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HIV Envelope Binding by Macrophage-Expressed gp340 Promotes HIV-1 Infection¹

Georgetta Cannon^*, Yanjie Yi, Houping Ni^*, Earl Stoddard^*, David A. Scales^*, Donald I. Van Ryk, Irwin Chaiken, Daniel Malamud^¶ and Drew Weissman^2,*

^* Division of Infectious Diseases and Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19104; and ^¶ Department of Basic Sciences, New York University College of Dentistry, New York, NY 10010

The scavenger receptor cysteine-rich protein gp340 functions as part of the host innate immune defense system at mucosal surfaces. In the genital tract, its expression by cervical and vaginal epithelial cells promotes HIV trans-infection and may play a role in sexual transmission. Gp340 is an alternatively spliced product of the deleted in malignant brain tumors 1 (DMBT1) gene. In addition to its innate immune system activity, DMBT1 demonstrates instability in multiple types of cancer and plays a role in epithelial cell differentiation. We demonstrate that monocyte-derived macrophages express gp340 and that HIV-1 infection is decreased when envelope cannot bind it. Inhibition of infection occurred at the level of fusion of M-, T-, and dual-tropic envelopes. Additional HIV-1 envelope binding molecules, such as dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN), mannose-binding lectin, and heparan sulfate, enhance the efficiency of infection of the cells that express them by increasing the local concentration of infectious virus. Our data suggest that gp340, which is expressed by macrophages in vivo, may function to enhance infection in much the same manner. Its expression on tissue macrophages and epithelial cells suggests important new opportunities for HIV-1 pathogenesis investigation and therapy.

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 Grants HL620600 and DE12930.

² Address correspondence and reprint requests to Dr. Drew Weissman, Division of Infectious Diseases, Department of Medicine, University of Pennsylvania, 522B Johnson Pavilion, Philadelphia, PA 19104. E-mail address: dreww{at}mail.med.upenn.edu

³ Abbreviations used in this paper: Env, envelope protein; DC, dendritic cells; DC-SIGN, dendritic cell-specific ICAM-3 grabbing nonintegrin; DMBT1, deleted in malignant brain tumors 1; MDM, monocyte-derived macrophages. SAG, salivary agglutinin; SRCR, scavenger receptor cysteine-rich.