Germinal center function in the spleen during simian HIV infection in rhesus monkeys

David H. Margolin, Erika H. Saunders, Benjamin Bronfin, Nicole De Rosa, Michael Axthelm, Olga G. Goloubeva, Sara Eapen, Rebecca S. Gelman, Norman L. Letvin

    Research output: Contribution to journalArticle

    15 Citations (Scopus)

    Abstract

    Infection with HIV-1, SIV, or simian HIV is associated with abnormalities in the number, size, and structure of germinal centers (GCs). To determine whether these histopathologic abnormalities are associated with abnormalities in Ab development, we analyzed necleotide sequences of Igs from splenic GCs of simian HIV-infected macaques. Virus-specific GCs were identified in frozen splenic tissue sections by inverse immunohistochemistry using rHIV-1 gp120 as a probe. B cells from envelope-specific GCs were isolated from these sections using laser capture microdissection. Their Igs were amplified from cDNA using nested PCR, then cloned and sequenced. Nucleotide sequences were recovered from nine multimember clonal lineages. Within each lineage, sequences had similar V-D-J or V-J junctions but differed by somatic mutations distributed throughout the variable domain. The clones were highly mutated, similar to that previously reported for HIV-1-specific human IgG Abs. The average clone had 37 mutations in the V region, for a frequency of 0.11 mutations/base. The mutational pattern was strikingly nonrandom, with somatic mutations occurring preferentially at RGYW/WRCY hotspots. Transition mutations were favored over transversions, with C→T and G→A replacements together accounting for almost one-third of all mutations. Analysis of replacement and silent mutations in the framework and CDRs suggests that the Igs were subjected to affinity selection. These data demonstrate that the process of Ab maturation is not seriously disrupted in GCs during the early stages of immunodeficiency virus infection, and that Env-specific Igs developing in GCs are subject to extensive somatic mutation and profound selection pressures.

    Original languageEnglish (US)
    Pages (from-to)1108-1119
    Number of pages12
    JournalJournal of Immunology
    Volume177
    Issue number2
    StatePublished - Jul 15 2006

    Fingerprint

    Germinal Center
    Macaca mulatta
    HIV Infections
    Spleen
    Mutation
    HIV-1
    Clone Cells
    HIV
    Laser Capture Microdissection
    Macaca
    Virus Diseases
    Mutation Rate
    B-Lymphocytes
    Complementary DNA
    Immunoglobulin G
    Immunohistochemistry
    Viruses
    Pressure
    Polymerase Chain Reaction
    Infection

    ASJC Scopus subject areas

    • Immunology

    Cite this

    Margolin, D. H., Saunders, E. H., Bronfin, B., De Rosa, N., Axthelm, M., Goloubeva, O. G., ... Letvin, N. L. (2006). Germinal center function in the spleen during simian HIV infection in rhesus monkeys. Journal of Immunology, 177(2), 1108-1119.

    Germinal center function in the spleen during simian HIV infection in rhesus monkeys. / Margolin, David H.; Saunders, Erika H.; Bronfin, Benjamin; De Rosa, Nicole; Axthelm, Michael; Goloubeva, Olga G.; Eapen, Sara; Gelman, Rebecca S.; Letvin, Norman L.

    In: Journal of Immunology, Vol. 177, No. 2, 15.07.2006, p. 1108-1119.

    Research output: Contribution to journalArticle

    Margolin, DH, Saunders, EH, Bronfin, B, De Rosa, N, Axthelm, M, Goloubeva, OG, Eapen, S, Gelman, RS & Letvin, NL 2006, 'Germinal center function in the spleen during simian HIV infection in rhesus monkeys', Journal of Immunology, vol. 177, no. 2, pp. 1108-1119.
    Margolin DH, Saunders EH, Bronfin B, De Rosa N, Axthelm M, Goloubeva OG et al. Germinal center function in the spleen during simian HIV infection in rhesus monkeys. Journal of Immunology. 2006 Jul 15;177(2):1108-1119.
    Margolin, David H. ; Saunders, Erika H. ; Bronfin, Benjamin ; De Rosa, Nicole ; Axthelm, Michael ; Goloubeva, Olga G. ; Eapen, Sara ; Gelman, Rebecca S. ; Letvin, Norman L. / Germinal center function in the spleen during simian HIV infection in rhesus monkeys. In: Journal of Immunology. 2006 ; Vol. 177, No. 2. pp. 1108-1119.
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