|
Journal of Endocrinology, Metabolism and Diabetes of South
Africa. ISSN: 003-8-2469
Mitochondrial dysfunction and human
immunodeficiency virus infection
Abstract
Human immunodeficiency virus (HIV) infection and the
pharmacological treatment thereof have both been shown to
affect mitochondrial function in a number of tissues, and
each may cause specific organ pathology through specific
mitochondrial pathways. HIV has been shown to kill various
tissue cells by activation of mitochondrial apoptosis.
Nucleoside analogues, used extensively to treat HIV
infection, are known to influence a number of steps
affecting mitochondrial DNA integrity. This review describes
the basic physiology, pharmacology and pathophysiology of
HIV infection and the nucleoside analogues regarding
mitochondrial function and discusses the progress made in
this field with respect to the measurement of these effects
and the prediction of potential drug toxicity.
2012 International AIDS Conference
Mitochondrial function and metabolic
abnormalities in children with
perinatally-aquired HIV infection in
the Pediatric HIV/AIDS Cohort Study (PHACS)
Background: Metabolic abnormalities,
common among perinatally HIV-infected children (HIV+), may
be caused by mitochondrial dysfunction that is induced by
antiretroviral therapy (ARV) or chronic viral infection. We
compared mitochondrial function [oxidative phosphorylation
(OXPHOS) enzyme activities and lactate levels] of HIV+ and
HIV-exposed, uninfected (HEU) children and, among HIV+,
determined associations with fasting glucose, insulin, and
homeostatic model assessment of insulin-resistance
(HOMA-IR).
Methods: HIV+ and HEU were enrolled from
the PHACS Adolescent Master Protocol. Children with known,
non-HIV-associated mitochondrial disorders were excluded.
Demographic and BMI [all] and CD4, HIV viral load, ARV
exposures, and fasting insulin/glucose [HIV+ only] were
collected. Main outcomes included venous and point-of-care
(POC) lactate, venous pyruvate, and PBMC NADH dehydrogenase
(CI) and cytochrome c oxidase (CIV) enzyme activities. A
Wilcoxon test was used to compare outcomes between HIV+ and
HEU; Spearman correlations were determined between
insulin/glucose and OXPHOS activity in HIV+.
Results: 112 HIV+ and 66 HEU children were
enrolled as of December 2011. HIV+ were older than HEU
(15.8yr vs 12.4yr) with similar gender and racial
distributions. BMI-Z was lower in HIV+ (0.41SD vs 0.54SD).
Among HIV+, 45% were CDC stage B/C and 74% had CD4 >500
cell/mm3 with 60% having viral load < 400cp/mL. 56% were on
HAART, PI-based ARVs. Median glucose was 87mg/dL (range
74-110), insulin was 13.6IU (range 4.7-83) and HOMA-IR was
3.1 (range 1-20.7). POC lactate was higher and venous
pyruvate lower among HIV+ vs HEU (Table), while C1 and CIV
activities did not differ between groups. Among HIV+ with
measures available, we observed a negative correlation of
fasting glucose with CI OXPHOS activity (n=26; r=-0.38;
p=0.06) and a positive correlation with venous lactate
(n=34; r=0.31; p=0.07).
Conclusions: Preliminary analyses show
higher POC lactate in HIV+ compared to HEU children and that
mitochondrial dysfunction may be associated with metabolic
abnormalities in HIV+ children.
XIX International AIDS Conference
July 22-27, 2012, Washington, DC
Mitochondrial Upsets May Underlie
Metabolic
Disorders in HIV-Positive Adolescents
A US study comparing HIV-infected youngsters with
HIV-exposed but uninfected (HEU) youth yielded data
suggesting that mitochondrial dysfunction lies behind
metabolic abnormalities in HIV-positive adolescents [1].
This Pediatric HIV/AIDS Cohort Study (PHACS) linked every 1
mg/dL higher venous lactate to an 18-mg/dL higher
triglyceride reading.
Metabolic abnormalities often affect HIV-positive people,
including perinatally infected children and adolescents
taking antiretrovirals for a decade or more. These metabolic
derangements may be caused by mitochondrial dysfunction
fostered by antiretroviral therapy or chronic HIV infection,
PHACS researchers suggested. To test those hypotheses, they
gauged mitochondrial function as oxidative phosphorylation
(OSPHOS) enzyme activities and lactate levels, then compared
those measures in HIV-infected and HEU adolescents. In the
HIV-positive group, the researchers also determined
associations between mitochondrial function and fasting
glucose, insulin, and HOMA-defined insulin resistance.
Researchers recruited youngsters without known non-HIV
mitochondrial disorders from the PHACS Adolescent Master
Protocol. The investigators gathered demographic and body
mass index data in both HIV-positive and HEU youth, and they
recorded CD4 counts, viral loads, antiretroviral exposure,
and fasting insulin and glucose in HIV-positive youngsters.
Principal outcomes were venous and point-of-care
(fingerprick) lactate, venous pyruvate, and PBMC NADH
dehydrogenase (CI) and cytochrome c oxidase (CIV) enzyme
activities.
