Vol. 284, Issue 1, H1-H9, January 2003
EDITORIAL
Defective mitochondrial DNA replication and NRTIs:
pathophysiological implications in AIDS cardiomyopathy
William
Lewis
Department of Pathology, Emory University, Atlanta, Georgia
30322
 |
INTRODUCTION |
DESPITE THE AVAILABILITY of newer and
more effective antiretroviral therapy (20) and some
promise from human immunodeficiency virus (HIV) vaccine studies
(39), the acquired immunodeficiency syndrome (AIDS)
epidemic causes increasing global mortality. At present, nucleoside
reverse transcriptase inhibitors (NRTIs) in combination with other
antiretrovirals (highly active antiretroviral therapy, HAART) are the
cornerstones of AIDS therapy, but their extensive use has brought
serious side effects to light, including cardiomyopathy (CM)
(134).
Clinical experience, pharmacological, cellular, and molecular
biological evidence links altered mitochondrial DNA (mtDNA) replication
to the toxicity of NRTI (8, 56, 57, 67, 68, 115, 132) in
many tissues. mtDNA replication defects and mtDNA depletion in
target tissues are observed clinically and experimentally. A working
hypothesis explains the varied clinical side effects and invokes
mitochondrial toxicity from NRTIs in HAART. Organ-specific pathological
changes or diverse systemic effects result from and are frequently
attributed to HAART, in which NRTIs are included (5, 7, 16, 35,
53, 81, 90, 96, 110, 117, 124).
Mitochondrial toxicity from NRTIs was established by clinical, in
vitro, and in vivo investigations that related mtDNA depletion in
target tissues to antiretroviral treatment. More recently, HAART
combinations caused mitochondrial toxicity, including lactic acidosis
and mtDNA depletion (16, 23). As the AIDS epidemic continues and as survival with HIV infection is prolonged by treatment with HAART, long-term side effects of NRTIs may be more commonly observed. The risk-to-reward ratio unambiguously favors treatment with
HAART because AIDS is fatal in the absence of treatment. This editorial
examines some proposed mechanisms of NRTI mitochondrial toxicity with
respect to key cell biological, pathological, and pharmacological
events and relates those events to the development of CM in AIDS.
The first clinical and experimental findings were presented in the
early 1990s (1, 24, 65, 69, 76). The shared features of
mtDNA depletion and energy depletion became key observations and
related the clinical and in vivo experimental findings to inhibition of
mtDNA replication by NRTI triphosphates in vitro (49, 62, 77, 86,
98, 132). Subsequent to those observations, another series of
observations suggested that mitochondrial energy deprivation is
concomitant with or the result of mitochondrial oxidative stress in
AIDS (from HIV, for example) or from NRTI therapy itself. In vivo
studies with NRTI treatment of inbred mice (4, 27) support
this hypothesis, and data from our group and others employing AIDS
transgenic mice revealed that oxidative stress results from transgenic
expression of HIV tat in the heart and liver (14, 15,
103).
An important correlate is that mtDNA mutations may result from
oxidative mtDNA damage, aberrant mtDNA replication, and altered mtRNA
transcription. Together, these interlinked events are the cornerstones
of the "mitochondrial dysfunction hypothesis" (67) that we applied in the laboratory in models of AIDS CM (66, 71-73, 76). Additionally, the same principles are
applicable to mitochondrial toxicity in other targets (70, 74,
75, 77). The "mitochondrial dysfunction hypothesis"
(67) clarifies important pathophysiological events in NRTI
toxicity. It is reviewed herein in the context of NRTI mitochondrial
metabolism and AIDS CM.
