DC-SIGN Points the Way to a Novel Mechanism for HIV-1 Transmission

Majid Masso

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Abstract and Introduction

Dendritic cell (DC)-specific intercellular adhesion molecule 3 (ICAM-3) grabbing nonintegrin (DC-SIGN), a recently discovered type II transmembrane protein on DCs with a C-type lectin extracellular domain, is capable of binding ICAM-3 on resting T cells in the secondary lymphoid organs, providing the initial contact between these cells during the establishment of cell-mediated immunity. DC-SIGN also binds the HIV-1 envelope glycoprotein gp120 but does not function as a receptor for viral entry into DCs. Instead, DC-SIGN allows DCs in the peripheral mucosa to carry HIV-1 through the lymphatics in a "Trojan horse" fashion, where it is eventually delivered to the T cells. Also, the period of infectivity of HIV-1 is increased by several days as a result of DC-SIGN-gp120 binding, allowing for efficient trans-infection of T cells on DC arrival. The discovery of a cluster of related genes colocalized with DC-SIGN on chromosome 19p13.2-3, all displaying complex alternative splicing patterns, has led to a reexamination of the mechanisms underlying both the interactions between antigen-presenting cells (APCs) and T cells and the pathogenesis of HIV-1 infection.

Peripheral mucosal tissues, such as those lining the cervix and rectum, contain DCs that capture invading infectious microorganisms and intracellularly digest them for presentation with proteins of the major histocompatibility complex (MHC) as MHC-peptide complexes on the DC plasma membrane.[1,2,3,4] Following antigen uptake, these immature DCs migrate to the T-cell areas of secondary organs to present the MHC-peptide ligands to antigen-specific T-cell receptors (TCRs) on resting T cells, while also maturing by altering their cell-surface receptor profile to make this initiation of cell-mediated immunity more effective.[2] Although ICAM-3 is expressed at high levels on resting T cells, no high-affinity receptors for ICAM-3 on DCs had been previously identified.[2]

Recently, though, an abundantly expressed receptor unique to DCs, referred to as DC-SIGN, has been discovered and shown to bind ICAM-3 with high affinity.[2,5] Additionally, DC-SIGN has been observed to bind the HIV-1 envelope glycoprotein gp120.[1,5] However, rather than being used by DCs to internalize HIV-1 for antigen processing, DC-SIGN allows DCs to unwittingly carry HIV-1 from the mucosal tissue to the lymph nodes while also increasing the period of infectivity of HIV-1 by several days and promoting efficient trans-infection of CD4+ T-helper cells.[1,5]

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