The B cell dysfunction observed in untreated and treated HIV infection has several manifestations, including a decrease in both the magnitude and isotype diversification of IgG antibody responses. As persistent type I interferon (IFN) activity is associated with a poor outcome in HIV infection, we examined the effect of IFN-α upon plasmablast induction and IgG subclass production following B cell stimulation.
PBMC from 20 HIV patients receiving antiretroviral therapy and 10 HIV-negative donors (controls) were stimulated with IL-21 and CD40L in the absence or presence of IFN-α2b for 5 days. Expression of the IFN-α receptor subunits, IFNAR1 and IFNAR2, by unstimulated B cells, and the proportion of plasmablasts (CD27hiCD38hi) after stimulation, were examined by flow cytometry. Total IgG, IgG1 (upstream isotype) and IgG2 (downstream isotype) concentrations in culture supernatants were quantified by ELISA.
Following IL-21/CD40L stimulation, plasmablast induction and total IgG levels in supernatants were lower in HIV patients (p=0.04 and 0.0007, respectively). IFN-α2b did not reduce plasmablast induction further but decreased production of IgG2 in both controls (p=0.002) and HIV patients (p=0.0001) while IgG1 production was not affected. Total IgG was also lower in HIV patients (p=0.01). In HIV patients, IFNAR1 expression was higher on all B cell subpopulations (p<0.001) and IFN-α2b-mediated inhibition of IgG2 production correlated with IFNAR1 expression on B cells (r=0.9; p=0.007).
IFN-α exerts an inhibitory effect on isotype-switching from IgG1 to IgG2, which is related to expression of IFNAR1 in HIV patients. Plasmablast induction is also lower in treated HIV patients.