Pneumocystis in Pathogenesis of HIV-associated Emphysema
Pneumocystis in Pathogenesis of HIV-associated Emphysema
A. Statement of Hypotheses:

 HIV-infected patients have an increased incidence of emphysema compared to non-HIV-infected
 smokers, and it has been hypothesized that this accelerated disease progression is the result
 of one or more latent infections that amplifies the pulmonary inflammatory response to
 cigarette smoke. Pneumocystis is one infectious agent that likely plays a key role in the
 development of HIV-associated emphysema. Colonization with Pneumocystis has been demonstrated
 in HIV-infected subjects, and HIV-infected smokers are particularly susceptible to Pc
 colonization regardless of CD4 cell count or use of prophylaxis. Pneumocystis colonization is
 also increased in non-HIV-infected patients with chronic obstructive pulmonary disease (COPD)
 and is directly related to the severity of the disease. The presence of Pneumocystis in the
 lungs, even at low levels as seen in colonization, produces inflammatory changes similar to
 those seen in COPD, with increases in the numbers of neutrophils and cytotoxic CD8+
 lymphocytes. We propose that Pneumocystis accelerates emphysema in HIV-infected smokers by
 stimulating inflammation and tissue destruction. We will examine the role of co-infection
 with Pneumocystis in the pathogenesis of HIV-associated emphysema and the mechanism by which
 it causes emphysema progression. These studies will lead to information that will provide a
 rational basis for prevention and therapy of HIV-associated emphysema and provide a model for
 emphysema in the general population
We propose that Pneumocystis accelerates emphysema in HIV-infected smokers by stimulating
 inflammation and tissue destruction. This grant will examine the role of co-infection with
 Pneumocystis in the pathogenesis of HIV-associated emphysema and the mechanism by which it
 causes emphysema progression. These studies will lead to information that will provide a
 rational basis for prevention and therapy of HIV-associated emphysema and provide a model for
 emphysema in the general population

 antiretroviral therapy (HAART), impressive declines in morbidity and mortality from HIV have
 been seen [18]. These improvements do not constitute a cure, however; and over 400,000 people
 are currently living with HIV in the United States and there are 40 million people infected
 worldwide. With improved treatment and increases in life expectancy, incidence of other types
 of lung diseases such as HIV-associated emphysema and pulmonary hypertension may become more
 common. Respiratory symptoms are extremely common in the HIV-infected population, even among
 those without a history of pulmonary infections. HIV-infected subjects have been noted to
 have an accelerated form of chronic obstructive pulmonary disease (COPD)/emphysema [4, 5].
 This disease is seen in those with untreated HIV disease and may become more common in the
 treated HIV population as it has frequently been reported in those without a history of
 AIDS-related pulmonary complications.

 Smoking-related diseases such as emphysema are of particular concern in the HIV+ population.
 Smoking rates are high in this population and long term exposure to cigarette smoke in the
 setting of HIV infection may increase the number of complications seen. Smoking in the HIV+
 population is associated with worse general health, physical functioning, quality of life,
 and cognitive functioning Before the HAART era, HIV+ subjects were noted to have an
 accelerated form of emphysema. Unlike many of the AIDS-defining opportunistic infections,
 HIV-associated emphysema may actually be more common in the current era of HIV as it is
 frequently reported in those without a history of AIDS-related pulmonary complications and
 because the aging HIV+ population has a longer exposure to smoking and HIV. HIV-associated
 emphysema was identified as a critical area for future research by a recent NIH workshop on
 pulmonary complications of HIV.

