HIV-infected individuals greatly suffer from B cell dysfunction, partly due to increased fibrosis and destruction of lymph node architecture. As we test curative strategies for HIV it is apparent that an improvement of the immune system is a necessity. To boost immunity, we treated HIV+ individuals with the TLR9 agonist lefitolimod (MGN1703). Here we report the effects on B cell differentiation as well as total plasma IgG levels as it has been shown that TLR9 agonists stimulation of B cells lead to enhanced humoral immunity.
We performed a single-arm phase 1b/2a clinical trial, where 13 HIV+ adults on ART received lefitolimod (60 mg s.c.) twice weekly for 24 weeks (NCT02443935). We analyzed B cell differentiation status on freshly isolated PBMCs (baseline, on weeks (wk)12 and 24) and on freshly isolated mononuclear cells from lymph nodes (baseline, wk24) via flow cytometry. We also analyzed total plasma IgG and IgG subtypes using a standard clinical assay. On-drug time-points were compared to baseline using Wilcoxon signed-rank test.
B cell differentiation and maturation can be identified through multiple phenotypic stages. We examined key B cell subsets and found a substantial increase in the proportions of peripheral blood plasmablasts (wk12 p=0.033), which is the precursor of the antibody-secreting plasma cell. In the lymph nodes, we found an increase in proportions of follicular B cells (p=0.016) and the germinal center B cells (p=0.078), the main B cell subsets that reside in primary and secondary B cell follicles. Consistent with these changes toward a more differentiated B cell phenotype we found increased levels of total IgG (p=0.019) as well as subclasses IgG1 (p=0.042), IgG2 (p=0.021), and IgG3 (p=0.002), after 12 wk treatment. Of note, the IgG3 subclass is superior in its binding affinity for Fc-receptors and is known to be particularly effective in the induction of effector functions.
Lefitolimod markedly enhanced B cell differentiation in circulating B cells. The increase in plasmablasts is indicative of an enhanced differentiation of activated antibody-secreting plasma cells, which is supported by observed increase in IgG plasma levels. In lymph nodes the increase in follicular and germinal center B cells point towards a restoration of lymph node architecture. Overall, these data suggest improved lymph node function and humoral immune response in HIV+ individuals on ART, when treated with lefitolimod.