Siglec-1 Is a Novel Dendritic Cell Receptor That Mediates HIV-1 Trans -Infection Through Recognition of Viral Membrane Gangliosides

Altres ajuts: This work was supported by the Spanish Ministry of Science and Innovation, the Spanish AIDS network "Red Temática Cooperativa de Investigació3n en SIDA" (RD06/0006), the Catalan HIV Vaccine Development Program (HIVACAT), Gala contra la sida: Barcelona 2011, and by a grant from the Deutsche Forschungsgemeinschaft to H.-G.K. (TRR83; project 14). N.I-U. was supported by the program "José Castillejo" from the Spanish Ministry of Education. M.T.R.-P. is supported by grant from the Spanish Ministry of Science and Innovation H.-G.K. is investigator of the Cell Networks Cluster of Excellence (EXC81). A.T. is supported by the Swiss National Science Foundation (31003A_132863). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.'The novel dendritic cell receptor Siglec-1 binds sialyllactose moieties on HIV-1 membrane gangliosides, thereby enhancing HIV-1 transinfection. Dendritic cells (DCs) are essential antigen-presenting cells for the induction of immunity against pathogens. However, HIV-1 spread is strongly enhanced in clusters of DCs and CD4 + T cells. Uninfected DCs capture HIV-1 and mediate viral transfer to bystander CD4 + T cells through a process termed trans -infection. Initial studies identified the C-type lectin DC-SIGN as the HIV-1 binding factor on DCs, which interacts with the viral envelope glycoproteins. Upon DC maturation, however, DC-SIGN is down-regulated, while HIV-1 capture and trans -infection is strongly enhanced via a glycoprotein-independent capture pathway that recognizes sialyllactose-containing membrane gangliosides. Here we show that the sialic acid-binding Ig-like lectin 1 (Siglec-1, CD169), which is highly expressed on mature DCs, specifically binds HIV-1 and vesicles carrying sialyllactose. Furthermore, Siglec-1 is essential for trans -infection by mature DCs. These findings identify Siglec-1 as a key factor for HIV-1 spread via infectious DC/T-cell synapses, highlighting a novel mechanism that mediates HIV-1 dissemination in activated tissues. Mature dendritic cells (mDCs) capture and store infectious HIV-1 and subsequently infect neighboring CD4 + T cells in lymphoid organs. This process, known as trans -infection, is a key contributor to HIV pathogenesis, but the precise mechanism and the identity of the receptor on the mDC surface that recognizes viral particles remain controversial. Although the interaction of HIV-1 envelope glycoproteins with the C-type lectin DC-SIGN has been suggested to mediate HIV-1 capture and trans -infection, later studies revealed an envelope glycoprotein-independent virus capture mechanism in mDCs. Here, we identify Siglec-1 as the surface receptor on mDCs that boosts their uptake of HIV-1 and their capacity to trans -infect CD4 + cells, leading in turn to HIV-1 disease progression. Siglec-1 captures the virus by interacting with sialyllactose-containing gangliosides exposed on viral membranes. This indicates that Siglec-1 functions as a general binding molecule for any vesicle carrying sialyllactose in its membrane, including exosomes and other viruses. We suggest that this natural pathway through mDC, which would normally lead to antigen processing and presentation, has been subverted by HIV-1 for its own storage and transmission