It may be reasonably argued that analysis of mechanisms of NRTI-induced
mitochondrial toxicity is analogous to approaches that examine defects
in genetic mitochondrial illnesses in which the defective mitochondrial
gene product, oxidative stress, and the environment contribute to
disease pathogenesis (109). It should be noted that
clinical and basic reviews of mitochondrial toxicity of NRTIs have been
presented elsewhere in which other aspects of the clinical and
biological events are detailed (8, 9, 57, 67, 68, 93).
| |
NRTIS AND RELATIONSHIP TO MITOCHONDRIAL TOXICITY IN
TARGET TISSUES IN AIDS |
At present there are at least five useful NRTIs in the treatment
of HIV infection (17). Zidovudine (AZT,
3'-azido-2',3'-deoxythymidine), zalcitibine (ddC,
2',3'-dideoxycytidine), didanosine (ddI, 2',3'-dideoxyinosine), stavudine (d4T, 2',3'-didehydro-3'-dideoxythymidine), and lamivudine {3TC, 3 thiacytidine;
cis-1-[2'-hydroxymethyl-5'-(1,3oxathiolanyl)]cytosine} are
formidable NRTIs that also serve as tools in vitro and in vivo in
biomedical and cell biological models of inhibition of DNA
polymerase-
(DNA pol-) and mtDNA replication. Today most agents
for HIV infection are given in combined antiretrovirals in HAART
(134). From the preclinical data alone, the clinical utility of NRTIs may not be ascertained. Although NRTIs with promising antiretroviral activity in vitro continue to be developed
(20), some NRTIs are toxic in vivo or clinically. One such
agent, fluorodideoxyadenosine (FDDA, 2'-fluoro-2',3'-dideoxyadenosine),
went into clinical trial but was discontinued because it later
exhibited severe adverse events, including lactic acidosis (19,
42).
Other NRTIs are used to treat common coinfections seen in patients
infected with HIV. Chronic hepatitis B infection is a serious and
common coinfection that increases morbidity and mortality (47). Accordingly, treatment of chronic hepatitis B
infection would benefit such patients. After in vitro studies
documented efficacy, the pyrimidine nucleoside analog fialuridine
(1-[2-deoxy-2-fluoro-
-D-arabinofuranosyl]-5-iodouracil, FIAU)
was used in clinical trials with promising early results. Later in the
trials, FIAU was found to be extremely toxic to the liver, skeletal and
cardiac muscle, the pancreas, and the peripheral nerve in treated
patients. Mitochondrial toxicity from FIAU was profound. Lactic
acidosis and hepatic failure required heroic clinical interventions and
necessitated early termination of the trials. Deaths occurred.
Abandonment of these compounds as pharmacological agents was
subsequently confirmed by findings of mitochondrial toxicity in animal
models (70, 118) and in humans (87).
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PREDISPOSITION TO NRTI TOXICITY |
Presently, genetic predispositions to NRTI toxicity or associated
somatic mutations that may have pharmacogenetic implications are
incompletely understood. Clinical correlates for NRTI toxicity were
made in some of the early studies in which AZT liver toxicity was
associated with obesity and female gender (22, 96), but more refined correlates were lacking. NRTI toxicity presents a variable
and complex diagnostic phenotype in the treated population and mimics
key features of mitochondrial diseases. As such, NRTI toxicity may
serve as an important model system for relevant pharmacogenomic studies.
For patients with lactic acidemia and treatment with NRTI-containing
regimens, a phenotype of mtDNA depletion was found in blood cells
(23). Depending on the biological system, deleterious effects on mitochondrial structure and function in selected targets have been documented (68). The specificity of blood cell
mtDNA as a surrogate markers for NRTI toxicity (mtDNA depletion) was impeded by the selection of control groups (105). The
impact on mitochondrial function in the surrogate tissue remains
unclear (11), despite the logic of the working hypothesis.
Standard methods for diagnosis suggest examination of plasma lactate or lactate-to-pyruvate ratios (12, 105), but these also
require careful sample preparation and handling. Overall, depletion of mtDNA appears to be an important marker of the toxic process and may
serve as a diagnostic hallmark (1, 69), as a way to
monitor successful HAART therapy (23), and a therapeutic
window that enables changes in HAART regimens. The ideal
surrogate tissue to monitor mtDNA depletion from NRTIs remains to be
determined, but blood samples or other samples may serve as promising,
noninvasive tissue sources.
The "DNA pol- hypothesis" (68) integrates clinical
observations and biochemical, pharmacological, and pathological data into a rational pathophysiological framework. First, the intracellular and intramitochondrial abundance of the NRTI must be sufficient to
impact on the intramitochondrial pool of nucleotides. The NRTI triphosphates (when synthesized by cellular enzymes) compete for incorporation into nascent mtDNA with their natural counterparts.
