Relationship of Pneumocystis jiroveci Humoral Immunity to Prevention of Colonization and Chronic Obstructive Pulmonary Disease in a Primate Model of HIV Infection

Abstract

Pulmonary colonization by the opportunistic pathogen Pneumocystis jiroveci is common in HIV؉ subjects and has been associated with development of chronic obstructive pulmonary disease (COPD). Host and environmental factors associated with colonization susceptibility are undefined. Using a simian-human immunodeficiency virus (SHIV) model of HIV infection, the immunologic parameters associated with natural Pneumocystis jiroveci transmission were evaluated. SHIV-infected macaques were exposed to P. jiroveci by cohousing with immunosuppressed, P. jiroveci-colonized macaques in two independent experiments. Serial plasma and bronchoalveolar lavage (BAL) fluid samples were examined for changes in antibody titers to recombinant Pneumocystis-kexin protein (KEX1) and evidence of Pneumocystis colonization by nested PCR of BAL fluid. In experiment 1, 10 of 14 monkeys became Pneumocystis colonized (Pc ؉ ) by 8 weeks post-SHIV infection, while 4 animals remained Pneumocystis colonization negative (Pc ؊ ) throughout the study. In experiment 2, 11 of 17 animals became Pneumocystis colonized by 16 weeks post-SHIV infection, while 6 monkeys remained Pc ؊ . Baseline plasma KEX1-IgG titers were significantly higher in monkeys that remained Pc ؊ , compared to Pc ؉ monkeys, in experiments 1 (P ‫؍‬ 0.013) and 2 (P ‫؍‬ 0.022). Pc ؊ monkeys had greater percentages of Pneumocystis-specific memory B cells after SHIV infection compared to Pc ؉ monkeys (P ‫؍‬ 0.037). After SHIV infection, Pc ؉ monkeys developed progressive obstructive pulmonary disease, whereas Pc ؊ monkeys maintained normal lung function throughout the study. These results demonstrate a correlation between the KEX1 humoral response and the prevention of Pneumocystis colonization and obstructive lung disease in the SHIV model. In addition, these results indicate that an effective Pneumocystis-specific memory B-cell response is maintained despite progressive loss of CD4 ؉ T cells during SHIV infection.

Colonization by Pneumocystis jirovecii and Its Role in Disease

“…We have reported evidence that Pneumocystis Kex or Kex-related antigens may play a role in protective immunity against Pneumocystis infection in a nonhuman primate model of HIV and Pneumocystis coinfection (153,154). In these studies, we found that a baseline anti-Kex plasma IgG titer of Ͼ1:12,500 in healthy macaques correlated with protection from Pneumocystis infection following SHIV immunosuppression and Pneumocystis exposure challenge (154).…”

“…In these studies, we found that a baseline anti-Kex plasma IgG titer of Ͼ1:12,500 in healthy macaques correlated with protection from Pneumocystis infection following SHIV immunosuppression and Pneumocystis exposure challenge (154). In contrast, monkeys with baseline titers of Ͻ1: 3200 were susceptible to Pneumocystis colonization following SHIV infection.…”

“…Recently, a second Pneumocystis protein has been investigated for potential use in serologic studies (102,154,219). The Pneumocystis protease, kexin (Kex1, Prt1), possesses similarity to the fungal subtilisin-like serine proteases Kex1 from Kluyveromyces lactis and Kex2 from Saccharomyces cerevisiae and Schizosaccharomyces pombe (165,173,181,182).…”

“…Kex is hypothesized to be involved in the proteolytic processing of Pneumocystis surface antigens, in particular, Msg, and in this respect may represent a new therapeutic target. Several recent studies with human subjects and with experimental animal models suggest that recombinant derivatives of Pneumocystis Kex may be a useful target for serologic studies and a potential target for immunologic control of Pneumocystis infection, as discussed below (154,316,328).…”

“…Colonization occurred despite prophylaxis with TMP-SMX. In another study of simian-human immunodeficiency (SHIV)-infected macaques, 68% of animals became colonized after immunosuppression (154).…”