces serious side effects mainly attributed to mitochondrial toxicity. Methods: To elucidate the molecular basis of HAART-related dysfunctions, we analysed the mitochondrial proteome of peripheral blood mononuclear cells from HIV-infected patients using two-dimensional gel electrophoresis and MALDI-TOF/TOF mass spectrometry. Proteomic analysis was performed on HIV patients who were either treatment- naive or under HAART therapy including zidovudine or stavudine as nucleoside reverse transcriptase inhibitors (NRTIs). Results: As compared to healthy donors, HAART-treated HIV-infected patients exhibited decreased levels of mitochondrial enzymes associated with energy production as well as mitochondrial chaperones. Moreover, significant alterations in the mitochondria-cytoskeleton network were observed. Notably, most of these changes were already detectable in untreated HIV carriers and persisted or worsened after HAART, indicating that relevant mitochondrial alterations were initially caused by HIV infection. Finally, in vitro experiments aimed at validating the proteomic results showed that down-regulation of the mitochondrial chaperone prohibitin is a causative event in NRTI-induced mitochondrial damage. Conclusions: Our results indicate a major role of HIV infection in the mitochondrial toxicity of HAART-treated patients and identify novel candidate markers for assessing the risk of HIV- and HAART-related pathologies.
AB - Background: Highly active antiretroviral therapy (HAART) has largely reduced the occurrence of AIDS-related diseases and death in HIV-infected patients. However, HAART produces serious side effects mainly attributed to mitochondrial toxicity. Methods: To elucidate the molecular basis of HAART-related dysfunctions, we analysed the mitochondrial proteome of peripheral blood mononuclear cells from HIV-infected patients using two-dimensional gel electrophoresis and MALDI-TOF/TOF mass spectrometry. Proteomic analysis was performed on HIV patients who were either treatment- naive or under HAART therapy including zidovudine or stavudine as nucleoside reverse transcriptase inhibitors (NRTIs). Results: As compared to healthy donors, HAART-treated HIV-infected patients exhibited decreased levels of mitochondrial enzymes associated with energy production as well as mitochondrial chaperones. Moreover, significant alterations in the mitochondria-cytoskeleton network were observed. Notably, most of these changes were already detectable in untreated HIV carriers and persisted or worsened after HAART, indicating that relevant mitochondrial alterations were initially caused by HIV infection. Finally, in vitro experiments aimed at validating the proteomic results showed that down-regulation of the mitochondrial chaperone prohibitin is a causative event in NRTI-induced mitochondrial damage. Conclusions: Our results indicate a major role of HIV infection in the mitochondrial toxicity of HAART-treated patients and identify novel candidate markers for assessing the risk of HIV- and HAART-related pathologies.
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U2 - 10.3851/IMP1530
DO - 10.3851/IMP1530
M3 - Article
C2 - 20516557
AN - SCOPUS:77952919203
VL - 15
SP - 377
EP - 390
JO - Antiviral Therapy
JF - Antiviral Therapy
SN - 1359-6535
IS - 3
ER -