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¹ Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892
² Department of Microbiology, Howard University College of Medicine, Washington, DC 20059
³ Toronto General Research Institute and ⁴ Toronto Western Research Institute, University Health Network, Toronto, Ontario M5G 2C4, Canada
⁵ Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada

CORRESPONDENCE Gary J. Nabel: gnabel{at}nih.gov

Dendritic cells (DCs) capture and internalize human immunodeficiency virus (HIV)-1 through C-type lectins, including DC-SIGN. These cells mediate efficient infection of T cells by concentrating the delivery of virus through the infectious synapse, a process dependent on the cytoplasmic domain of DC-SIGN. Here, we identify a cellular protein that binds specifically to the cytoplasmic region of DC-SIGN and directs internalized virus to the proteasome. This cellular protein, leukocyte-specific protein 1 (LSP1), was defined biochemically by immunoprecipitation and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. LSP1 is an F-actin binding protein involved in leukocyte motility and found on the cytoplasmic surface of the plasma membrane. LSP1 interacted specifically with DC-SIGN and other C-type lectins, but not the inactive mutant DC-SIGN35, which lacks a cytoplasmic domain and shows altered virus transport in DCs. LSP1 diverts HIV-1 to the proteasome. Down-regulation of LSP1 with specific small interfering RNAs in human DCs enhanced HIV-1 transfer to T cells, and bone marrow DCs from lsp1^–/– mice also showed an increase in transfer of HIV-1_BaL to a human T cell line. Proteasome inhibitors increased retention of viral proteins in lsp1^+/+ DCs, and substantial colocalization of virus to the proteasome was observed in wild-type compared with LSP1-deficient cells. Collectively, these data suggest that LSP1 protein facilitates virus transport into the proteasome after its interaction with DC-SIGN through its interaction with cytoskeletal proteins.

A. Smith and L. Ganesh contributed equally to this work.

Dr. Ganesh died on 14 October 2006.

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