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count that intact human osteosarcoma cells may undergo MPT and mitochon-
drial swelling in a fully reversible manner, without inducing cell death.
In any case, the analysis of DC, a reliable mirror of the capacity to syn-
thesize ATP and of mitochondrial membrane impermeability, is an important
parameter to considered when studying apoptosis.
INTERACTIONS BETWEEN HIV, ANTIRETROVIRAL THERAPIES, AND
MITOCHONDRIA
More than 10 years ago, Flomembaum et al. studied portions of myocardium
obtained postmortem to ascertain whether cardiac tissue from patients who
died from acquired immunode®ciency syndrome (AIDS) might be infected by
the human immunode®ciency virus (HIV ) type-1 ( Flomenbaum et al., 1989).
The three hearts they analyzed were positive for HIV-1 DNA sequences, and
the researchers performed electron microscopy to localize the virus. They de-
scribed as ``unexpected'' the ®nding that large numbers of proliferating multi-
lamellated membrane bodies predominantly associated with mitochondria were
identi®ed in myocytes contained in these organs, as well as in the heart of an
HIV-positive individual. Immunocytochemistry of membrane bodies did not
reveal the presence of p24 or gp120 HIV antigens. After this pivotal report,
Dalakas et al. showed that either HIV infection or treatment with zidovudine
(azidothymidine, AZT ), the ®rst antiretroviral drug that consistently increased
survival in HIV-infected persons, was capable of causing myopathy ( Dalakas
et al., 1990). A retrospective study of 20 HIV-positive patients with myopathy
(15 treated with AZT and 5 individuals naive for antiretroviral therapy) re-
vealed that such myopathy had in¯ammatory features and was characterized by
the presence of degenerating ®bers, cytoplasmic bodies, and endomysial in®l-
trates consisting of CD8 cells and macrophages. However, numerous ``ragged-
red'' ®bers, indicative of abnormal mitochondria with paracrystalline inclusions,
were found in the biopsy specimens from the AZT-treated patients but not in
those from the others. Together with the observation that suspending therapy
resulted in a remarkable histological improvement, it was suggested that long-
term treatment with AZT could cause a mitochondrial myopathy.
The presence of ragged-red ®bers was then found in association with ubiq-
uitous abnormal mitochondria, that proliferated at the subsarcolemmal level
and had marked variations in size and shape accompanied by proliferation and
disorganization of their cristae ( Pezeshkpour et al., 1991). As AZT is a chain
terminator that inhibits mitochondrial g-DNA polymerase, the amount of
mitochondrial (mt) DNA was also measured, and it was observed that AZT-
treated patients showed a signi®cant reduction of mtDNA, likely caused by the
drug as such rather than by the virus (Arnaudo et al., 1991).
After these reports, several researchers focussed their attention on the
role of di¨erent antiretroviral drugs, the ®rst of which was AZT, in causing
mitochondrial damages. Magnetic resonance spectroscopy suggested impaired
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