Mitotically quiescent tissues like the myocardium and liver possess
intramitochondrial nucleoside kinases for salvage [including thymidine
kinase 2 (TK2), the mammalian mitochondrial isoform] (2).
These kinases must phosphorylate NRTI sufficiently to provide substrate
for downstream phosphorylation to the pharmacologically active (and
toxic) moiety. The NRTI triphosphate must be an effective inhibitor of
DNA pol- so that so that the inhibitory constant (Ki) with DNA pol- authentically reflects
both enzymological inhibition and tissue toxicity. Inhibition
is dependent (in part) on the ability of NRTI triphosphate to compete
with the native nucleotide at the nucleotide binding site of DNA
pol-. Subsequently, its ability to adulterate the nascent mtDNA
depends on the incorporation of monophosphate and chain termination of
mtDNA. Target tissues must be significantly affected by energy
deprivation in the face of depleted mtDNA. This follows the oxidative
phosphorylation (OXPHOS) paradigm (125-127) as the
phenotype from the toxic events relates to a "dose effect" of mtDNA replication.
Aspects of the DNA pol- hypothesis are founded in the principles of
mitochondrial medicine (83). If the intramitochondrial pool of nucleosides is disrupted, altered energetics may occur. This is
seen in the neurogastric syndrome [mitochondrial
neurogastrointestinal encephalomyopathy;
(95)]. Inefficient monophosphorylation of thymidine in mitochondria (by mitochondrial TK2) results in genetic illnesses with lactic acidosis and muscle weakness (107).
Arnold Katz (58) explained the role of mitochondrial
alterations in the development of low output congestive heart failure
using such reasoning. The inability of mitochondria to function
normally in that latter setting related to decreased cardiac
performance. It is generally considered axiomatic that many genetic
mitochondrial illnesses manifest with a threshold based at least in
part to the heteroplasmic effects of the associated mtDNA mutation as stated in the OXPHOS paradigm (125-127). Energy
deprivation, possibly the initiating step of NRTI toxicity based on
mtDNA depletion, relates decreased energy abundance in tissues (e.g.,
heart) to decreased functional mitochondria. To that extent, the
threshold phenomenon is intimately involved with phenotypic change.
| |
NUCLEOTIDE POOLS, NRTIS, AND MTDNA
REPLICATION |
One important aspect of NRTI toxicity that is part of the DNA
pol- hypothesis (68) is the requirement of sufficient
intramitochondrial NRTI mass to alter mtDNA replication through DNA
pol- inhibition by NRTI triphosphate. Because the active
pharmacological (and toxic) element of AZT is the triphosphate (i.e.,
AZTTP), and AZTTP is inhibits both HIV reverse transcriptase (34,
88) and mammalian DNA pol- in vitro (77), it
follows logically that sufficient NRTI triphosphate must be available
for inhibition of mtDNA synthesis, depletion of mtDNA
(112), and development of toxic manifestations.
For the pyrimidine AZT, phosphorylation occurs in three intracellular
steps. TK phosphorylates AZT to AZTMP (detailed below). TK
phosphorylates AZTMP to AZTDP. Nucleoside diphosphate kinase yields the
active AZTTP (21) from AZTDP. Accordingly, a key step in
the pathophysiology of NRTI pharmacology and toxicity are regulation of
natural dNTP and NRTI triphosphate pool sizes that impact on mtDNA
replication as well as the maintenance of function of key elements
involved in NRTI phosphorylation.
Mitochondrial ribonucleotide reductase is not reported, so import of
dNTPs or deoxyribonucleosides (or the analogous NRTIs) into
mitochondria must occur. dNTPs are synthesized by the cytosolic ribonucleotide reductase and can be imported directly through the
mitochondrial membrane (6). Deoxyribonucleosides are
derived from dNTP catabolism and from extracellular sources
(104). Import into mitochondria allows for phosphorylation
by specific kinases (52).
| |
NUCLEOSIDE KINASES FOR NUCLEOSIDE PROCESSING: MAMMALIAN TK
ISOFORMS AND DEOXYGUANOSINE KINASE |
The salvage pathway activates deoxynucleosides by sequential
phosphorylation to their biological active triphosphates. The first
step is usually rate limiting (2). Deoxynucleosides are phosphorylated to their respective monophosphates by deoxynucleoside kinases (2). In the cytoplasmic compartment, this is
accomplished by deoxycytidine kinase (44) and the isoform
TK1, an S phase-regulated kinase expressed in dividing cells
(2).
