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Inhibition of HIV-1 Infectivity through an Innate Mechanism Involving Naturally Occurring IgM Anti-Leukocyte Autoantibodies¹

Peter I. Lobo^2,*,,, Kailo H. Schlegel^*,, Wen Yuan^,, Gregory C. Townsend and Jennifer A. White

^* Division of Nephrology and Division of Infectious Diseases and International Health, Department of Medicine, Center for Immunity Inflammation and Regenerative Medicine, and Myles H. Thaler Center for AIDS and Human Retrovirus Research, University of Virginia Health System, Charlottesville, VA 22908

In prior studies, we show that naturally occurring IgM anti-leukocyte autoantibodies (IgM-ALA) bind to CD3, CD4, CCR5, and CXCR4 receptors. These observations prompted us to determine whether IgM-ALA have a role in inhibiting HIV-1 infectivity by inhibiting viral entry into cells. We show that purified IgM, but not IgG, from individual sera of both normal and HIV-1 infected individuals is highly inhibitory (>95%) to HIV-1 viral infectivity both in vitro using PHA plus IL-2 activated PBL and in vivo using the human PBL-SCID mouse. Inhibition was observed with physiological doses of purified serum IgM and even after IgM was added 3 days postinfection in the in vitro assays. Absorbing purified serum IgM either with leukocytes or immobilized recombinant CD4 significantly decreased (>80%) the inhibitory effect on HIV-1 infectivity. IgM inhibited by >90% syncytia formation with the X4-IIIB infected SupT-1 cells indicating therefore that IgM inhibits viral attachment to core-receptors. IgM mediated anti-HIV-1 activity was highly specific as only certain IgM-ALA, obtained from human B cell clones inhibited HIV-1. IgM from certain HIV-1 infected individuals were not inhibitory to some R5-HIV-1 viral strains indicating that certain HIV-IgM may lack Abs reactive to strain specific coreceptor epitopes. These data indicate that an innate immune mechanism which is present from birth i.e., IgM-ALA, has a role in inhibiting HIV-1 viral entry into cells. Validation of this data with other in vivo models will be needed to determine whether in vivo administration or enhancement of IgM-ALA, e.g., through a vaccine, could prolong the asymptomatic state in HIV-1 infected individuals.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health, National Institute of Allergy and Infectious Diseases Grant 5R21AI052740-02 (to P.I.L.), Nephrology Division Research Development Funds, and the University of Virginia Research Development Funds.

² Address correspondence and reprint requests to Dr. Peter I. Lobo, Department of Internal Medicine and Nephrology, University of Virginia Health System, P.O. Box 800133, Charlottesville, VA 22908. Email: pil{at}virginia.edu

³ Abbreviations used in this paper: IgM-ALA, IgM anti-leukocyte autoantibodies; ESRD, end-stage renal disease patients; MCF, mean (geometric) channel fluorescence.