Proteomic analysis identifies prohibitin down-regulation as a crucial event in the mitochondrial damage observed in HIV-infected patients.
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.
National Institute for Infectious Diseases, 'Lazzaro Spallanzani' IRCCS, Rome, Italy.
Fabiola
F
Ciccosanti
Marco
M
Corazzari
Fabio
F
Soldani
Paola
P
Matarrese
Vittoria
V
Pagliarini
Valentina
V
Iadevaia
Antonella
A
Tinari
Mauro
M
Zaccarelli
Jean-Luc
JL
Perfettini
Walter
W
Malorni
Guido
G
Kroemer
Andrea
A
Antinori
Gian Maria
GM
Fimia
Mauro
M
Piacentini
D019380:Anti-HIV Agents / Q000009:adverse effects* / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects / Q000379:methods; D015536:Down-Regulation; D015180:Electrophoresis, Gel, Two-Dimensional; D015658:HIV Infections / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D000091402:Prohibitins; D040901:Proteomics; D012097:Repressor Proteins / Q000378:metabolism*; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D018119:Stavudine / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D015215:Zidovudine / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use
D019380:Anti-HIV Agents; D000091402:Prohibitins; D012097:Repressor Proteins; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D018119:Stavudine