As mentioned previously, in the mitochondrial compartment, TK2 is the
isoform that catalyzes the first step in the mitochondrial salvage
pathway for pyrimidines, including deoxythymidine, deoxyuridine, and
deoxycytidine, and NRTIs like FIAU and AZT. With respect to purines, deoxyguanosine kinase (dGK) initiates salvage in mitochondria for mtDNA synthesis. This 60-kDa mitochondrial enzyme
monophosphorylates deoxyguanosine, deoxyadenosine, and deoxyinosine
(38, 97).
Whereas TK1 (cytosolic isoform) has relatively low activity in extracts
of striated skeletal muscle (29, 30), TK2 (mitochondrial) has higher activity in muscle. Although TK2 phosphorylates AZT, TK2
performs the phosphorylation relatively poorly compared with TK1
(94). TK2 has a broader substrate range and phosphorylates deoxycytidine and 5'-substituted deoxythymidine and deoxycytidine analogs. When compared with TK2, TK1 tolerates more sugar
modifications. This allows for phosphorylation of 2',3'-ddN
analogs that are less effective substrates for TK2 (94).
ddNTPs function as either competitive inhibitors of the natural
substrates of polymerases (reviewed in Ref. 89); or lead
to chain termination (88, 121). Bovine striated muscle TK2
has been purified to homogeneity (50).
Unlike TK2 (which resides in the mitochondrial matrix)
(61), the submitochondrial location of dGK was unknown for
some time. A potential mitochondrial targeting peptide
(128) suggested that dGK is a bona fide mitochondrial
matrix protein. Although the targeting peptide does not guarantee a
matrix localization, Eriksson's group (100) localized dGK
to the mitochondrial matrix. Human dGK efficiently phosphorylates dG
and dA, whereas TK2 phosphorylates deoxythymidine, deoxycytidine,
deoxyuridine. Genetic mutations in dGK result in a
mitochnondrial phenotype (discussed below).
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NRTI INHIBITION OF MTDNA REPLICATION AND DNA
POLY- |
Nuclear DNA encodes 80% of the OXPHOS genes (the principal source
of myocardial energy). Thirteen OXPHOS gene products are encoded by
mtDNA (reviewed in Ref. 125). In contrast to mitochondrial genetic diseases where mutations are documented (126),
acquired defects in mtDNA replication resulting from inhibition of NRTI of mtDNA replication may yield phenotypic OXPHOS defects that mimic the
genetic illnesses.
It should be understood that mtDNA replication is governed by nuclear
encoded polypeptides. DNA pol- (the mitochondrial DNA polymerase) is
the nuclear-encoded mtDNA replication enzyme in eukaryotic cells. DNA
pol- extracted from the fly, the frog, and the human reveals
significant sequence homology. DNA pol- contains two subunits. One
subunit (25-140 kDa) contains polymerase and exonuclease catalytic
activity. An accessory subunit of 41-55 kDa is required for
processive synthesis (10, 40, 48, 78, 129, 131).
Polymerase function in DNA pol- is pathophysiologically linked to
the "mitochondrial dysfunction hypothesis" (67).
Decreased energy production is secondary to decreased mtDNA abundance
and results in a phenotypic changes. When DNA pol- kinetics are
inhibited by NRTI triphosphates, mtDNA synthesis is inhibited and mtDNA depletion results. Moreover, NRTI toxicity appear to be cumulative, reinforcing the similarity to mitochondrial genetic diseases.
