Metabolic Abnormalities and Mitochondrial Function in Children with Perinatally-Acquired HIV Infection in the Pediatric HIV/AIDS Cohort Study (PHACS) Mariana Gerschenson, Ph.D. Tracie L. Miller MD, Jiajia Wang MS, Denise L. Jacobson PhD, MPH, Jody K. Takemoto PhD, Tanvi Sharma MD, Mitchell Geffner MD, Daniel E. Libutti BS, Susanne Siminski MS, MBA, Gabriel Somarriba DPT, and Patricia Graham MS for the Pediatric HIV/AIDS Cohort Study July 23, 2012 XIX International AIDS Conference
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Metabolic Abnormalities and Mitochondrial Function in Children with Perinatally-Acquired HIV Infection in the
Pediatric HIV/AIDS Cohort Study (PHACS)
Mariana Gerschenson, Ph.D.Tracie L. Miller MD, Jiajia Wang MS, Denise L. Jacobson PhD, MPH, Jody K. Takemoto PhD, Tanvi Sharma MD, Mitchell Geffner MD, Daniel E. Libutti BS,
Susanne Siminski MS, MBA, Gabriel Somarriba DPT, and Patricia Graham MSfor the Pediatric HIV/AIDS Cohort Study
July 23, 2012XIX International AIDS Conference
Background• Insulin resistance is common among
perinatally HIV-infected children (HIV+)• Mitochondrial dysfunction, induced by
antiretroviral therapy (ARV) or chronic viral infection, is a possible mechanism for metabolic dysfunction
Mitochondrial Function
• Make ATP– Oxidative phosphorylation ATP– Citric acid cycle: NADH and FADH ATP – Fat metabolism: beta oxidation ATP
• Responsible for 90% of the oxygen radicals/oxygen stress
• Mitochondrial DNA (mtDNA)– 16 kb, 2-10 copies/mitochondrion in matrix– Replication: mitochondrial genes
• The mtDNA polymerase-γ is the principal polymerase required for mtDNA replication
– Transcription: mitochondrial proteins• Mitochondrial RNA (mtRNA) polymerase and
Hypothetical Model for HIV Pediatric Metabolic Disease
BMI/ Body Measurements
LDL/HDL/TG/HOMA-IR (Glucose)
OXPHOSKrebs
β-oxidation
LactateHIV/ART
Objectives• To compare mitochondrial function [oxidative
phosphorylation (OXPHOS) enzyme activities and lactate levels] of 191 HIV+ and 117 HIV-exposed, uninfected (HEU) children and among HIV+, determine associations with homeostatic model assessment of insulin resistance (IR) (HOMA-IR) and hyperlipidemia
• In HIV+ children, to determine if mitochondrial function (oxidative phosphorylation [OXPHOS] enzyme activities and lactate and pyruvate levels) are associated with metabolic abnormalities (IR and hyperlipidemia)
Mitochondrial Determinant Component of PHACS
• The Adolescent Master Protocol (AMP), a part of the Pediatric HIV/AIDS Cohort Study (PHACS), is a prospective cohort study conducted at 12 US sites designed to define the impact of HIV infection and ARV on pre-adolescents and adolescents with perinatal HIV infection.
• The Mitochondrial Determinants Component (MDC) is a separately funded study (R01 NR12885) that has co-enrolled AMP participants since May 2011.
• The objective of MDC is to determine the influence of mitochondrial abnormalities on metabolic outcomes in HIV+ children who were previously enrolled in AMP from 7 years of age until their 16th birthday. HIV-exposed, uninfected children (HEU) are also enrolled to serve as controls.
Multivariable Model for HDL-Cholesterol in HIV+Children
Effect Estimate SE P-value
Gender (male) 0.42 2.42 0.86
Age (per year) -0.73 0.44 0.10
Viral load (per copy/mL) -0.00009 0.00003 0.010
Venous lactate (mg/dL) -1.75 1.18 0.14
Multivariable Model for Triglycerides in HIV+ Children
Effect Estimate SE P-value
Gender (male) 8.34 11.1 0.45
Age (per year) -2.58 2.12 0.22
PI duration (per year) 2.63 1.21 0.03
NNRTI duration (per year) 4.19 1.42 0.004
Venous lactate (per mg/dL) 17.7 5.19 0.0008
Conclusions in HIV+ Children• Insulin resistance is associated with higher
lactate and pyruvate levels• Hypertriglyceridemia is associated with
higher lactate levels• Low HDL-cholesterol is associated with
lower CI and CIV enzyme activities• Venous lactate is independently associated
with higher triglyceride levels
Overall ConclusionsMitochondrial dysfunction induced by either
HIV or ARV may be responsible for the observed metabolic changes
Acknowledgments
We thank the study participants, PHACS Community Advisory Board, Frontier Science Inc., and Westat.
PHACS is funded by:
Under cooperative agreements with Harvard School of Public Health (HD052102, 3 U01 HD052102-05S1, 3 U01 HD052102-06S3) and Tulane School of Medicine (HD052104, 3U01HD052104-06S1)
• The following institutions participated in conducting PHACS in 2011:
•Baylor College of Medicine•Bronx Lebanon Hospital Center•Children's Diagnostic & Treatment Center•Children’s Hospital, Boston•Children’s Memorial Hospital•Jacobi Medical Center•New York University School of Medicine•St. Christopher’s Hospital for Children•St. Jude Children's Research Hospital•San Juan Hospital/Department of Pediatrics•SUNY Downstate Medical Center
•Tulane University Health Sciences Center•University of Alabama, Birmingham•University of California, San Diego•University of Colorado Health Sciences Center•University of Florida/Jacksonville•University of Illinois, Chicago•University of Medicine and Dentistry of New Jersey•University of Miami•University of Southern California•University of Puerto Rico Medical Center
Acknowledgments
Funding for this study is from DHHS/NIH/NINR grant R0112885 to M. Gerschensonand T.L. Miller. We also acknowledge the support from the John A. Burns School of