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Decreased Mutation Frequencies among Immunoglobulin G Variable Region Genes during Viremic HIV-1 Infection

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      Abstract

      Background/objective

      HIV-1 infection is complicated by high rates of opportunistic infections against which specific antibodies contribute to immune defense. Antibody function depends on somatic hypermutation (SHM) of variable regions of immunoglobulin heavy chain genes (V H-D-J). We characterized the frequency of SHM in expressed IgG mRNA immunoglobulin transcripts from control and HIV-1-infected patients.

      Design

      We compared utilization of genes in the most prominent V H family (V H3) and mutation frequencies and patterns of cDNA from V H3-IgG genes from 10 seronegative control subjects and 21 patients with HIV-1 infection (6 without and 15 patients with detectable plasma viremia).

      Methods

      Unique IgG V H3 family cDNA sequences (n = 1,565) were PCR amplified, cloned, and sequenced from blood. Sequences were analyzed using online (Vbase) and in-house immunoglobulin alignment resources.

      Results

      Mutation frequencies in the antigen-binding hypervariable complementarity determining regions (CDR1/2) of IgG class-switched B cells were lower among viremic HIV-1-infected patients vs. controls for nucleotides (CDR1/2: 10±5% vs. 13.5±6%, p = 0.03) and amino acids (CDR: 20%±10 vs. 25%±12, p = 0.02) and in structural framework regions. Mutation patterns were similar among groups. The most common V H3 gene, V H3-23, was utilized less frequently among viremic HIV-1-infected patients (p = 0.03), and overall, mutation frequencies were decreased in nearly all V H3 genes compared with controls.

      Conclusions

      B cells from HIV-1-infected patients show decreased mutation frequencies, especially in antigen-binding V H3 CDR genes, and selective defects in gene utilization. Similar mutation patterns suggest defects in the quantity, but not quality, of mutator activity. Lower levels of SHM in IgG class-switched B cells from HIV-1-infected patients may contribute to the increased risk of opportunistic infections and impaired humoral responses to preventative vaccines.

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      Most cited references 47

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      A simple method for displaying the hydropathic character of a protein.

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        B cells in HIV infection and disease.

         A Fauci,  Susan Moir (2009)
        In recent years, intense research efforts have been dedicated to elucidating the pathogenic mechanisms of HIV-associated disease progression. In addition to the progressive depletion and dysfunction of CD4(+) T cells, HIV infection also leads to extensive defects in the humoral arm of the immune system. The lack of immune control of the virus in almost all infected individuals is a great impediment to the treatment of HIV-associated disease and to the development of a successful HIV vaccine. This Review focuses on advances in our understanding of the mechanisms of B-cell dysfunction in HIV-associated disease and discusses similarities with other diseases that are associated with B-cell dysfunction.
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          Abnormalities of B-cell activation and immunoregulation in patients with the acquired immunodeficiency syndrome.

          We studied B-lymphocyte function in 12 homosexual male patients with the acquired immunodeficiency syndrome, 5 healthy homosexual men, and 12 heterosexual controls. In comparison with the heterosexual controls, the patients were found to have elevated numbers of cells spontaneously secreting immunoglobulin, decreased B-cell proliferative responses to T-cell-independent B-cell mitogens, and qualitatively deficient helper T cells. The hyperactive spontaneous B-cell responses as well as the refractoriness to signals for T-cell-independent B-cell activation were highly suggestive of an in vivo polyclonal activation of B cells and may have been responsible for the manifestations of B-cell hyperreactivity, such as hypergammaglobulinemia, seen in these patients. We conclude that the scope of immune dysfunction in the acquired immunodeficiency syndrome involves B cells as well as T cells.
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            Author and article information

            Affiliations
            [1 ]Mucosal and Vaccine Research Program Colorado (MAVRC), University of Colorado Denver, Aurora, Colorado, United States of America
            [2 ]Infectious Disease Division, University of Colorado Denver, Aurora, Colorado, United States of America
            [3 ]Department of Microbiology, University of Colorado Denver, Aurora, Colorado, United States of America
            [4 ]Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado, United States of America
            [5 ]Denver Veterans Affairs Medical Center, Denver, Colorado, United States of America
            [6 ]Minneapolis VA Health Care System, University of Minnesota, Minneapolis, Minnesota, United States of America
            [7 ]GIMAP EA 3064, Faculté de Médecine, Université Jean Monnet, Saint Etienne, France
            South Texas Veterans Health Care System and University Health Science Center San Antonio, United States of America
            Author notes

            Competing Interests: The authors have declared that no competing interests exist.

            Conceived and designed the experiments: EB RWS LB ENJ. Performed the experiments: EB RWS AA KMK. Analyzed the data: EB RWS SM. Contributed reagents/materials/analysis tools: JRT. Wrote the paper: EB ENJ. Patient recruitment: JRT.

            Journal
            PLoS One
            PLoS ONE
            plos
            plosone
            PLoS ONE
            Public Library of Science (San Francisco, USA )
            1932-6203
            2014
            7 January 2014
            : 9
            : 1
            3883639 PONE-D-12-40577 10.1371/journal.pone.0081913

            This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

            Counts
            Pages: 13
            Funding
            This work has been supported by the Veterans Affairs Research Service and the University of Colorado Denver Mucosal and Vaccine Research Program Colorado (MAVRC) (ENJ) and facilitated by the infrastructure and resources provided by the Colorado Center for AIDS Research Grant (P30 AI054907), the University of Colorado Cancer Center Core Sequencing Facility (P30CA046934), a grant from “Conseil Régional Rhône-Alpes” (Recontres Régionales de la Recherche) (LB) and National Institutes of Health (NIH) grants F32DE005703-01 and RO1A10495752-01 (RWS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
            Categories
            Research Article
            Biology
            Genetics
            Human Genetics
            Immunology
            Immune Cells
            Antibody-Producing Cells
            B Cells
            Immunity
            Humoral Immunity
            Immunoglobulins
            Microbiology
            Virology
            Immunodeficiency Viruses
            Host-Pathogen Interaction
            Pathogenesis
            Medicine
            Clinical Immunology
            Immunity
            Humoral Immunity

            Uncategorized

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