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Role for CD21 in the Establishment of an Extracellular HIV Reservoir in Lymphoid Tissues¹

Jason Ho^2,*, Susan Moir^2,3,*, Liudmila Kulik, Angela Malaspina^*, Eileen T. Donoghue^*, Natalie J. Miller^*, Wei Wang^*, Tae-Wook Chun^*, Anthony S. Fauci^* and V. Michael Holers

^* Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and Department of Medicine and Immunology, University of Colorado Health Sciences Center, Denver, CO 80262

Follicular dendritic cells (FDC) represent a major extracellular reservoir for HIV. A better understanding of the mechanisms of virion attachment to FDC may offer new avenues for reducing viral burdens in infected individuals. We used a murine model to investigate the establishment of extracellular HIV reservoirs in lymph nodes (LN). Consistent with findings in human tissues, CD21 was required for trapping of HIV to LN cells, as evidenced by significantly reduced virion binding when mice were pretreated with a C3 ligand-blocking anti-CD21 mAb and absence of virion trapping in CD21 knockout mice. Also consistent with findings in human tissues, the majority of HIV virions were associated with the FDC-enriched fraction of LN cell preparations. Somewhat surprisingly, HIV-specific Abs were not essential for HIV binding to LN cells, indicating that seeding of the FDC reservoir may begin shortly after infection and before the development of HIV-specific Abs. Finally, the virion-displacing potential for anti-CD21 mAbs was investigated. Treatment of mice with anti-CD21 mAbs several days after injection of HIV significantly reduced HIV bound to LN cells. Our findings demonstrate a critical role for CD21 in HIV trapping by LN cells and suggest a new therapeutic avenue for reducing HIV reservoirs.

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 the Intramural Research Program of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health and by Grant R01-CA53615 from the National Institutes of Health (to V.M.H.).

² J.H. and S.M. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Susan Moir, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10, Room 6A02, 10 Center Drive, Bethesda, MD 20892. E-mail address: smoir{at}niaid.nih.gov

⁴ Abbreviations used in this paper: FDC, follicular dendritic cell; LN, lymph node.