 Whether emphysema continues to be increased in the HIV+ population in the HAART era is
 unknown. We hypothesize that emphysema may actually have increased as subjects live longer
 with chronic pulmonary exposure to the virus, to smoking, and to the inflammation that occurs
 in even treated HIV+ patients. We believe that prevalence will be increased compared to HIV-
 controls and that progression will be accelerated. Assessment of degree of emphysema and its
 distribution can be accomplished using quantitative CT morphometry density analysis. This
 technique measures lung density by pixel analysis expressed in Hounsfield units (HU) or its
 inverse (ml of gas/gram of tissue) which increases proportionately with the magnitude of
 emphysema. These measurements have been histologically-verified and give quantitative,
 reproducible measurements of percentage and distribution of lung considered normal, mildly
 emphysematous, and severely emphysematous. By adding the lung images to this protocol, we
 will be maximizing the information gained from this study with minimal increases in risk or
 subject inconvenience.

 Pneumocystis jirovecii Based on our preliminary data in humans and primates, we believe that
 Pneumocystis (Pc) is one infectious agent that is critical in the pathogenesis of
 HIV-associated emphysema. Pneumocystis jirovecii (formerly known as Pneumocystis carinii f.
 sp. hominis)[19] is a eukaryotic pathogen that causes pneumonia in immunocompromised hosts.
 Despite the fact that PCP is responsible for a large degree of morbidity and mortality in
 immunosuppressed populations, little is understood about the organism's epidemiology. The
 recent development of molecular techniques to identify and genotype Pc has provided an
 important tool with which to explore the epidemiology of the organism. Polymerase chain
 reaction (PCR) detects low numbers of organisms, particularly in cases where routine
 histochemical staining methods are negative [21, 22]. Use of PCR, particularly nested PCR,
 for detection of Pc has led to discovery of the organism among asymptomatic subjects. The
 rate of colonization in asymptomatic HIV-infected subjects appears to be higher than that
 seen in the general population with estimates ranging from 12 to 46% depending on the subject
 population and respiratory samples studied [11, 12, 14, 16, 22].

 Evidence linking HIV-associated emphysema and Pc colonization Pathogenesis of HIV-associated
 emphysema is not understood. The disease is likely multifactorial with contributions from
 smoking, HIV infection, and subclinical infections. Based on several lines of preliminary
 data, we believe that Pc plays a key role in development of HIV-associated emphysema. The
 evidence linking Pc and emphysema includes the high rates of both emphysema and Pc
 colonization in HIV-infected smokers, COPD-like changes that occur after PCP, an increase in
 Pc colonization in COPD that corresponds to disease severity and is independent of smoking
 history, and similarity between the inflammatory response in Pc colonization and COPD. The
 role of Pc colonization in HIV-associated emphysema has not been tested directly.

 With the completion of the human genome project and advances in human genetic research, it is
 now possible for us to conduct comprehensive population genetic studies aimed at the
 identification of genetic factors associated with development of, and outcomes from,
 different diseases. Separately, newer technologies such as Luminex, microarray, SAGE, and
 proteomic analyses have made it possible to study expression profiles of thousands of genes.
 Simultaneous development of statistical methods to detect patterns of gene expression and
 link these patterns with clinical outcomes, have facilitated the identification of prognostic
 markers of disease (e.g. breast cancer and BRCA-1, and markers of tumor metastasis in
 melanoma). In particular, these studies both elucidate the mechanisms of disease
 pathogenesis, as well as identify targets for potential therapeutic intervention. It is
 crucial to the success of these scientific endeavors to link the cellular, protein, and gene
 expression and genetic data to clinical and demographic data on a large substrate of
 subjects, or the interpretation and results of these statistical analyses will be flawed.
Inclusion Criteria:

 -  Subject is Male / Female 18years of age or older.

 -  Subject has been previously determined to be HIV-infected or has been participating in
 the Pitt Men's study or is seen at the UPMC HIV/AIDS program

 Exclusion Criteria:

 -  Subject is experiencing acute onset of shortness of breath, cough, fevers or heart
 conditions problems such as tachycardia, angina or arrhythmias

 -  Female subject has told us she is pregnant (this might affect pulmonary function
 values,we will not require pregnancy testing.)

 -  Subject has had an MI, CVA, or cardiovascular event within the past 3 months.

 -  Subject has had eye or abdominal surgery within past 3 months.