Serologic Responses to Pneumocystis Proteins in HIV Patients With and Without Pneumocystis jirovecii Pneumonia

Abstract

Background Immune responses to Pneumocystis jirovecii are not well understood in HIV infection, but antibody responses to proteins may be useful as a marker of Pneumocystis risk or presence of Pneumocystis pneumonia (PcP). Design Retrospective analysis of a prospective cohort Methods Enzyme-linked immunosorbent assays of antibodies to recombinant Pneumocystis proteins of major surface glycoprotein fragments (MsgC1, C3, C8, and C9) and of antibody titers to recombinant kexin protein (KEX1) were performed on three sequential serum samples up to 18 months prior to and three samples after first AIDS-defining illness from Multicenter AIDS Cohort Study participants and compared between those who had PcP or a non-PcP AIDS-defining illness. Results Fifty-four participants had PcP and 47 had a non-PcP AIDS-defining illness. IgG levels to MsgC fragments were similar between groups prior to first AIDS-defining illness, but the PcP group had higher levels of IgG to MsgC9 (median units/ml 50.2 vs. 22.2, p=0.047) post-illness. Participants with PcP were more likely to have an increase in MsgC3 (OR 3.9, p=0.02), MsgC8 (OR 5.5, p=0.001), and MsgC9 (OR 4.0, p=0.007). The PcP group was more likely to have low KEX1 IgG prior to development of PcP (OR 3.6, p=0.048) independent of CD4 cell count and to have an increase in high IgG titers to KEX1 after PcP. Conclusion HIV-infected individuals develop immune responses to both Msg and kexin proteins after PcP. Low KEX1 IgG titers may be a novel marker of future PcP risk before CD4 cell count has declined below 200 cells/μl.

Colonization by Pneumocystis jirovecii and Its Role in Disease

“…These experimental studies are supported by a recent human study in which plasma anti-Kex and anti-Msg IgG levels were evaluated in HIV-infected patients with PCP and those with another AIDS-defining illness, both before and after their AIDSdefining illness (102). Antibody titers to Pneumocystis Msg and Kex increased after acute PCP, but low baseline Kex levels were associated with subsequent development of PCP, even in persons not yet at risk for PCP by CD4 cell count criteria.…”

“…HIV-infected patients with active PCP have significantly higher antibody titers to MsgC than patients with pneumonia due to other causes (68). Recent studies have supported the utility of MsgC titers as indicators of acute or recent PCP (102).…”

“…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).…”

Overcoming Hurdles to Development of a Vaccine against Pneumocystis jirovecii

“…This is important since it is possible that circulating antibody can be maintained long after CD4 T cells have been compromised. In fact, Gingo et al found that elevated antibodies specific for the P. jirovecii kexin protein (KEX1) were associated with reduced risk for developing PCP in human immunodeficiency virus (HIV)-infected individuals (9). Most papers addressing immunization or vaccine development have utilized animal models of infection, including mice, rats, ferrets, and nonhuman primates.…”

An Emerging Role of B Cell Immunity in Susceptibility to Pneumocystis Pneumonia

“…Some of this antibody response is directed against major surface glycoproteins of the organism (16), and now that we have draft genomes for the mouse, rat, and human organisms, this family of major surface glycoproteins is the most divergent between the fungal species. This may explain the host specificity of these organisms (rat Pneumocystis does not infect mice, and vice versa), similar to what has been elegantly reproved with other host-specific commensals, such as segmented filamentous bacteria (17).…”