slide1 n.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
National Institute on Deafness and Other Communication Disorders PowerPoint Presentation
Download Presentation
National Institute on Deafness and Other Communication Disorders

Loading in 2 Seconds...

play fullscreen
1 / 22

National Institute on Deafness and Other Communication Disorders - PowerPoint PPT Presentation


  • 77 Views
  • Uploaded on

National Institute of Allergy and Infectious Diseases. National Heart, Lung and Blood Institute. National Institute on Deafness and Other Communication Disorders.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'National Institute on Deafness and Other Communication Disorders' - moeshe


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
slide1

National Institute of Allergy

and Infectious Diseases

National Heart, Lung and Blood

Institute

National Institute on Deafness and

Other Communication Disorders

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

background

National Institute of Allergy

and Infectious Diseases

National Heart, Lung and Blood

Institute

National Institute on Deafness and

Other Communication Disorders

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

Mitochondria Inner Structure

HIV

Inner

Membrane

Matrix

Cristae

Outer

Membrane

Adipocyte TEM

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 transcription factors
  • Apoptosis
  • Lactic acidosis

Adipocyte TEM courtesy of Courtney Kim and Mariana Gerschenson

hypothesis potential consequences of mitochondrial dysfunction

ART

Cytokines

HIV

HIV

Hypothesis: Potential Consequences of Mitochondrial Dysfunction
  • Metabolic Disease
    • (LD, IR,  TGs)
  • DNA polymerase-g
  • Transcription
  • Uncoupling
  • Transport
  • Oxidative Stress
  • Apoptosis
  • Phosphorylation
  • Proteolytic Processing
  • Glycosylation

Cardiovascular Disease

Lipodystrophy

  • Neuropathies
  • Hepatic Steatosis
  • Myopathy
  • Pancreatitis
  • Lactic Acidosis

Day L, et al. Mitochondrion. 2004;4:95–109. AACTG Metabolic Guides: http://aactg.s-3.com/metabolic/lactic.pdf. McComsey GA, Morrow JD. J Acquir Immune Defic Syndr. 2003;34:45-9. Dagan T, Sable C, Bray J, Gerschenson M. Mitochondrion. 2002;1:397-412. Gerschenson, M. and Brinkman, K. Mitochondrion. 2004;4(5-6):763-777.

hypothetical model for hiv pediatric metabolic disease

National Institute of Allergy

and Infectious Diseases

National Heart, Lung and Blood

Institute

National Institute on Deafness and

Other Communication Disorders

Hypothetical Model for HIV Pediatric Metabolic Disease

 BMI/ Body Measurements

 LDL/HDL/TG/HOMA-IR (Glucose)

β-oxidation

Krebs

OXPHOS

HIV/ART

 Lactate

objectives
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
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.
demographics of cohort by hiv status

National Institute of Allergy

and Infectious Diseases

National Heart, Lung and Blood

Institute

National Institute on Deafness and

Other Communication Disorders

Demographics of Cohort by HIV Status

*Wilcoxon Test

** Fisher’s Exact Test

clinical characteristics of hiv children at study entry

National Institute of Allergy

and Infectious Diseases

National Heart, Lung and Blood

Institute

National Institute on Deafness and

Other Communication Disorders

Clinical Characteristics of HIV+ Children at Study Entry
baseline metabolic outcomes in hiv infected children

National Institute of Allergy

and Infectious Diseases

National Heart, Lung and Blood

Institute

National Institute on Deafness and

Other Communication Disorders

Baseline Metabolic Outcomes in HIV-Infected Children
insulin resistance is associated with increased venous lactate and pyruvate in hiv children

National Institute of Allergy

and Infectious Diseases

National Heart, Lung and Blood

Institute

National Institute on Deafness and

Other Communication Disorders

Insulin Resistance is Associated with Increased Venous Lactate and Pyruvate in HIV+ Children

IR - YES

IR – NO

IR - YES

IR – NO

Lactate Pyruvate

hypertriglyceridemia is associated with point of care poc and venous lactate in hiv children

National Institute of Allergy

and Infectious Diseases

National Heart, Lung and Blood

Institute

National Institute on Deafness and

Other Communication Disorders

Hypertriglyceridemia is Associated with Point-of-Care (POC) and Venous Lactate in HIV+ Children

P=0.024

P<0.001

High TG

Normal TG

High TG

Normal TG

POC Lactate Venous Lactate

slide14

National Institute of Allergy

and Infectious Diseases

National Heart, Lung and Blood

Institute

National Institute on Deafness and

Other Communication Disorders

Low HDL-Cholesterol is Associated with Lower PBMC OXPHOS CI and CIV Enzyme Activities in HIV+ Children

P=0.085

P=0.024

Low HDL

Normal HDL

Low HDL

Normal HDL

Complex I Complex IV

venous lactate is positively correlated with total cholesterol in hiv children
Venous Lactate is Positively Correlated with Total Cholesterol in HIV+ Children

P=0.04; r=0.16

multivariable model for hdl cholesterol in hiv children

National Institute of Allergy

and Infectious Diseases

National Heart, Lung and Blood

Institute

National Institute on Deafness and

Other Communication Disorders

Multivariable Model for HDL-Cholesterol in HIV+Children
multivariable model for triglycerides in hiv children

National Institute of Allergy

and Infectious Diseases

National Heart, Lung and Blood

Institute

National Institute on Deafness and

Other Communication Disorders

Multivariable Model for Triglycerides in HIV+ Children
conclusions in hiv children
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 conclusions
Overall Conclusions

Mitochondrial dysfunction induced by either HIV or ARV may be responsible for the observed metabolic changes

acknowledgments
Acknowledgments

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)

We thank the study participants, PHACS Community Advisory Board, Frontier Science Inc., and Westat.

slide22

Acknowledgments

  • 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

Funding for this study is from DHHS/NIH/NINR grant R0112885 to M. Gerschenson

and T.L. Miller. We also acknowledge the support from the John A. Burns School of

Medicine, University of Hawaii at Manoa.