HIV-related Accelerated Aging of the Airway Epithelium

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.

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