DNA pol- is processive because of its accessory subunit. High
processivity allows the enzyme: template complex to replicate the
mitochondrial genome completely in one binding event (78). Heteroplasmy is an intracellular or intramitochondrial mix of normal
and mutant mitochondrial DNA molecules that ultimately may reflect a
phenotype (40, 129). With high DNA pol-
processivity, deletion mutants (intrinsically smaller, truncated mtDNA
templates) may be replicated more quickly and efficiently than the
native mtDNA counterparts (78, 129).
| |
GENETIC MTDNA DEPLETION SYNDROMES MOLECULAR AND
PHENOTYPIC SIMILARITIES TO NRTI MITOCHONDRIAL TOXICITY |
Analogies may be drawn between genetic mtDNA depletion syndromes
(MDS; OMIM 251880) and mtDNA depletion caused by NRTI therapy in AIDS.
It should be emphasized that in the genetic MDS, quantitative mtDNA
depletion is the critical point not necessarily the accumulation of
mtDNA mutations. Like NRTI-induced mitochondrial toxicity, MDS are
heterogeneous, autosomal-recessive disorders with tissue-specific reduction in mtDNA abundance (46, 85, 92, 123). Clinical manifestations in the hepatocerebral form of MDS include progressive liver failure, neurological abnormalities, hypoglycemia, and increased plasma lactate. Target tissues show decreased activity of respiratory chain complexes (I, III, IV, and V) and mtDNA depletion
(116). This genetic syndrome shares features with NRTI
toxicity. Treatment with AZT depletes mtDNA in the skeletal muscle of
humans and rodents (1, 69), and FIAU treatment causes
similar events in woodchucks and humans (87, 115).
TK2 mutations represent an etiology for mtDNA depletion and have been
associated syndromically with that finding. Two substitution mutations
in TK2 (His90Asn; Ile181Asn), resulted in a
phenotype of infantile myopathy and mtDNA depletion in muscle
(107). TK2 activity in muscle mitochondria was reduced to
14-45% of that found in healthy controls. This emphasizes the
importance of the mitochondrial dNTP pool in the pathogenesis of mtDNA
depletion and suggests a relationship to the myopathy found with mtDNA
depletion caused by AZT administration (24).
A single-nucleotide deletion (204delA) was identified within the coding
region of dGK that segregated with the disease in three kindreds
(84). mtDNA depletion and mutated dGK suggests that the
salvage-pathway enzymes are involved in the maintenance of balanced
mitochondrial dNTP pools. Muscle weakness, liver failure, and
multisystem involvement with lactic acidosis all are described. Many of
these findings resemble those of NRTI mitochondrial toxicity (67,
68) where heart muscle, skeletal muscle, liver, and peripheral nerve have been identified as targets.
Other genes that control mtDNA replication may play important roles
pathogenetically in heritable diseases of mtDNA depletion. Among the
gene targes included are adenine nucleotide translocator [ANT1; locus
4q34-35; (59)], thymidine phosphorylase [locus 22q.13.32qter; (95)], an unidentified gene [at
3p14-21; (60)], and DNA pol- [15q22-26;
(106)].
DNA sequences obtained from patients with progressive external
ophthalmoplegia (PEO) revealed a heterozygous A 
G mutation at codon
955 (Y955C), a highly conserved residue at the DNA pol- active site
(122). A recent series of experiments from Copeland's group (102) at the National Institute of Environmental
Health Sciences indicated that error-prone DNA polymerase with Y955C mutation is associated with decreased stringency for dNTPs and relates
to PEO. Predisposition to accumulation of mtDNA mutations (as in PEO
with Y955C) follows a course of progressive, cumulative effects.
Identification of exonuclease-deficient DNA pol- (82), the Y955C DNA pol- mutation (102), and a transgenic
mouse described by Zassenhaus and colleagues (135), in
which exonuclease-deficient DNA pol- overexpressed in the heart was
associated with CM, mtDNA point mutations, deletions, and direct
repeats points to the phenotypic correlate of the genetic alterations.
Mutations that reduce fidelity of DNA pol- cause mtDNA diseases
through ineffective or mutagenic mtDNA replication. (122). "Twinkle" is another gene encoding a putative mitochondrial
helicase that is causally related to PEO with mtDNA deletions
(113). Alternatively, ANT1 and phosphorylase mutations may
result in a similar mtDNA depletion phenotype based on alterations of
dNTP pools (59, 95). Imbalance in mitochondrial nucleotide
pools enhances base substitution errors in DNA pol- in vitro
(64, 130). In other studies, Wallace's group
(31) found mtDNA rearrangements and increased reactive
oxygen species in ANT
/ knockout mice. These
suggested that oxidative damage was integral to mtDNA defects
(31).