The PHACS team enrolled 191 HIV-positive adolescents and 117
HEU youngsters. The HIV-positive adolescents were older than
HEU youth (average 15.8 versus 12.7 years, P < 0.001), and a
higher proportion of HIV-positive youngsters were
non-Hispanic blacks (70% versus 56%, P = 0.05). But the
gender distribution was similar in the two groups (54% and
51% boys). Body mass index Z scores were significantly lower
in adolescents with HIV (average 0.46 versus 0.91, P =
0.005).
In the HIV group, 50% had CDC stage B or C HIV infection,
58% were taking a protease inhibitor (PI)-based
antiretroviral combination, only 11% had a viral load below
400 copies, and median CD4 count stood at 624. HIV-positive
youngsters had a median fasting glucose of 86 mg/dL
(interquartile range [IQR] 81 to 91), median fasting insulin
of 12.1 uu/mL (IQR 8.0 to 20.9), and HOMA insulin resistance
of 2.5 (IQR 1.7 to 4.5). Median total cholesterol stood at
159 mg/dL (IQR 137 to 186) and median triglycerides at 86.5
mg/dL (IQR 63 to 116).
Median point-of-care lactate levels (measured by
fingerprick) were marginally higher in adolescents with HIV
(1.45 mg/dL, IQR 1.0 to 1.9) than in HEU youth (1.4 mmol/L,
IQR 1.1 to 1.9), and that difference was not significant (P
= 0.98). But median venous lactates were significantly lower
in the HIV group (1.0 mg/dL, IQR 0.79 to 1.40) than in HEU
youngsters (1.26 mg/dL, IQR 0.89 to 1.70) (P < 0.001).
Median venous pyruvate was also significantly lower in the
HIV group (0.09 mg/dL, IQR 0.05 to 0.11) than in the HEU
group (0.10 mmol/L, IQR 0.07 to 0.13) (P = 0.005). Pyruvate
may be metabolized to lactate or to acetyl CoA.
Median CI OXPHOS enzyme activity was similar in HIV-positive
and HEU adolescents (37.9 and 36.9 OD/min/ug e-6, P = 0.71),
but median CIV OXPHOS enzyme activity was higher in the HIV
group (69.4 versus 60.8 OD/min/ug e-6, P = 0.048).
In children with HIV, insulin resistance was associated with
higher venous lactate (P = 0.046) and pyruvate (P = 0.028),
while high triglycerides were associated with higher
point-of-care lactate (P = 0.024) and venous lactate (P <
0.001). Venous lactate correlated positively with total
cholesterol (r = 0.16, P = 0.04) and with triglycerides (r =
0.37, P < 0.0001) in HIV-positive children. Low "good"
high-density lipoprotein (HDL) cholesterol was associated
with lower PBMC OXPHOS CI enzyme activity (P = 0.024) and
lower OXPHOS CIV enzyme activity (P = 0.085).
Multivariate analysis identified associations between longer
PI duration and higher triglycerides (+2.63 mg/dL per year
of PIs, P = 0.03) and longer nonnucleoside duration and
higher triglycerides (+4.19 mg/dL per year of
nonnucleosides, P = 0.004). Higher venous lactate was also
associated with higher triglycerides (+17.7 mg/dL per 1
mg/dL lactate, P = 0.0008).
The PHACS investigators concluded that (1) insulin
resistance is associated with higher lactates and pyruvate
in HIV-positive children, (2) high triglycerides are
associated with higher lactates, (3) low HDL cholesterol is
associated with lower OXPHOS CI and CIV enzyme activities,
and (4) venous lactate is independently associated with
higher triglycerides. They proposed the overall conclusion
that "mitochondrial dysfunction induced by either HIV or
antiretrovirals may be responsible for the observed
metabolic changes" in HIV-positive youngsters.
Previous studies yielded additional findings on
mitochondrial function in HIV-positive, HIV-exposed, and
HIV-negative youth. A Spanish cross-sectional comparison of
47 asymptomatic antiretroviral-treated youngsters and 27
healthy HIV-negative controls found significantly lower
mitochondrial DNA (mtDNA) in PBMCs from the HIV group, but
similar levels of mitochondrial RNA in the two groups [2].
CIV protein subunit content and enzymatic activity were also
similar in the two groups.
J Infect Dis. (2010)
Possible Mitochondrial Dysfunction
and Its Association with
Antiretroviral Therapy Use in
Children Perinatally Infected with HIV
Abstract
Background. Mitochondrial dysfunction has been associated
with both human immunodeficiency virus (HIV) infection and
exposure to antiretroviral therapy. Mitochondrial
dysfunction has not been widely studied in HIV-infected
children. We estimated the incidence of clinically defined
mitochondrial dysfunction among children with perinatal HIV
infection.
Methods. Children with perinatal HIV infection enrolled in a
prospective cohort study (Pediatric AIDS Clinical Trials
Group protocols 219 and 219C) from 1993 through 2004 were
included. Two clinical case definitions of mitochondrial
dysfunction, the Enquête Périnatale Française criteria and
the Mitochondrial Disease Classification criteria, were used
to classify signs and symptoms that were consistent with
possible mitochondrial dysfunction. Adjusted odds ratios of
the associations between single and dual nucleoside
reverse-transcriptase inhibitor use and possible
mitochondrial dysfunction were estimated using logistic
regression.
