Research Highlights

HIV transmission: A C-type lectin block

HIV is captured by Langerin expressed in Langerhans cells (arrows).

Dendritic cells (DCs) in the genital mucosa transmit HIV to T cells. In the first step of this process, mannose residues on the HIV envelope glycoprotein gp120 specifically bind to C-type lectins on DCs. DCs expressing the C-type lectin DC-SIGN (DC-specific intercellular adhesion molecule-3 grabbing nonintegrin) have been shown to transmit HIV to T cells. Likewise, Langerhans cells (LCs), the first DC subset to encounter invading viruses, were also thought to pass on the virus due to their expression of the C-type lectin Langerin. In results published in Nature Medicine, de Witte et al. now call this hypothesis into question.

HIV transmission by DCs is blocked upon inhibition of DC-SIGN binding activity by the mannose polysaccharide mannan. Surprisingly, the authors observed that LCs treated with mannan efficiently passed the virus on to T cells, whereas transmission was effectively prevented in the absence of mannan if the viral concentration did not exceed a certain limit. This suggests that an LC C-type lectin acted as a transmission barrier.

de Witte et al. went on to discover that the Langerin-specific antibody 10E2 blocked the binding of gp120 to LCs. Thus, the authors concluded that Langerin caused the HIV transmission blockage from LCs to T cells. In addition, Langerin was also found to colocalize with HIV particles on the LC surface and in intracellular vesicles called Birbeck granules, leading the authors to hypothesize that HIV particles are degraded after being endocytosed by Langerin into Birbeck granules.

These results indicate that Langerin acts as a first line of defence for the body against HIV transmission as LCs reside in the outermost part of the mucosa; DC-SIGN positive DCs, on the other hand, are located in the mucosal subepithelia. Interestingly, LCs taken from different donors exhibited a different virus concentration limit for HIV transmission, pointing to a variable expression of Langerin. This variation might be caused by genetic polymorphisms or by inflammation and pathogen co-infection. Apart from these restrictions, the discovery of the Langerin barrier function could support the development of anti-HIV microbicides based on glycan structures that block HIV binding to DC-SIGN, but not to Langerin. Indeed, the authors identified Lewis X carbohydrates as potential microbicides due to the fact they blocked DC-SIGN — but not Langerin — binding to gp120.

Author: Mirko von Elstermann