On a biochemical basis, one potential defense against NRTI toxicity
that is intrinsic to DNA pol- function is in the 3' 5'
exonuclease activity of the enzyme. This exonucleolytic function (63, 64) is inhibited by nucleoside 5'-monophosphates
(55).
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OXIDATIVE STRESS AND ITS RELATIONSHIP TO MTDNA
ALTERATIONS AND HIV INFECTION |
Although energy depletion from altered mtDNA replication in NRTI
toxicity is a logical consequence (68-70, 72,
74-77), related events of oxidative stress also impact on
energetics in striated muscle (27, 133) and mtDNA
replication, on heart failure in general, and on HIV infection and
AIDS. In the context of NRTI toxicity, oxidative stress is an imbalance
between the production of reactive oxygen species (such as superoxide,
hydrogen peroxide, lipid peroxides, hydroxyl radical, and
peroxynitrite) and the antioxidant defenses that prevent damage to
cells (3). Mitochondria serve as both a logical target for
the stress and as a source of the biochemical moieties that contribute
to or cause it. The proximity of mtDNA, mtRNA, mitochondrially and
nuclear-encoded proteins, and lipids to the highest gradient of
oxidants (near the source) is a crucial factor as well. Thus it is
reasonable to implicate mitochondria and oxidative stress in some
aspects of the toxicity of NRTIs. Conversely, it may be reasonable to use therapeutic strategies that are focused on the prevention of
oxidative stress as a means to prevent, attenuate, or ameliorate NRTI
toxicity. Some studies in our laboratories focus on this important
issue. The role of oxidative stress in the development of NRTI toxicity
has been reviewed in greater detail (67).
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CM AND NRTIS IN AIDS |
NRTIs cardiovascular toxicity, particularly from AZT, is a bona
fide complication of therapy. A cumulative mitochondrial skeletal myopathy occurred in AZT-treated, adult AIDS patients (24, 41, 120). "Ragged red fibers" (111) and
ultrastructural paracrystalline inclusions (24) were
observed in muscle samples and indicated subsarcolemmal accumulation of
mitochondria in the skeletal muscle with long-term, high-dose AZT
treatment. Mitochondria were enlarged and swollen ultrastructurally and
contained disrupted cristae and occasional paracrystalline inclusions
(65, 68, 76, 101). Extracts of muscle biopsy specimens of
AZT-treated patients revealed decreased skeletal muscle mtDNA.
Mitochondrial dysfunction in AZT-induced myopathy, results in
inefficient utililzation of long-chain fatty acids for -oxidation.
Fat droplets accumulated. AZT myopathy developed after at least 6 mo of
therapy and occurred in up to 17% of treated patients (25,
99). Dalakas and colleagues (24, 25) showed that it
occurs with the high-dose therapy and with current low-dose regimens.
The case for CM resulting from NRTIs in AIDS is less clear. CM related
to AZT and/or other antiretroviral therapy has been reported.
Interestingly, discontinuation of NRTIs resulted in improved left
ventricular function (45), perhaps the earliest report of
planned therapeutic interruption of antiretroviral therapy. Clinical
features of AZT CM resemble some of those described for CM of other
etiologies but with the addition of AIDS or HIV infection. Data suggest
that cardiomyopathy in the setting of AIDS has an ominous prognosis
(32), but the direct relationship to NRTI or HAART therapy
has not been made. Clinical features of CM from NRTIs include
congestive heart failure, left ventricle dilatation, and reduced
ejection fraction. Endomyocardial biopsy data in AZT CM is incomplete.
One small study showed ultrastructural changes of intramyocytic
vacuoles, myofibrillar loss, dilated sarcoplasmic reticulum, and
disruption of mitochondrial cristae (26), features consistent with mitochondrial CM.
The role of NRTI in the development of CM in HIV-infected children also
remains controversial. Clinical studies are inconclusive. In studies of
pediatric patients with AIDS and of neonates treated with AZT, both in
utero and perinatally, Lipshultz and colleagues (79, 80)
reported that impaired cardiac function was not attributed to AZT.
