In 2015, we pursued studies that can be broken down into three sections. 1) plasma cells in the bone marrow of HIV-infected individuals and the antibodies they produce; 2) assessment of antibodies generated from single-cell sorting and cloning strategies; and 3) B-cell features and functions in non-HIV immunodeficiencies. First, in a study published in the Journal of Immunology, we investigated B cells in the bone marrow of HIV-infected individuals during the chronic clinically asymptomatic phase of disease. We found that while there were no obvious perturbations in hematopoiesis, alterations in the frequencies of various B-cell subsets were noted when compared to bone marrow cells of HIV-negative individuals, including an increased frequency of plasma cells, the terminally differentiated B-cell subset responsible for making antibodies. This abnormality is consistent with other hallmarks of HIV infection, namely hypergammaglobulinemia and increased frequencies in the periphery of precursors of plasma cells, plasmablasts. Furthermore, we found that there was a strong correlation between the frequency of HIV-specific plasma cells in the bone marrow and HIV-neutralizing antibodies in the serum of HIV-infected individuals. These findings suggest that despite HIV-induced systemic B-cell perturbations in infected individuals, their bone marrow remains the repository for long-lived plasma cells responsible for antibodies that circulate in the periphery. Second, in studies involving collaborative efforts with the VRC/NIAID and Yale University, we have used single-cell sorting and cloning strategies to express monoclonal antibodies (mAbs) derived from immunoglobulin (Ig) genes of B cells in the peripheral blood and secondary lymphoid tissues of HIV-infected individuals. In a study submitted for peer review, involving B cells isolated from the peripheral blood of HIV-viremic individuals, we compared Ig genes and derived mAbs from B cells of two subsets: tissue-like memory B cells that are over-represented in chronically infected HIV-viremic individuals and have been associated with B exhaustion and resting memory B cells that represent the majority of circulating memory B cells in healthy donors. We found that despite a higher number of cell divisions that should correlate with affinity maturation of the antibody response, Ig genes and HIV-specific mAbs isolated from the tissue-like memory B-cell compartment displayed reduced levels of somatic hypermutation and HIV neutralization potential compared to their resting memory B-cell counterparts. These findings suggest that HIV-induced B-cell exhaustion is associated with a relatively inefficient memory response, which in turn, may help explain why humoral immunity in HIV-infected individuals does little to control viral replication. In preliminary analyses of lymph node B cells, we found that the highest frequency of HIV-specific B cells was within germinal centers and we are currently comparing the antibodies derived from this subset to those derived from other memory B cell subsets in the tissue and in the peripheral blood of the same individuals. Third, we continue to pursue several collaborative efforts with colleagues in the LIR, as well as other laboratories at NIAID and other NIH institutes. Over the past year we have contributed to the investigation of B cells in various disease settings, including HIV/HCV co-infection; congenital B-cell lymphocytosis associated with mutations in the adaptor protein CARD11; B-cell reconstitution following kinase-targeted treatment of individuals with chronic lymphocytic leukemina (CLL); and auto-inflammatory diseases that dysregulate cytokine pathways. Based on our knowledge of human B-cell immunology accumulated over almost two decades of work on HIV-induced B-cell pathogenesis, we have been called upon to provide expertise in other disease settings that involve B cells. Some processes and affected pathways are common to different diseases, such as type I interferon dysregulation in both auto-inflammatory and HIV diseases. By collaborating with other investigators, we have gained a greater understanding of B cells and their role in the pathogenesis of various diseases than if we studied our respective diseases independently. Collectively, these collaborative efforts advance our understanding of human B-cell immunology, the dysregulation that occurs in various disease settings, and potential means of intervening to restore health.

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Kononchik, Joseph; Ireland, Joanna; Zou, Zhongcheng et al. (2018) HIV-1 targets L-selectin for adhesion and induces its shedding for viral release. Nat Commun 9:2825
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