Trimethoprim-sulfamethoxazole treatment does not reverse obstructive pulmonary changes in pneumocystis-colonized
Heather M Kling1, Timothy W Shipley, Siobhan Guyach
1Departments of *Immunology; and †Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA.
Background:
Despite antiretroviral therapy and trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis, Pneumocystis pneumonia remains an important serious opportunistic infection in HIV-infected persons. Pneumocystis (Pc) colonization in HIV-infected individuals and in HIV-uninfected smokers is associated with chronic obstructive pulmonary disease (COPD). We previously developed a nonhuman primate model of HIV infection and Pc colonization and demonstrated that Pc colonization correlated with COPD development. In the present study, we examined kinetics of COPD development in non-human primate and tested the effect of Pc burden reduction on pulmonary function by TMP-SMX treatment.
Methods:
Cynomolgus macaques (n = 16) were infected with simian/human immunodeficiency virus (SHIV89.6P), and natural Pc colonization was examined by nested polymerase chain reaction of serial bronchoalveolar lavage fluid and anti-Pc serology.
Results:
Eleven of 16 monkeys became Pc colonized by 16 weeks post simian-human immunodeficiency virus (SHIV) infection. Pc colonization of SHIV-infected monkeys led to progressive declines in pulmonary function as early as 4 weeks after Pc detection. SHIV-infected and Pc-negative monkeys maintained normal lung function. At 25 weeks post-SHIV infection, TMP-SMX treatment was initiated in 7 Pc-positive (Pc+) (TMP: 20 mg/kg and SMX: 100 mg/kg, daily for 48 weeks) and 5 Pc-negative (Pc-) monkeys. Four SHIV+/Pc+ remained untreated for the duration of the experiment. Detection frequency of Pc in serial bronchoalveolar lavage fluid (P < 0.001), as well as plasma Pc antibody titers (P = 0.02) were significantly reduced in TMP-SMX-treated macaques compared with untreated.
Conclusions:
Reduction of Pc colonization by TMP-SMX treatment did not improve pulmonary function, supporting the concept that Pc colonization results in early, permanent obstructive changes in the lungs of immunosuppressed macaques.
Insights
Pneumocystis pneumonia (PCP) colonization in HIV-infected macaques leads to permanent lung damage. Reducing PCP colonization with trimethoprim-sulfamethoxazole (TMP-SMX) did not improve pulmonary function, indicating early, irreversible obstructive changes.
Area of Science:
- Immunology
- Pulmonology
- Infectious Diseases
Background:
- Pneumocystis pneumonia (PCP) remains a significant opportunistic infection in HIV-infected individuals, even with antiretroviral therapy and prophylaxis.
- PCP colonization is linked to chronic obstructive pulmonary disease (COPD) in both HIV-infected and HIV-uninfected smokers.
- A nonhuman primate model of HIV infection and PCP colonization was previously established, showing a correlation between PCP colonization and COPD development.
Purpose of the Study:
- To investigate the kinetics of COPD development in a nonhuman primate model following simian/human immunodeficiency virus (SHIV) infection.
- To evaluate the efficacy of trimethoprim-sulfamethoxazole (TMP-SMX) in reducing Pneumocystis (Pc) burden.
- To determine the impact of reduced Pc burden on pulmonary function in SHIV-infected macaques.
Main Methods:
- Cynomolgus macaques (n=16) were infected with SHIV89.6P.
- Pneumocystis (Pc) colonization was monitored using nested PCR on bronchoalveolar lavage fluid and anti-Pc serology.
- TMP-SMX treatment was administered to some SHIV-infected, Pc-colonized macaques to assess its effect on Pc burden and pulmonary function.
Main Results:
- Eleven out of 16 macaques became Pc-colonized by 16 weeks post-SHIV infection.
- Pc colonization was associated with progressive pulmonary function decline starting as early as 4 weeks after Pc detection.
- TMP-SMX treatment significantly reduced Pc detection frequency and plasma Pc antibody titers in treated macaques compared to untreated controls.
- SHIV-infected, Pc-negative macaques maintained normal lung function throughout the study.
Conclusions:
- Reduction of Pc colonization via TMP-SMX treatment did not restore or improve pulmonary function in immunosuppressed macaques.
- These findings support the hypothesis that Pc colonization leads to early and permanent obstructive lung changes in the context of HIV infection.
- The study highlights the irreversible nature of lung damage caused by Pc colonization in this model, even with successful reduction of the organism.
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