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Trimethoprim–Sulfamethoxazole Treatment Does Not Reverse Obstructive Pulmonary Changes in Pneumocystis-Colonized Nonhuman Primates With SHIV Infection

Kling, Heather M. PhD*; Shipley, Timothy W. PhD*; Guyach, Siobhan BS*; Tarantelli, Rebecca CVT*; Morris, Alison MS, MD*,†; Norris, Karen A. PhD*

JAIDS Journal of Acquired Immune Deficiency Syndromes: 1 April 2014 - Volume 65 - Issue 4 - p 381–389
doi: 10.1097/QAI.0000000000000007
Basic and Translational Science

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.

Departments of *Immunology; and

Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA.

Correspondence to: Karen A. Norris, PhD, Department of Immunology, HIV Lung Research Center, University of Pittsburgh, 1057 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15261 (e-mail: kan1@pitt.edu).

Presented in part at the American Thoracic Society International Conference, May 22, 2012, San Francisco, CA.

Supported by the National Institutes of Health (NIH) Grant HL077095-01A1 and HL077914-01 (K.A.N.) and NIH training Grant T32 AI49820 (H.M.K.).

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.jaids.com).

The authors have no conflicts of interest to disclose.

Received September 10, 2013

Accepted September 10, 2013

© 2014 by Lippincott Williams & Wilkins