The idea of organizing a meeting on different aspectsof the interactions between mitochondria, HIV infectionand its treatment emerged as a result of thegrowing interest the scientific community has shown inthis topic during recent years. Many of the scientistswho have been conducting clinical as well as morebasic research in this field responded enthusiastically tothe invitation to present and discuss their ongoingresearch at the first international conference on“Mitochondrial toxicity and HIV infection: understandingthe pathogenesis for a therapeutic approach”,held in Modena (Italy) from May 19-21, 2005. Theinitiative for this conference was taken by ProfessorAndrea Cossarizza, Chair of Immunology at theUniversity of Modena and Reggio Emilia, and hiscolleagues from the Department of Infectious Diseasesat the same University, Professor Roberto Esposito andDr Cristina Mussini.The meeting was made possible by un unrestrictededucational grant from Gilead Sciences, Italy, andpublication of part of the proceedings of the meeting inthis supplement of Antiviral Therapy was madepossible by an unrestricted grant from Sigma Tau, Italy.We wish to underline that the conference organizershad full responsibility for the content of theprogramme as well as the choice of speakers andsession chairs, without any interference from the pharmaceuticalsponsors. All papers appearing in thissupplement underwent peer-review prior to beingconsidered for publication.The meeting started with a lectura magistralis given byProfessor Vladimir Skulachev (State University ofMoscow, Russia), one of the founding fathers of thefield of “bioenergetics”, who provided an overview onprogrammed death in relation to ageing, at the level ofindividual cells (apoptosis), whole organisms (phenoptosis)as well as subcellular organelles includingmitochondria (mitoptosis). This stimulated discussionon whether several of the adverse effects of treatmentfor HIV infection might be a reflection of “acceleratedageing” by mechanisms including mitochondrialtoxicity.The talks and related discussions that took place in thefollowing days revealed that several issues concerningthe detrimental effects which HIV, other concomitantinfections such as those with hepatitis C, and HIVtherapy may have on mitochondria warrant furtherinvestigation and clarification in the years to come.What is becoming increasingly clear is that antiretrovirals,and nucleoside analogue reverse transcriptaseinhibitors (nRTI) in particular, may affect mitochondriain more ways than one. Inhibition by nRTI ofDNA γ-polymerase resulting in mitochondrial DNA(mtDNA) depletion remains one of the cornerstones bywhich nRTI may induce mitochondrial toxicity. It isevident however that nRTI and even other classes ofantiretrovirals such as HIV protease inhibitors, mayhave additional effects on mitochondria, for instanceby way of exerting direct effects on mtRNA transcriptionand mitochondrial enzymes. Differences betweenindividual agents as well as differences in the extent towhich these effects may play a role in different celltypes remain to be further delineated.An important problem still remaining is the choice ofthe type of cell in which to best measure mitochondrialmarkers as a possible reflection of treatment toxicity.Blood obviously remains the easiest tissue to obtainfrom patients, but contamination with platelets whichcontain numerous mitochondria may yield poorlyinterpretable results when using whole blood orperipheral blood mononuclear cells (PBMCs). Betterpurified cell populations such as isolated CD4+ orCD8+ T lymphocytes, or platelet-depleted lymphocytes or monocytes may provide more reliable results andneed to be investigated further. Nevertheless, othertissues and cells coming directly from the organsystems affected by the treatment toxicity being studied(for instance adipose, hepatic or renal) may be moreinformative, and more appropriate when trying toassess the possible mitochondrial pathogenesis underlyinga specific drug toxicity.In order for any marker of mitochondrial toxicity tobecome clinically useful for the early detection of drugtoxicity, its sensitivity, specificity and predictive valuewould have to be adequately demonstrated in thecontext of appropriate clinical studies. Several technologies,assays and methodologies are nowadays usedby several groups to analyse different aspects ofmitochondrial biology. Flow cytometry and confocalmicroscopy, utilizing specific fluorescent probes, candetect at the single cell level changes in several mitochondrialparameters (including changes in internalmembrane potential or organelle mass), as well asmodification in the morphology of the cell or tissueunder investigation, and are widely used in differentlaboratories. Classic biochemical assays, which canmeasure different aspects of mitochondrial respiratorychain function, are also quite popular, even if theyoften require large amounts of biological material,classically skeletal muscle. Thanks to the improvementin molecular biological techniques, including assaysbased upon the real time polymerase chain reaction,the measurement of the amount of mitochondrial DNAper cell is becoming easier, and a variety of scientists –even if different genes are used as target – are obtainingsimilar results, also as far as the absolute number ofmtDNA copies in a given cell is concerned.Nevertheless, adequate quality control and assuranceprogrammes are key in order to allow comparison ofresults obtained by different groups of investigators.Of note, a task force focussing on the further standardizationof mtDNA quantification, involvinginvestigators in the US, Canada, Australia, and Europe,has just been created. Similar approaches should beadvocated for the evaluation of additional mitochondrialmarkers such as the quantification ofmitochondrial RNA.Conferences such as the one held in Modena will hopefullycontribute to the further unravelling of the rolemitochondria play in the setting of HIV infection andits treatment, ultimately leading to safer treatments forour patients.
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|Anno di pubblicazione:||2005|
|Titolo:||Mitochondria, HIV infection and its treatment: where do we go from here?|
|Autori:||Cossarizza A; Reiss P|
|Autori interni:||COSSARIZZA, Andrea|
|Appare nelle tipologie:||Articolo su rivista|
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