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Pneumocystis Colonization and Chronic Obstructive Pulmonary Disease in a Simian Model of HIV Infection

Shipley, Timothy W (2010) Pneumocystis Colonization and Chronic Obstructive Pulmonary Disease in a Simian Model of HIV Infection. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Potent anti-retroviral therapy has transformed HIV infection from an acute to a chronic disease. Consequently, diseases previously not prevalent in HIV+ persons have emerged. For example, HIV-infected persons are at increased risk for developing COPD. Pneumocystis (Pc), a fungal opportunistic pathogen, has been associated with HIV and COPD. Pc colonization- the presence of Pc in subjects without clinical symptoms of Pneumocystis pneumonia- is increased in COPD patients. Furthermore, HIV+ individuals are at elevated risk for both Pc colonization and emphysema. Together, these observations suggest that COPD in HIV+ individuals involves Pc colonization. We used a simian/human immunodeficiency virus (SHIV) model of HIV infection to study pulmonary effects of Pc colonization. SHIV-infected/Pc-colonized monkeys developed obstructive pulmonary disease characterized by increased emphysematous tissue and bronchial-associated lymphoid tissue. Elevated Th2 cytokines and pro-inflammatory mediators in bronchoalveolar lavage fluid coincided with Pc colonization and pulmonary function decline. These results indicate that Pc colonization may be a risk factor for development of HIV-associated COPD.Gene expression profiles in the lung tissue of these animals evaluated by microarray analysis revealed differential expression of 243 genes in the obstructed SHIV/Pc monkeys compared to SHIV-only monkeys with normal lung function. Potentially relevant differentially expressed genes included genes involved in inflammation, protease/antiprotease balance, redox balance and tissue homeostasis, thus indentifying factors and pathways involved in early development of SHIV-associated COPD and revealing several novel, possible therapeutic targets.In a second cohort of animals, airway obstruction development associated with Pc colonization was recapitulated. To directly correlate pulmonary function decline with presence of Pc, a subset of the Pc-colonized monkeys was treated with the anti-Pc drug, TMP-SMX, after significant airway obstruction had occurred. No further pulmonary function decline was observed in either the treated or untreated animals up to a year after initiating TMP-SMX treatment. These results indicate that Pc-associated induction of airway obstruction takes place early after onset of colonization followed by an extended period of containment of the effects of Pc.These results demonstrate a key role for Pc in the early development of SHIV-associated COPD. Furthermore, they reveal multiple potential mediators of Pc-induced airway obstruction.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Shipley, Timothy
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairNorris, Karen Akan1@pitt.eduKAN1
Committee MemberMorris, Alisonmorrisa@upmc.eduAMG126
Committee MemberNau, Jerrygjnau@mgb.pitt.eduGJNAU
Committee MemberRay, Prabirrayp@pitt.eduRAYP
Committee MemberReinhart, Toddreinhar@pitt.eduREINHAR
Date: 26 July 2010
Date Type: Completion
Defense Date: 23 June 2010
Approval Date: 26 July 2010
Submission Date: 14 July 2010
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: COPD; Emphysema; HIV; SHIV; Siman Model
Other ID:, etd-07142010-141346
Date Deposited: 10 Nov 2011 19:51
Last Modified: 19 Dec 2016 14:36


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