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Mitochondrial Effects of HIV In ART-Naive
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"Mitochondrial Effects of HIV Infection on the Peripheral Blood Mononuclear Cells of HIV-Infected Patients Who Were Never Treated with Antiretrovirals"
Clinical Infectious Diseases Sept 1, 2004;39:710-716
Òscar Miró,1 Sònia López,1 Esteban Martínez,2 Enric Pedrol,3 Ana Milinkovic,2 Elisabeth Deig,3 Glòria Garrabou,1 Jordi Casademont,1 Josep M. Gatell,2 and Francesc Cardellach1
1Mitochondrial Research Laboratory, Muscle Research Unit, Department of Internal Medicine, and 2Infectious Disease Unit, Hospital Clínic, August Pi i Sunyer Biomedical Research Institute, School of Medicine, University of Barcelona, Barcelona, and 3HIV-Unit, Department of Internal Medicine, Fundació HospitalAsil de Granollers, Granollers, Catalonia, Spain
ABSTRACT/SUMMARY
To investigate the effects of HIV infection on mitochondrial DNA (mtDNA) content and other mitochondrial parameters, we used peripheral blood mononuclear cells (PBMCs) from 25 asymptomatic antiretroviral-naive human immunodeficiency virus (HIV)infected patients and from 25 healthy control subjects.
HIV-infected patients had significant decreases in mtDNA content (decrease, 23%; P < .05) and in the activities of mitochondrial respiratory chain (MRC) complex II (decrease, 41%; P < .001), MRC complex III (decrease, 38%; P < .001), MRC complex IV (decrease, 19%; P = .001), and glycerol-3-phosphate dehydrogenase (decrease, 22%; P < .001), along with increased lipid peroxidation of PBMC membranes (P = .007).
Therefore, HIV infection is associated not only with mtDNA depletion, but also with extensive MRC disturbances and increased oxidative damage.
BACKGROUND
Antiretroviral therapy that contains nucleoside reverse-transcriptase inhibitors (NRTIs) may induce adverse effects due to mitochondrial toxicity. The main pathogenic mechanism suspected involves the inhibition of mtDNA polymerase g (mtDNA g-pol), which is the only enzyme responsible for the replication of mtDNA (a circular, double-stranded DNA molecule of 16.5 kb), which only encodes for some components of some mitochondrial respiratory chain (MRC) complexes. Depletion of mtDNA, deletions, and point mutations have been reported to occur in some tissues as a consequence of inhibition of mtDNA g-pol by NRTIs. In some instances, these abnormalities may lead to an impairment of MRC function.
Although previous studies that have assessed the mitochondrial effects of NRTIs have systematically included a group of untreated HIV-infected patients, they have essentially lacked a control group of non-HIV-infected people. Although this fact does not negate the conclusions reached by these studies regarding the harmful effects of NRTIs against mitochondria, the role (if any) of HIV in the diminishment of mtDNA content remains unclear. A recent study by Côté et al. found that the mtDNA content in the buffy coats of 47 asymptomatic HIV-infected patients who had never received antiretroviral therapy was significantly reduced (56%), compared with that of 24 non-HIV-infected people (100%). This difference was not explained by the lower CD4+ T lymphocyte count of the HIV-infected patients, compared with the nonHIV-infected subjects. Similarly, a very recent study by Miura et al. showed a significant reduction in the mtDNA content (70%) of PBMCs from 46 antiretroviral-naive HIV-infected patients, compared with 29 healthy people (100%). In the study by Miura et al., mtDNA content was positively correlated with CD4+ T cell count and was inversely correlated with HIV load. Nonetheless, it currently has not been ascertained whether mtDNA depletion is an isolated finding or whether it is associated with impaired MRC function or, even, with more-extensive damage of mitochondrial enzyme capacity that leads to increased oxidative damage.
