Immunomodulation of antiretroviral drug-suppressed chronic HIV-1 infection in an oral probiotic double-blind placebo-controlled trial

Abstract

A putative source of inappropriate immune activation that drives human immunodeficiency virus (HIV)-1 immunopathogenesis is the gastrointestinal tract. Even with effective antiretroviral treatment, residual activation persists. We hypothesized that an oral probiotic could improve the residual immune activation in chronic treated HIV-1 infection, and tested a Bacillus coagulans GBI-30, 6086 capsule probiotic in HIV-1-infected persons with suppressed viremia on stable antiretroviral therapy in a 3-month double-blind placebo-controlled trial (10 probiotic, 7 placebo). The Gastrointestinal Symptom Rating Scale (GSRS) was administered monthly. Blood was tested at the start and end of placebo/probiotic administration for viremia, CD4(+) T cell percentage/concentration, soluble (s)CD14, soluble intestinal fatty acid binding protein, sCD163, D-dimer, C-reactive protein (CRP), interleukin-8, and tumor necrosis factor-α. All participants maintained viremia <40 RNA copies/ml. The probiotic was safe and well tolerated, and appeared to improve chronic gastrointestinal symptoms. Its administration was associated with a significant increase in the percentage of blood CD4(+) T cells compared to placebo (+2.8% versus -1.8%, p=0.018) although CD4(+) T cell concentrations were generally unchanged in both groups. None of the biomarkers showed significant changes on probiotic treatment or between-group differences in change (although significance was borderline for a greater sCD163 drop in the probiotic versus placebo group, p=0.05). Some biomarkers showed significant correlations to each other, particularly D-dimer with CRP and sCD14 with tumor necrosis factor (TNF)-α. These data demonstrate the safety and possible benefit of this probiotic for residual inflammation in treated HIV-1 infection, although further study will be required to determine the immune pathways involved.

FIG. 1.

Gastrointestinal symptoms. Median scores from the Gastrointestinal Symptom Rating Scale (GSRS) for five categories of symptoms and all combined are plotted for placebo (n=7) and probiotic (n=9) groups. Subject GAN 009 was excluded because survey information was not provided for two study visits. The maximal value on the y-axis is the highest possible score on the GSRS. Asterisks indicate probiotic group significant differences from week 0 (paired Student's t-test); there were no significant differences from week 0 in the placebo group. Comparisons of placebo versus probiotic groups showed significant differences only for the constipation category at week 8 (p=0.049) and the combination of all symptoms at week 8 (p=0.049).

FIG. 2.

Changes in blood CD4⁺ T cell counts and percentages during the study. For each group, the changes in blood CD4⁺ T cell counts (A) and percentages (B) during the 90 days of placebo or probiotic administration are plotted. Each point represents one individual, and the bars indicate the medians for each group.

FIG. 3.

Levels of blood biomarkers during the study. For each individual, the blood concentrations of the indicated biomarkers are plotted for values at start to end of placebo/probiotic administration (thin lines), on log₁₀ scales. Thick lines indicate the medians for each group. Not shown are lipopolysaccharide (LPS), interleukin (IL)-1β, and IL-6 because these were not detected (<0.05 EU/ml, <7.1 pg/ml, and <0.6 pg/ml, respectively). Changes in these markers within groups were not statistically significant. Comparisons of changes between groups approached significance (p<0.2) only for soluble (s)CD163 (p=0.05). Units were μg/ml for D-dimer, mg/dl for C-reactive protein (CRP), pg/ml for IL-8, pg/ml for tumor necrosis factor (TNF)-α, ng/ml for sCD163, μg/ml for sCD14, and ng/ml for serum intestinal-type fatty acid binding protein (sI-FABP).

FIG. 4.

Changes in percentage of CD4⁺ T cells versus changes in proinflammatory blood biomarkers during the study. Changes in the biomarkers and CD4% T cells between the start and end of placebo/probiotic administration are plotted against each other.