Again, myocardial biopsy findings could suggest or disprove an etiology
but were not included. Additionally, because myopathy is uncommon in
AZT-treated children with AIDS (51), it may be reasonable
to expect that the pediatric striated and cardiac muscle tissue
responds differently to NRTI-related toxicity. Other reports (28,
79, 80) suggest that AZT CM in pediatric patients may be more
prevalent than previously recognized. In contrast to some of the above
studies, a causal relationship between NRTI therapy and cardiac
dysfunction was suspected. Interesting correlative data come from in
vivo studies in primates using pregnant Erythrobcebus patas.
Neonatal E. patas treated with AZT in utero reveal features of mitchondrial toxicity to heart and skeletal muscle (36,
37) that resemble those described in experimental systems with
rodents. Although not extensively evaluated, the effects of
NRTI-induced oxidative stress in arteries may impact on the development
of CM as well.
| |
NRTI TOXICITY AND OTHER TISSUE TARGETS |
On the basis of the OXPHOS paradigm (126) and our
working hypothesis (67, 68), it is logical to expect
mitochondrial events from NRTIs to impact on diverse tissues. Hepatic
toxicity from AZT, ddI, and ddC was reported (13, 33, 54).
It is presumed to relate to toxicity to liver mitochondria. Fatal
hepatomegaly with severe steatosis (33), severe lactic
acidosis (13), and adult Reye's syndrome
(54) in AZT-treated HIV seropositive patients were all
pathogenetically linked to AZT-induced hepatotoxicity. Clinical
features resembled some of those seen in FIAU toxicity. The prevalence
of metabolic abnormalities is increasing in AIDS patients treated NRTI
analogs, and the relationships to a variety of metabolic and
cardiovascular changes in AIDS are being investigated more closely.
Clinical treatment with certain NRTIs (d4T/3TC) results in anion gap
acidosis (91). Moreover, the lactic acidosis/hepatic steatosis syndrome may be more common than previously appreciated in
adults (5, 81, 119) and children (16) treated
with NRTIs. d4T treatment caused lipodystrophy (108).
Mechanisms may involve altered mitochondrial biogenesis and/or
oxidative changes and possibly adipocyte apoptosis (43,
68). Recently, we demonstrated arterial dysfunction in FVB/n
mice treated with AZT (114), which may be another
important target of toxicity. NRTIs have associated peripheral
neuropathies as side effects (18, 68). The role of altered
mtDNA replication in the development of the clinical manifestations is
a major effort in our laboratories.
In summary, NRTI toxicity now is an important clinical problem with
long-term significance to AIDS patients. mtDNA replication defects
result from NRTI toxicity. Their manifestations clinically are
increasing with asymptomatic hyperlactatemia being fairly common in the
HIV-infected patient population receiving HAART. Tissue-specific
toxicities include skeletal myopathy, cardiomyopathy, peripheral
neuropathy, and other changes. Toxicities may be severe enough to limit
antiretroviral therapy in some cases, but in others, the clinical
impact of NRTI toxicity is less clear.
Understanding subcellular mechanisms of handling nucleosides in
mitochondria is an important step to elucidate the pathophysiological mechanisms of mitochondrial toxicity from NRTIs. mtDNA and energy depletion, oxidative stress, and mtDNA mutations (articulated in the
mitochondrial dysfunction hypothesis) appear crucial, but the
initiating event remains to be clarified. Future studies will pinpoint
subcellular mechanisms of NRTI toxicity, susceptible patient
populations in which NRTI toxicity may be prevalent, genetic predispositions for development of NRTI toxicity, and pharmacological approaches to prevent or diminish this important side effect.
| |
ACKNOWLEDGEMENTS |
The author thanks National Heart, Lung, and Blood Institute for
support through Grant R01 HL-59798.
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FOOTNOTES |
Address for reprint requests and other correspondence: W. Lewis, Dept. of Pathology, Emory Univ., 1639 Pierce Dr., Rm. 7117, Atlanta, GA 30322 (E-mail:
wlewis{at}emory.edu).
10.1152/ajpheart.00814.2002
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