AUTHOR DISCUSSION
Previous studies have noted that some degree of mtDNA depletion is present in the PBMCs, skeletal muscle, adipose tissue, liver, or placenta of HIV-infected patients. However, these data were indirectly obtained in studies with main objectives that did not focus on the effects of HIV on mitochondria. In addition, to date, no studies demonstrating mitochondrial dysfunction associated with mtDNA depletion in human PBMCs have been reported. Therefore, the results of the present study show that HIV-infected patients who have never been treated with antiretrovirals have decreased mtDNA levels, along with decreased enzyme activity of the MRC complexes and other metabolic pathways, as well as increased oxidative damage of the PBMC membranes. This is the first direct evidence that HIV is associated with extensive functional mitochondrial damage, which does not seem to only be limited to MRC complexes encoded by mtDNA.
The mechanism by which HIV causes this mtDNA depletion is currently elusive. Nonetheless, the coexistence of a generalized impairment that affects both mtDNA- and nuclear DNA-encoded MRC complexes, as well as G3Pdh activity, indicates that mtDNA depletion may be better interpreted as resulting from generalized mitochondrial damage rather than from a specific mechanism of the mtDNA lesion induced by HIV. This hypothesis agrees with the findings of recent studies that have reported signs of mitochondrial necrosis in HIV-infected cells. Moreover, a main feature of HIV pathogenesis is cell death of CD4+ T lymphocytes as a result of apoptosis, and, currently, it is well known that several HIV-1-encoded proteins (Env, Vpr, Tat, and PR) are directly or indirectly associated with the dissipation of mitochondrial membrane potential, thereby causing apoptotic cell death. In fact, the appearance of morphologic mitochondrial abnormalities, along with increased apoptosis, has been demonstrated in both ex vivo studies of individuals with seroconversion and in vitro experiments involving acutely infected monocytoid and lymphoblastoid cells. Therefore, it is conceivable that, in addition to contributing to CD4+ T lymphocyte depletion, proapoptotic effects of virion proteins also have a role in the mtDNA depletion and the mitochondrial functional disturbances observed in the present study. This hypothesis, which probably is better addressed to cultured HIV-infected cells, revolves around the adverse effects of the viral gene products against mitochondria.
Although some authors have suggested that the intensity of HIV infection could correlate with the degree of mitochondrial damage, other authors have reported discordant data. In this sense, although Miura et al. reported that mtDNA levels in HIV-infected individuals have a direct correlation with the CD4+ T cell count and an inverse correlation with the number of HIV RNA copies, Côté et al. did not identify such an association. In our series, no significant association was found between markers of severity of infection and mitochondrial function; only a tendency toward an increase in the mitochondrial content in patients with a higher number of circulating HIV copies was remarkable. This fact could reflect that the classically known mitochondrial proliferation observed in the skeletal muscle in primary MRC defects is a form that responds to toxic insults.
The combined effects of HIV and antiretrovirals on mitochondria should be considered, because mitochondriotoxicity is a well known side effect of antiretrovirals. On one hand, the negative effects of HIV infection, per se, on mtDNA could render HIV-infected patients more susceptible to the mitochondrial toxicities of NRTIs, compared with the general population, because HIV-infected patients can reach the "threshold" for clinically relevant adverse effects faster. As an example, we have found that untreated HIV-infected patients with greater viremia showed less complex IV activity; this finding, although not statistically significant, suggests that HIV-infected patients may be more susceptible than non-HIV-infected individuals to the mitochondrial toxic effects of antiretrovirals. In addition, NRTIs also induce apoptotic death in several cell types. Conversely, protease inhibitors exert antiapoptotic effects, which seem to be relevant for their clinical benefit, in a way different from that achieved by means of their antiviral activity. Thus, the net effect of HIV and antiretrovirals on mitochondrial function may differ from one patient to another, and it may explain, at least in part, the existence of discordant results of studies of the mitochondrial toxicity of antiretrovirals.
Whatever the mechanism involved in the effects of HIV on mitochondria, we believe that the findings of the present study support the hypothesis that the effects of HIV on mtDNA content are nonspecific and would be better reflected in a scenario of more diffuse mitochondrial damage, probably in association with apoptotic changes caused by HIV. Moreover, our results should also be taken into account in the design of further studies evaluating the mitochondrial toxic effects of antiretrovirals, because untreated individuals with HIV infection should be included in the control group of such studies.
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