Widespread B cell perturbations in HIV-1 infection afflict naive and marginal zone B cells

Perturbations in B cells are a hallmark of HIV-1 infection. This is signified by increased numbers of exhausted CD21(neg) memory B cells, driven by continuous antigen-specific and bystander activation. Using high-dimensional flow cytometry, we demonstrate that this exhausted phenotype is also prevalent among peripheral antigen-inexperienced naive and marginal zone (MZ) B cells in acute and chronic HIV-1 infection. A substantial fraction of naive and MZ B cells exhibit down-regulated CD21 levels and diminished response to B cell receptor (BCR)–dependent stimulation. Compared with CD21(pos) subsets, the CD21(neg) naive and MZ B cells differ in the expression of chemokine receptors and activation markers. Effective antiretroviral treatment normalizes peripheral naive and MZ B cell populations. Our results emphasize a more widely spread impairment of B cells in HIV-1 infection than previously appreciated, including antigen-inexperienced cells. This highlights the importance of monitoring functional capacities of naive B cells in HIV-1 infection, as exhausted CD21(neg) naive B cells may severely impair induction of novel B cell responses.