Cardiac and pulmonary diseases have historically been a leading cause of morbidity and mortality in HIV, but relatively little work has focused on heart and lung disorders in HIV+ children. Because HIV+ children now survive for decades, chronic changes in heart and lung function that occur early in life may have significant impact in adulthood. Causes of cardiac and pulmonary dysfunction in HIV+ children are not well-understood. In HIV+ adults, persistent systemic exposure to microbial antigens from microbial translocation (MT) may play a role in progression of chronic cardiac and pulmonary disorders via persistent immune activation. Limited information exists regarding MT in HIV+ children, but peripheral lipopolysaccharide (LPS), a component of bacterial membranes, appears to be increased in HIV+ children and persists despite antiretroviral therapy. Our preliminary data show that MT in HIV+ adults occurs both from bacteria and also from fungi, an entirely novel observation. We find that MT is correlated with pulmonary hypertension on echocardiography, increased airway obstruction, impairment of diffusing capacity for carbon monoxide, and more rapid progression of pulmonary abnormalities. We also find that MT is associated with peripheral and pulmonary inflammation. Based on these findings, we postulate that MT induces systemic inflammation leading to end-organ damage. MT is an attractive therapeutic target because it can be modulated directly with probiotics and/or antibiotics, and resultant inflammation can be targeted as well. The overall goal of this proposal is to utilize existing NHLBI biorepository specimens collected from HIV+ children in the Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection in order to evaluate the novel hypothesis that MT results in peripheral inflammation and cardiopulmonary decline. We will test our hypothesis with the following aims:
Aim 1 : To determine the prevalence, nature, and longitudinal changes in MT in HIV+ children.
Aim 2 : To test the hypothesis that MT is associated with systemic inflammation and predicts decline in cardiac and pulmonary function. We will use polymerase chain reaction to detect bacterial 16S ribosomal DNA (rDNA) and fungal18S rDNA and will also measure peripheral LPS and (1 3)-?-D-glucan (a polysaccharide in fungal cell walls) in 138 HIV+ children with corresponding clinical data, echocardiography, and pulmonary function testing. We will determine if MT is primarily bacterial, fungal, or both, if MT is persistnt or transient, and associated risk factors. We hypothesize that MT leads to systemic inflammation that has deleterious end-organ effects and will measure peripheral cytokines and chemokines. We will then determine if MT is associated with worse cardiac and pulmonary function and will model association of MT and peripheral inflammation with changes in cardiac and pulmonary function over time. The proposal will clarify the nature of MT in HV+ children, explore the novel role of fungi, and determine the relationship of MT to cardiac and pulmonary dysfunction. Results could translate into new methods to treat or prevent cardiac and pulmonary disease in HIV+ children.

Public Health Relevance

Cardiac and pulmonary diseases have historically been a leading cause of morbidity and mortality in HIV, but relatively little work has focused on heart and lung disorders in HIV+ children. Causes of cardiac and pulmonary dysfunction in HIV+ children are not well-understood, but preliminary data suggest that persistent systemic exposure to microbial antigens from microbial translocation may play a role in progression of chronic cardiac and pulmonary disorders via persistent immune activation. The proposed research is relevant to public health because cardiac and pulmonary abnormalities are common in HIV+ children despite antiretroviral therapy and even subtle deficits that occur early in life can have lasting effects as these children survive until adulthood. This proposal responds to RFA-HL-12-004, Maximizing the Scientific Value of the NHLBI Biologic Specimen Repository: Scientific Opportunities and proposes a new paradigm linking microbial translocation to cardiac and pulmonary function decline in HIV+ children who were part of the Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection study.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL114231-02
Application #
8470704
Study Section
Special Emphasis Panel (ZHL1-CSR-P (F2))
Program Officer
Wagner, Elizabeth
Project Start
2012-05-18
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$108,171
Indirect Cost
$36,771
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213