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Journal of Virology, March 2007, p. 2497-2507, Vol. 81, No. 5
0022-538X/07/$08.00+0     doi:10.1128/JVI.01970-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

CD4 Coexpression Regulates DC-SIGN-Mediated Transmission of Human Immunodeficiency Virus Type 1{triangledown}

Jian-Hua Wang,1 Alicia M. Janas,1 Wendy J. Olson,1 Vineet N. KewalRamani,2 and Li Wu1*

Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226,1 HIV Drug Resistance Program, National Cancer Institute, Frederick, Maryland 217022

Received 11 September 2006/ Accepted 20 November 2006

Dendritic cells (DCs) potently stimulate the cell-cell transmission of human immunodeficiency virus type 1 (HIV-1). However, the mechanisms that underlie DC transmission of HIV-1 to CD4+ T cells are not fully understood. DC-SIGN, a C-type lectin, efficiently promotes HIV-1 trans infection. DC-SIGN is expressed in monocyte-derived DCs (MDDCs), macrophage subsets, activated B lymphocytes, and various mucosal tissues. MDDC-mediated HIV-1 transmission to CD4+ T cells involves DC-SIGN-dependent and -independent mechanisms. DC-SIGN transmission of HIV-1 depends on the donor cell type. HIV-1 Nef can upregulate DC-SIGN expression and promote DC-T-cell clustering and HIV-1 spread. Nef also downregulates CD4 expression; however, the effect of the CD4 downmodulation on DC-mediated HIV-1 transmission has not been examined. Here, we report that CD4 expression levels correlate with inefficient HIV-1 transmission by monocytic cells expressing DC-SIGN. Expression of CD4 on Raji B cells strongly impaired DC-SIGN-mediated HIV-1 transmission to T cells. By contrast, enhanced HIV-1 transmission was observed when CD4 molecules on MDDCs and DC-SIGN-CD4-expressing cell lines were blocked with specific antibodies. Coexpression of CD4 and DC-SIGN in Raji cells promoted the internalization and intracellular retention of HIV-1. Interestingly, internalized HIV-1 particles were sorted and confined to late endosomal compartments that were positive for CD63 and CD81. Furthermore, in HIV-1-infected MDDCs, significant downregulation of CD4 by Nef expression correlated with enhanced viral transmission. These results suggest that CD4, which is present at various levels in DC-SIGN-positive primary cells, is a key regulator of HIV-1 transmission.

* Corresponding author. Mailing address: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, 8701 Watertown Plank Road, BSB 203, Milwaukee, WI 53226. Phone: (414) 456-4075. Fax: (414) 456-6535. E-mail: liwu{at}mcw.edu.

{triangledown} Published ahead of print on 6 December 2006.

Journal of Virology, March 2007, p. 2497-2507, Vol. 81, No. 5
0022-538X/07/$08.00+0     doi:10.1128/JVI.01970-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Wang, J.-H., Kwas, C., Wu, L. (2009). Intercellular Adhesion Molecule 1 (ICAM-1), but Not ICAM-2 and -3, Is Important for Dendritic Cell-Mediated Human Immunodeficiency Virus Type 1 Transmission. J. Virol. 83: 4195-4204 [Abstract] [Full Text]  
  • Dong, C., Kwas, C., Wu, L. (2009). Transcriptional Restriction of Human Immunodeficiency Virus Type 1 Gene Expression in Undifferentiated Primary Monocytes. J. Virol. 83: 3518-3527 [Abstract] [Full Text]  
  • Dong, C., Janas, A. M., Wang, J.-H., Olson, W. J., Wu, L. (2007). Characterization of Human Immunodeficiency Virus Type 1 Replication in Immature and Mature Dendritic Cells Reveals Dissociable cis- and trans-Infection. J. Virol. 81: 11352-11362 [Abstract] [Full Text]  
  • Wang, J.-H., Janas, A. M., Olson, W. J., Wu, L. (2007). Functionally Distinct Transmission of Human Immunodeficiency Virus Type 1 Mediated by Immature and Mature Dendritic Cells. J. Virol. 81: 8933-8943 [Abstract] [Full Text]  


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