Despite the availability of highly active antiretroviral therapy (HAART), lung diseases remain a leading cause of morbidity and mortality in HIV infection. There have been no large-scale studies detailing pulmonary complications in the HAART era. Substantial gaps exist in our knowledge of the spectrum and pathogenesis of pulmonary disorders in this population, particularly in women and minorities. The Multicenter AIDS Cohort Study (MACS) and the Women's Interagency Health Study (WIHS) are prospective, multi-center cohorts that follow almost 5000 HIV-infected subjects and HIV-negative controls and includes a large number of women and minorities. Although pulmonary disease has not been an area of focus, these established cohorts provide a unique opportunity to systematically study pulmonary complications of HIV infection. Emphysema is of particular interest in the current HIV era because it is likely to increase as this population with a high rate of smoking lives longer with chronic HIV. Pathogenesis of HIV-associated emphysema is poorly understood, but accelerated disease in this population may be the result of one or more latent infections that upregulate expression of HIV in the lungs, amplify the pulmonary inflammatory response, and lead to release of proteases. Preliminary data from our group suggest that low level infection with Pneumocystis is increased in HIV+ subjects and associated with anatomic emphysema. In a primate model of HIV, Pneumocystis colonization results in airway obstruction and emphysema. Other infections alone or in combination might also be important in disease pathogenesis. We will use the MACS and WIHS cohorts to achieve the following goals: 1. To identify and characterize HIV-associated pulmonary complications in the era of highly active antiretroviral therapy. 2. To test the hypothesis that emphysema is accelerated in HIV+ subjects compared to HIV-negative controls. 3. To test the hypothesis that persistent, sub-clinical infection in HIV+ subjects augments the pulmonary inflammatory response and leads to emphysema. Public health significance: This proposal will help us determine the lung diseases that currently affect people with HIV and will explain why HIV-infected individuals develop emphysema faster than non-HIV-infected people. This information will help us understand and treat emphysema in these patients and in the many non-HIV-infected people who suffer from emphysema.
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