Systems Biology of Diffusion Impairment in Human Immunodeficiency Virus (HIV)

Study Overview
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Brief Summary
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Diffusing capacity for carbon monoxide (DLco) abnormalities are common in HIV+ individuals and associated with significant morbidity and mortality. The complexity and the individualized differences in causes of these abnormalities have been challenging to unravel using traditional approaches. In this proposal, the investigators construct a systems' modeling approach to identify novel molecular and clinical pathways contributing to DLco impairment in HIV+ individuals and to determine predictive signatures of DLco decline in order to develop strategies to treat and prevent abnormal lung function in this susceptible population.

Detailed Description
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Mechanisms of impairment of diffusing capacity for carbon monoxide (DLco), which affects over 50 percent of HIV+ individuals, are poorly understood. No therapies exist despite significant impact on quality of life and mortality. Identifying molecular pathways of DLco impairment in HIV+ individuals and developing ability to predict HIV+ individuals at risk of DLco impairment is thus of utmost importance for improving care. In this proposal, the investigators construct a systems' modeling approach to identify molecular and clinical pathways contributing to DLco impairment in HIV+ individuals. The investigators collect multiple parallel molecular datasets integrated with detailed pulmonary function, radiographic, and echocardiographic measurements to build a comprehensive, systems level model of DLco abnormalities in HIV and to develop predictive models of susceptibility to DLco worsening. As our preliminary data suggest that certain micro ribonucleic acid (miRNAs), such as the hypoxia-induced and metabolically active gene (miR-210), may play an important role in DLco abnormalities in HIV, the investigators then perform hypothesis-testing experiments to determine the impact of miRNAs on lung epithelial and endothelial cells. The investigators will utilize a well phenotyped cohort of over 500 HIV+ individuals with associated biospecimens to execute the aims. Participants identified to already have specimens available will be scheduled to have PFT testing, bronchoscopy including bronchial wash with brushes and blood collection.

Official Title
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Systems Biology of Diffusion Impairment in HIV--BoDI

Conditions
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HIV Infections, Pulmonary Disease

Intervention / Treatment
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* Diagnostic Test: PFT's (pulmonary function testing)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women age 18 to 80 HIV positive and participated in previous HLRC(HIV Lung Research Center) study (PRO10060177, PRO09050521, PRO14070355, PRO08030011, PRO00606151, PRO13050229, PRO17060077). Negative pregnancy test (for women of child barring capabilities). Have undergone bronchoscopy with BAL(bronchial lavage) and/or brushing for AECs in storage. Receiving ART (Anti-Retroviral Therapy)and virally-suppressed for at least 6 months. Exclusion Criteria: Pregnancy or breast-feeding. (urine pregnancy done on all females of child bearing potential-males and females who are at least 1 year post menopausal or surgically sterile will not be tested) Contraindication to pulmonary function testing (i.e. abdominal or cataract surgery within 3 months, recent myocardial infarction, etc.). Increasing respiratory symptoms or febrile (temperature >100.40F [380C]) within 4 weeks of study entry. Acute cardiopulmonary issue in the past 4 months. Uncontrolled hypertension at screening visit (systolic > 180 mm Hg or diastolic > 100 mm Hg) from an average of two or more readings. Subject may return for screening after blood pressure is controlled. Active cancer requiring systemic chemotherapy or radiation. Active infection of lungs, brain, or abdomen. Intravenous drug use or alcohol use that will impair ability to complete study investigations in the opinion of the investigator. subjects with an upper or lower respiratory tract infection individuals receiving chronic or acute antibiotics in the prior 4 months.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| HIV positive with normal PFT's<br>HIV positive with normal baseline DLco. Subjects with DLco>80% predicted after adjustments for Hgb and Co | Diagnostic Test: PFT's (pulmonary function testing)<br>* The routine lung function endpoints of FVC(forced vital capacity), FEV1, FEV1/FVC, and FEF25-75% will be measured with the flow-volume loop recorder before and after bronchodilator administration. The system is calibrated for body temperature and pressure of saturated gas and volumes, per American Thoracic Society (ATS) standards . DLco will be measured using the automated single-breath procedure of the integrated testing system, which conforms with ATS standards.<br>* Other names: 6MWT (6 minute walk test);|
| HIV positive with mild DLco impairment<br>HIV positive with mild DLco impairment DLco <80% predicted after adjustments for Hgb and Co. | Diagnostic Test: PFT's (pulmonary function testing)<br>* The routine lung function endpoints of FVC(forced vital capacity), FEV1, FEV1/FVC, and FEF25-75% will be measured with the flow-volume loop recorder before and after bronchodilator administration. The system is calibrated for body temperature and pressure of saturated gas and volumes, per American Thoracic Society (ATS) standards . DLco will be measured using the automated single-breath procedure of the integrated testing system, which conforms with ATS standards.<br>* Other names: 6MWT (6 minute walk test);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Identify key causal molecular pathways of DLco impairment. | elucidating complex associations and causal relationships between clinical characteristics, the host inflammatory response, cellular metabolism, the microbiome, and miRNAs. | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, emphysema, diffusing capacity, chronic obstructive pulmonary disease(COPD)