Results. Overall, 982 (33.5%) of 2931 children met 1 or both
case definitions of possible mitochondrial dysfunction.
Mortality was highest among the 96 children who met both
case definitions (20%). After adjusting for confounders,
there was a higher risk of possible mitochondrial
dysfunction among children who received stavudine regardless
of exposure to other medications (odds ratio, 3.44 [95%
confidence interval, 1.91–6.20]) or who received
stavudine-didanosine combination therapy (odds ratio, 2.23
[95% confidence interval, 1.19–4.21]). Exposure to
lamivudine and to lamivudine-stavudine were also associated
with an increased risk of mitochondrial dysfunction.
Conclusions. Receipt of nucleoside reverse-transcriptase
inhibitors, especially stavudine and lamivudine, was
associated with possible mitochondrial dysfunction in
children with perinatal HIV infection. Further studies are
warranted to elucidate potential mechanisms of nucleoside
reverse-transcriptase inhibitor toxicities.
2003 - J Acquir Immune Defic Syndr.
Factors Associated With Mitochondrial
Dysfunction in Circulating
Peripheral Blood Lymphocytes From
HIV-Infected People
Nucleoside analogue reverse transcriptase inhibitor
(NRTI)-associated mitochondrial toxicity is an important
issue in the clinical management of HIV infection. The aim
of this study was the detection of mitochondrial dysfunction
by flow cytometry in lymphocytes from HIV-infected
individuals and its association with blood lactate levels,
clinical and virologic status, and the different NRTI-based
therapies. Lower peripheral blood lymphocytes with
mitochondrial dysfunction (PBLmd) percentages were observed
in healthy controls (1.2, interquartile range [IQR] =
0.4-1.9) than in patients (2.2, IQR = 0.9-3.7; P < 0.01).
Stavudine-containing therapy showed higher PBLmd percentages
(3.0, IQR = 1.1-4.5) than no treatment (2.1, IQR = 0.8-2.8;
P < 0.05) or zidovudine-based therapy (0.9, IQR = 0.3-1.4; P
< 0.01). A significant inverse correlation was found between
PBLmd and CD4 T-cell percentage and absolute count. Patients
with an AIDS diagnosis had higher PBLmd percentage (2.7, IQR
= 1.1-4.4) than HIV-positive non-AIDS patients (1.4, IQR =
0.6-3.0; P = 0.012). In multivariate analysis, use of
stavudine (odds ratio [OR] = 5.86, 95% CI = 1.81-19.01, P =
0.003) and CD4 T-cell counts <200/µL (OR = 4.51, 95% CI =
1.38-14.70, P = 0.012) were independent predictors of high
PBLmd percentage. This cross-sectional study shows that
antiretroviral drugs can impair the in vivo mitochondrial
function of PBLs.
Nucleoside analogue reverse transcriptase inhibitors (NRTIs)
were the first drugs used in therapy for HIV infection. The
development of new therapeutic compounds marked the
beginning of the highly active antiretroviral therapy era in
the management of HIV infection. Therapy combines typically
NRTIs with either HIV protease inhibitors (PIs) or
nonnucleoside reverse transcriptase inhibitors (NNRTIs). The
benefits of the NRTI combination therapies in morbidity and
mortality of HIV-infected patients are clear; however,
adverse effects associated with the therapy have impaired
the clinical management of the disease. Inhibition of DNA
polymerase γ by NRTIs can cause mitochondrial dysfunction
and cellular toxicity, and it seems to be the common pathway
underlying the adverse effects of NRTIs on tissues.[1, 2]
Mitochondria are the main source of ATP by oxidative phosphorylation; therefore mitochondrial dysfunction leads
to increased dependence on cytosolic glycolysis to obtain
energy. This oxidative pathway results in an increased
production and accumulation of lactate, which indicates
mitochondrial dysfunction. NRTI-associated hyperlactatemia
has been detected in HIV-infected patients.[3-5] In general,
this finding represents a mild, asymptomatic, and
nonprogressive hyperlactatemia. An approach for directly
studying mitochondrial dysfunction is the measurement of
mitochondrial membrane potential (Δψ) loss at cellular
level. Depolarization of mitochondria is detected by using
cationic lipophilic fluorochromes that enter in the
mitochondria and are retained by the Δψ. Therefore,
diminished fluorescence indicates a decreased mitochondrial
potential and mitochondrial dysfunction.[6] Significant Δψ
loss has been observed in peripheral blood lymphocytes
(PBLs) during acute HIV syndrome[7] and chronic HIV-infected
patients without antiretroviral treatment or taking
zidovudine.[8, 9]
To our knowledge, no studies have been published on Δψ
changes associated with NRTI combination therapy in
peripheral lymphocytes in chronic HIV infection. The
objective of this study was the detection of Δψ decreases in
freshly collected peripheral blood lymphocytes from
HIV-infected patients and to determine their association
with blood lactate levels, clinical and virologic status,
and antiretroviral therapy.
|
