HIV-related Accelerated Aging of the Airway Epithelium

Sponsor

Weill Medical College of Cornell University (Other)

Overall Status

Completed

CT.gov ID

NCT01974219

Collaborator

National Heart, Lung, and Blood Institute (NHLBI) (NIH)

330

Enrollment

Location

61.7

Actual Duration (Months)

5.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

In cigarette smokers that are HIV+, one of the most common HIV-associated non-AIDS conditions is the accelerated development of chronic obstructive pulmonary disease (COPD), a disorder associated with significant morbidity and mortality. Based on the knowledge that COPD in smokers starts in the small airway epithelium, this study is focused on examining the hypothesis that the accelerated development of COPD associated with HIV infection results, in part, from an interaction of HIV directly on the small airway epithelium or through infection of cellular components of the immune system, with mediators released by these immune cells evoking premature biologic aging of the small airway epithelium. By identifying the early events in the pathogenesis of the HIV-associated accelerated COPD in smokers, we aim to identify biologic targets to which pharmacologic therapies could be addressed.

Condition or Disease	Intervention/Treatment	Phase
HIV COPD Chronic Obstructive Pulmonary Disease Smoking

Detailed Description

While the epidemiologic data linking HIV infection to an increased risk for COPD is clear, the pathogenesis of the accelerated development of COPD in HIV infected smokers is not understood. We have focused on the SAE as the central target for the accelerated development of COPD in HIV infected smokers, as there is extensive data pointing to the SAE as the initial site of lung pathology in cigarette smokers and the small airways are the major site of airflow obstruction in COPD. Further, the emphysema associated with COPD begins in alveoli surrounding the SAE, and prior to the development of clinical evidence of lung disease, the SAE of smokers exhibit marked disordered biology, including changes in DNA methylation and gene expression, and disordered differentiation. Importantly, we have observed that HIV infection "ages" the SAE, with exaggerated shortening of SAE telomeres in individuals infected with HIV compared to HIV - smokers.

We propose that the early events in the pathogenesis of the accelerated development of COPD in smokers with HIV infection results from the premature biologic aging of the small airway epithelium (SAE) mediated by the effects of direct HIV infection of the SAE and/or through the interaction of HIV-infected T cells and/or alveolar macrophages (AM) with the SAE, resulting in the disordered biology of the SAE that is central to the pathogenesis of COPD.

In cigarette smokers that are HIV+, one of the most common HIV-associated non-AIDS conditions is the accelerated development of chronic obstructive pulmonary disease (COPD), a disorder associated with significant morbidity and mortality. Based on the knowledge that COPD in smokers starts in the SAE, this proposal is focused on examining the hypothesis that the accelerated development of COPD associated with HIV infection results, in part, from an interaction of HIV directly on the small airway epithelium or through infection of cellular components of the immune system, with mediators released by these immune cells evoking premature biologic aging of the small airway epithelium. By identifying the early events in the pathogenesis of the HIV-associated accelerated COPD in smokers, we aim to identify biologic targets to which pharmacologic therapies could be addressed.

Study Design

Study Type:

Observational

Actual Enrollment :

330 participants

Observational Model:

Case-Control

Time Perspective:

Prospective

Official Title:

HIV-related Accelerated Aging of the Airway Epithelium

Actual Study Start Date :

Dec 23, 2013

Actual Primary Completion Date :

Feb 14, 2019

Actual Study Completion Date :

Feb 14, 2019

Arms and Interventions

Arm	Intervention/Treatment
Healthy nonsmokers Healthy nonsmokers
Healthy smokers Healthy smokers
COPD smokers COPD smokers

Outcome Measures

Primary Outcome Measures

Gene expression changes in airway epithelium [One Year]
We examine the pathogenesis of the accelerated development of COPD in smokers with HIV infection and the premature biologic aging of the small airway epithelium (SAE) mediated by the effects of direct HIV infection of the SAE and/or through the interaction of HIV-infected T cells and/or alveolar macrophages (AM) with the SAE, resulting in the disordered biology of the SAE that is central to the pathogenesis of COPD.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

HEALTHY VOLUNTEER RESEARCH SUBJECTS

All study subjects should be able to provide informed consent
Males or females ages 18 years and older
Must provide HIV informed consent

VOLUNTEER RESEARCH SUBJECTS WITH LUNG DISEASE

Must provide informed consent
Males and females age 18 years and older
Lung disease proven by at least one of the following: symptoms consistent with pulmonary disease; (2) chest X-rays consistent with lung disease; (3) pulmonary function tests consistent with lung disease; (4) lung biopsy consistent with lung disease; (5) family history of lung disease; and/or (6) diseases of organs with known association with lung disease
Must provide HIV informed consent

Exclusion Criteria:

HEALTHY VOLUNTEER RESEARCH SUBJECTS

Individuals not deemed in good overall health by the investigator will not be accepted into the study.
Habitual use of drugs and/or alcohol within the past six months (Acceptable: - Marijuana one time in three months; average of two alcoholic beverages per day; drug and/or alcohol abuse is defined as per the DSM-IV Substance Abuse Criteria).
Individuals with history of chronic lung disease, including asthma or with recurrent or recent (within three months) acute pulmonary disease will not be accepted into the study.
Individuals with allergies to atropine or any local anesthetic will not be accepted into the study.
Individuals with allergies to pilocarpine, isoproterenol, terbutaline, atropine or aminophylline will not be accepted into the study.
Females who are pregnant or nursing will not be accepted into the study

VOLUNTEER RESEARCH SUBJECTS WITH LUNG DISEASE

Any history of allergies to xylocaine, lidocaine, versed, valium, atropine, pilocarpine, isoproterenol, terbutaline, aminophylline, or any local anesthetic will not be included in the study.
Habitual use of drugs and/or alcohol within the past six months (Acceptable: Marijuana one time in three months; average of two alcoholic beverages per day; drug and/or alcohol abuse is defined as per the DSM-IV Substance Abuse Criteria)
Females who are pregnant or nursing