Randomized Clinical Trial for the Evaluation of Immune Modulation by Yogurt Enriched with ß-Glucans from Lingzhi or Reishi Medicinal Mushroom, Ganoderma lucidum (Agaricomycetes), in Children from Medellin, Colombia.

Pattern recognition receptor (PRR) agonists are promising for use in modulating immune responses in clinical settings characterized by immune immaturity or deficiency. ß-Glucans derived from Ganoderma lucidum have demonstrated immune-modulatory activity both in vitro and in vivo. To evaluate the immunomodulatory activity of orally administered ß-glucans, a randomized, double-blinded, placebo-controlled clinical study was performed in asymptomatic children, aged 3 to 5 years old, from Medellin, Colombia. Primary outcomes were the circulating CD8+ T lymphocyte and natural killer cell counts; secondary outcomes were circulating lymphocyte counts (total, CD3+, and CD4+ T cells), serum concentrations of total immunoglobulin A and cytokines, and various hematological parameters. The treatments were administered daily for 12 weeks, and physical and laboratory evaluations were performed at days 0 and 84. Children in the group receiving a yogurt with ß-glucans presented a significantly higher absolute count of peripheral blood total lymphocytes (CD3+, CD4+, and CD8+ T cells) than that in the group receiving placebo. The interventions were safe and well tolerated; no abnormal increases in serum creatinine or hepatic aminotransferases occurred, and adherence was higher than 90% in the intervention groups. This study demonstrates that ß-glucans from G. lucidum increase the frequency of immune system cells in the peripheral blood; these cells are critical in the defense against infectious threats in asymptomatic children 3 to 5 years old. These findings warrant longer controlled clinical trials that aim to evaluate the efficacy of ß-glucans in preventing infections in healthy children and to define their potential to enhance lymphoid cell number and functions in various lymphoid immune deficiencies.

In vivo effect of statins on the expression of the HIV co-receptors CCR5 and CXCR4.

BACKGROUND: During the HIV-1 replication cycle, several molecules including chemokine receptors and cholesterol are crucial, and are therefore potential targets for therapeutic intervention. Indeed statins, compounds that inhibit cellular synthesis of cholesterol and have anti-inflammatory and immunomodulatory properties were shown to inhibit HIV-1 infection by R5 tropic strains but not by X4 strains in vitro, mainly by altering the chemokine receptor/ligands axes. Therefore, the objective of this study was to characterize in vivo, the capacity of statins to modulate in HIV seronegative and chronically HIV-1-infected adults the expression of CCR5 and CXCR4, of their ligands and the tropism of circulating HIV-1 strains. METHODS: Samples from asymptomatic HIV-1-infected adults enrolled in a clinical trial aimed at evaluating the antiretroviral activity of lovastatin were used to evaluate in vivo the modulation by lovastatin of CCR5, CXCR4, their ligands, and the shift in plasma viral tropism over one year of intervention. In addition, ten HIV negative adults received a daily oral dose of 40 mg of lovastatin or 20 mg of atorvastatin; seven other HIV negative individuals who received no treatment were followed as controls. The frequency and phenotype of immune cells were determined by flow-cytometry; mRNA levels of chemokine receptors and their ligands were determined by real-time PCR. Viral tropism was determined by PCR and sequencing, applying the clonal and clinical model of analyses. RESULTS: Our study shows that long-term administration of lovastatin in HIV-infected individuals does not induce a shift in viral tropism, or induce a significant modulation of CCR5 and CXCR4 on immune cells in HIV-infected patients. Similar results were found in HIV seronegative control subjects, treated with lovastatin or atorvastatin, but a significant increase in CCL3 and CCL4 transcription was observed in these individuals. CONCLUSIONS: These findings suggest that long-term administration of statins at therapeutic doses, does not significantly affect the expression of HIV-1 co-receptors or of their ligands. In addition it is important to point out that based on the results obtained, therapeutic administration of statins in HIV-infected patients with lipid disorders is safe in terms of selecting X4 strains.

Randomized clinical trial of lovastatin in HIV-infected, HAART naïve patients (NCT00721305).

BACKGROUND: Evidence suggests that statins may modify the immune response against HIV. The aim was to evaluate the antiretroviral and immunomodulatory effects of lovastatin in HIV-infected patients, naïve for antiretroviral therapy. METHODS: Randomized, double-blinded, placebo-controlled, phase-II clinical trial. Primary outcomes were plasma viral load and circulating CD4+ T cell count, after 6 and 12 months of treatment; secondary outcomes were CD8+ T cell count, expression of activation markers (CD38 and HLA-DR) on T cells, and clinical outcomes. With a power of 90% to detect both a decrease of 0.3 log10 in plasma HIV-1 RNA copies and an increase of 20% in the CD4+ T cell count, we estimated a required sample size of 110 HIV-infected patients (55 per group). The results were analyzed by a model of repeated measurements using Generalized Estimating Equations. RESULTS: Patients were randomized to receive either lovastatin (n = 55) or placebo (n = 57). During the 12-month follow-up, there was no effect of lovastatin either on viral load (estimated average change = 0.157 copies/mL; CI 95% = -0.099 to 0.414), or on the CD4+ T cell count (estimated average change = -26.1 cells/µL; CI 95% = -89.8 to 37.6). Moreover, there were no significant differences in secondary outcomes. CONCLUSIONS: Daily administration of lovastatin (40 mg) for one year in HIV-infected patients, naïve for antiretroviral therapy, had no significant effect on HIV replication, the CD4+ T cell count, or the activation level of T cells. (www.clinicaltrials.gov; ID NCT00721305).

Antiretroviral effect of lovastatin on HIV-1-infected individuals without highly active antiretroviral therapy (The LIVE study): a phase-II randomized clinical trial.

BACKGROUND: Highly active antiretroviral therapy produces a significant decrease in HIV-1 replication and allows an increase in the CD4 T-cell count, leading to a decrease in the incidence of opportunistic infections and mortality. However, the cost, side effects and complexity of antiretroviral regimens have underscored the immediate need for additional therapeutic approaches. Statins exert pleiotropic effects through a variety of mechanisms, among which there are several immunoregulatory effects, related and unrelated to their cholesterol-lowering activity that can be useful to control HIV-1 infection. METHODS/DESIGN: Randomized, double-blinded, placebo controlled, single-center, phase-II clinical trial. One hundred and ten chronically HIV-1-infected patients, older than 18 years and naïve for antiretroviral therapy (i.e., without prior or current management with antiretroviral drugs) will be enrolled at the outpatient services from the most important centres for health insurance care in Medellin-Colombia. The interventions will be lovastatin (40 mg/day, orally, for 12 months; 55 patients) or placebo (55 patients). Our primary aim will be to determine the effect of lovastatin on viral replication. The secondary aim will be to determine the effect of lovastatin on CD4+ T-cell count in peripheral blood. As tertiary aims we will explore differences in CD8+ T-cell count, expression of activation markers (CD38 and HLA-DR) on CD4 and CD8 T cells, cholesterol metabolism, LFA-1/ICAM-1 function, Rho GTPases function and clinical evolution between treated and not treated HIV-1-infected individuals. DISCUSSION: Preliminary descriptive studies have suggested that statins (lovastatin) may have anti HIV-1 activity and that their administration is safe, with the potential effect of controlling HIV-1 replication in chronically infected individuals who had not received antiretroviral medications. Considering that there is limited clinical data available on this topic, all these findings warrant further evaluation to determine if long-term administration of statins may benefit the virological and immunological evolution in HIV-1-infected individuals before the use of antiretroviral therapy is required. TRIAL REGISTRATION: Registration number NCT00721305.