Relationship of Pneumocystis jiroveci humoral immunity to prevention of colonization and chronic obstructive pulmonary disease in a primate model of HIV infection - PubMed (original) (raw)

Relationship of Pneumocystis jiroveci humoral immunity to prevention of colonization and chronic obstructive pulmonary disease in a primate model of HIV infection

Heather M Kling et al. Infect Immun. 2010 Oct.

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.

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Figures

FIG. 1.

FIG. 1.

CD4+ T-cell counts, peak plasma viral loads, and Gag antibody responses were not significantly different between Pc+ and Pc− monkeys. (A and D) Mean peripheral blood CD4+ T cells (experiment 1 [A, P = 0.488], experiment 2 [D, P = 0.326]); (B and E) peak plasma virus titers (experiment 1 [B, P = 0.749], experiment 2 [E, P = 0.595]); (C) SHIV anti-gag protein antibody titers (P = 0.419, two-way repeated measures ANOVA).

FIG. 2.

FIG. 2.

Baseline plasma anti-KEX1 IgG reciprocal endpoint titer and numbers of KEX-specific ASCs predict Pneumocystis colonization following SHIV immunosuppression. Baseline anti-KEX1 IgG titers between monkeys that became colonized after SHIV infection and monkeys that remained Pc− were analyzed. Pc− monkeys had significantly higher baseline KEX titers than monkeys that remained Pc+ in both experiment 1 (A) and experiment 2 (B). (C) Low-baseline KEX1-IgG titers are associated with Pneumocystis colonization after SHIV immunosuppression (P = 0.011, Fisher exact test). (D) Monkeys that remained Pc− had higher numbers of KEX1-specific ASCs at baseline than monkeys that became Pc+ (P = 0.018).

FIG. 3.

FIG. 3.

Representative KEX1 antibody and CD4+ T-cell profiles of macaques with low baseline KEX1 titers and high baseline KEX1 titers. Serial plasma anti-KEX1 titers and CD4 T-cell counts in two macaques with low (A) or high (B) baseline anti-KEX1 antibody titers were determined. BAL samples were tested at each time point for Pneumocystis DNA (by nested PCR). Time points marked by “+” had detectable Pneumocystis DNA.

FIG. 4.

FIG. 4.

KEX1-IgA production in the BAL fluid. Baseline plasma KEX1-IgG titers positively correlate with peak KEX1-IgA titers in the BAL fluid (A, P = 0.043). A total of 75% of Pc− macaques were producing KEX1-IgA in the BAL fluid by week 4 post-SHIV infection compared to only 10% of Pc+ macaques (B, P = 0.041, Fisher exact test).

FIG. 5.

FIG. 5.

Percentages of peripheral blood KEX1-specific memory B cells were significantly higher in Pc− monkeys than in Pc+ monkeys (experiment 2). PBMC from macaques in experimental group 2 were isolated at 9 to 12 months post-SHIV infection and stimulated in culture for 6 to 7 days and evaluated by using B-cell ELISPOT assays for total IgG and KEX1-specific IgG-secreting cells. KEX1-specific cells are expressed as a percentage of total IgG-secreting cells. The mean percentages of KEX1-specific memory cells for Pc− monkeys were significantly higher than for Pc+ monkeys (P = 0.037, Student t test).

FIG. 6.

FIG. 6.

Pneumocystis colonization of immunosuppressed monkeys results in pulmonary obstruction, as measured by pulmonary function testing. Pulmonary function parameters were measured at baseline and 10 months post-SHIV infection, and changes were analyzed according to Pneumocystis colonization status. PEF (peak expiratory flow) and FEV0.4 (forced expiratory volume in 0.4 s) for Pc+ and Pc− animals in both experiment 1 (A and B) and experiment 2 (C and D) were compared by paired Student t test from baseline to 10 months post-SHIV infection. The corresponding P values for each comparison are given in each panel.

FIG. 7.

FIG. 7.

KEX1-specific antibody production is associated with protection from pulmonary function decline. (A) Monkeys that exhibited at least a 12% decline in peak expiratory flow (PEF) after immunosuppression and subsequent Pneumocystis exposure had a median baseline KEX1-IgG titer of 4,400, whereas animals that did not exhibit this decline exhibited a median baseline KEX1-IgG RET of 9,600 (P = 0.021) (combined data set from experiments 1 and 2). (B) Association of timing of KEX1-specific IgA detected in BAL fluid supernatant with PEF declines. Monkeys that produced KEX1-IgA later than 4 weeks post-SHIV infection exhibited a greater decline in PEF (mean change in PEF = 12% ± 4.3% decrease from baseline), compared to monkeys that were producing KEX1-IgA by week 4 (mean change in PEF = 1% increase) (experiment 1).

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