HIV gp120 receptors on human dendritic cells

Abstract

Dendritic cells (DCs) are important targets for human immunodeficiency virus (HIV) because of their roles during transmission and also maintenance of immune competence. Furthermore, DCs are a key cell in the development of HIV vaccines. In both these settings the mechanism of binding of the HIV envelope protein gp120 to DCs is of importance. Recently a single C-type lectin receptor (CLR), DC-SIGN, has been reported to be the predominant receptor on monocyte-derived DCs (MDDCs) rather than CD4. In this study a novel biotinylated gp120 assay was used to determine whether CLR or CD4 were predominant receptors on MDDCs and ex vivo blood DCs. CLR bound more than 80% of gp120 on MDDCs, with residual binding attributable to CD4, reconfirming that CLRs were the major receptors for gp120 on MDDCs. However, in contrast to recent reports, gp120 binding to at least 3 CLRs was observed: DC-SIGN, mannose receptor, and unidentified trypsin resistant CLR(s) . IntroductionDendritic cells (DCs) play a major role in human immunodeficiency virus (HIV) pathogenesis. Peripheral or surveillance mucosal DCs are one of the first cell types infected and are distributed in the vaginal, ectocervical, and anal mucosa, 1,2 allowing contact with HIV during mucosal exposure. Thus, after vaginal inoculation with simian immunodeficiency virus in macaques, DCs are the predominant cell type infected. 3 Furthermore, the ability of DCs to cluster with and stimulate T cells may also play a key role in establishing infection. DCs from skin, mucosa, and blood of humans and macaques can participate in highly productive HIV and simian immunodeficiency virus infection in DC-T-cell cocultures and illustrates the importance of this natural DC-T-cell synergy. [4][5][6][7] Key aspects of HIV binding to DC via gp120 are ill-defined, particularly to the different types of DCs. CD11c ϩve and CD11c Ϫve blood DCs, Langerhans cells (LCs), and in vitro-derived monocytederived DCs (MDDCs) all express CD4 and CCR5 and can be productively infected in vitro. [8][9][10][11][12] However, HIV also bound several DC populations independently of CD4. 8,13,14 The heavy glycosylation of gp120 with mannose and fucose saccharides suggested HIV bound to cells also via lectin receptors. Binding of gp120 to a novel C-type lectin receptor (CLR), originally identified from a placental complementary DNA (cDNA) library 15 on the basis of HIV gp120 binding and named clone 11, on MDDCs was recently reported. 14,16 The adhesion properties of this CLR were also defined and the receptor subsequently renamed DC-SIGN (dendritic cell specific ICAM-3 grabbing nonintegrin). Although MDDCs express a diverse and abundant array of CLRs in addition to DC-SIGN, [16][17][18][19][20][21][22][23][24] and given substantial overlap in saccharide recognition by such CLRs, they may also serve as receptors for gp120 on MDDCs. The roles of CD4 and CLRs on most other in vivo DC types are unknown.This study aimed to define the contributions of CD4 and CLRs in binding gp120, to address and identify the capacity o...

PU.1 Regulates the Tissue-specific Expression of Dendritic Cell-specific Intercellular Adhesion Molecule (ICAM)-3-grabbing Nonintegrin

“…Together with other C-type lectins on the surface of dendritic cells, DC-SIGN appears as a key player in the initial stages of HIV infection through its ability to capture and transfer virus to T lymphocytes (45). DC-SIGN is found in both peripheral blood dendritic cell precursors and mucosal dendritic cells and is therefore adequately positioned for HIV spread both after sexual transmission and after contamination with blood.…”

Subset of DC-SIGN+ dendritic cells in human blood transmits HIV-1 to T lymphocytes

“…However, recent studies demonstrated that myeloid and lymphoid precursor DC subsets in blood lack DC-SIGN expression. 20,21 We set out to investigate the expression of DC-SIGN by human blood mononuclear cells. Initial experiments showed the presence of a small population of cells (0.02% of total PBMCs) that expressed DC-SIGN and that could be visualized by direct staining in human blood ( Figure 1A).…”

“…19 In recent studies, it was demonstrated that DC-SIGN is not expressed by plasmacytoid DCs, by myeloid blood precursor DC subsets, or by monocytes. 3,20,21 However, these DC subsets were purified by depletion of CD14 ϩ cells, which included monocytes. We observed that upon in vitro culture, DC-SIGN expression is rapidly induced in CD14 ϩ monocytes, indicating that a DC-SIGN ϩ precursor DC might coexpress CD14.…”

Syndecan-3 is a dendritic cell-specific attachment receptor for HIV-1

“…HIV-1 binds to DCs. However, the identity of the HIV-1 receptors on DCs is currently under intense debate (11)(12)(13)(14)(15). Different receptors have been demonstrated to interact with HIV-1 on DCs, such as the C-type lectin DC-SIGN (11,16), the mannose receptor (17), langerin (18), and CD4 (17).…”