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Posted: 15 Sep 2011
30 years in 30 weeks, 2000

The importance of mucosa in the early events of HIV transmission is widely appreciated today. It represents the first line of defense against the virus and it is there that the virus initially enters the body and infects first cells before spreading systemically. The physiology, biology and immunology of mucosal surfaces are currently under thorough investigation to better understand the initial phase of infection and identify ways to prevent it. One of the first cells that HIV encounters in mucosa is the dendritic cell, which plays an unusual role in viral transmission that was uncovered in the paper by Geijtenbeek et al. in 2000.

DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells.
Cell. 2000 Mar 3;100(5):587-97.
Geijtenbeek TB, Kwon DS, Torensma R, van Vliet SJ, van Duijnhoven GC, Middel J, Cornelissen IL, Nottet HS, KewalRamani VN, Littman DR, Figdor CG, van Kooyk Y.

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Commentary by Dr. Teunis Geijtenbeek

Dr. Teunis Geijtenbeek
In this paper, my co-authors and I described the mechanism of HIV-1 transmission by dendritic cells. At that time it was unclear how HIV-1 could pass the mucosal barrier after sexual transmission and reach the CD4+ T cells that are mostly present in the lymph nodes. In this paper, we identified a novel receptor for HIV-1 called DC-SIGN that was expressed by mucosal dendritic cells and showed that mucosal dendritic cells capture HIV-1 through DC-SIGN. Normally, pathogens captured by dendritic cells are degraded for antigen processing, but we showed that DC-SIGN capture of HIV-1 protects the virus from degradation. The virus remains infectious for several days, which allows dendritic cells to migrate to the lymph nodes where the virus is efficiently transmitted to T cells. This mechanism explained the ability of dendritic cells to efficiently transmit HIV-1 to T cells without being infected themselves.

This finding changed the field considerably and initiated a lot of interest not only in the receptor DC-SIGN but also in the role of dendritic cells in HIV-1 transmission. We had identified a novel HIV-1 receptor with a very specific function in HIV-1 transmission and that could be a potential target to prevent HIV-1 dissemination. Many other studies have shown that this mechanism is not unique to HIV-1 but is also used by other viruses. It also placed the C-type lectin receptor family to which DC-SIGN belongs on the scientific map as pattern recognition receptors.

The attention to our findings came for us as a surprise. We had been investigating the interaction of dendritic cells with a cellular ligand expressed by T cells called ICAM-3. Our efforts led to the discovery of the C-type lectin DC-SIGN as an adhesion receptor for ICAM-3 that is required for DC-T cell interactions. Interestingly, a database screening showed that the sequence was identical to a C-type lectin found in placenta and that was shown to bind HIV-1 gp120 (Curtis et al. PNAS 1992). This set us upon the path to investigate the function of DC-SIGN in the binding to HIV-1 gp120 and finally lead the publication of both papers back-to-back in the same Cell issue.

The most challenging part of the paper was to understand what occurred after the virus bound to DC-SIGN. Initially we thought that DC-SIGN was similar to CD4 and allowed infection of dendritic cells. Therefore, I went to the laboratory of Dan Littman at NYU Medical Center to investigate this in detail because we did not have the required HIV-1 strains and virological techniques in the lab. There I found that expression of DC-SIGN in cell-lines did not increase susceptibility to HIV-1 without CD4 and CCR5, which was initially a disappointment. However, I observed consistently that HIV-1 bound to DC-SIGN was much more efficiently transmitted to target CD4+CCR5+ cells than virus alone and without the need for viral replication in the DC-SIGN-expressing cells. At first, we did not understand the implications until after an ad-hoc Friday afternoon discussion everything came together.

I think that it became such a highly cited paper because it was a novel receptor for HIV-1 with a completely different function than CD4. It showed that these so-called attachment receptors are important in viral infections. Furthermore, the term Trojan Horse was coined, which nicely explained the mechanism of virus protection by binding to DC-SIGN. The mechanism is quite simple and therefore attractive.

Now after 11 years, the paper has initiated many studies about dendritic cells and DC-SIGN and the mechanism of HIV-1 transmission. There have been refinements to our study and it is clear that DC-SIGN is doing more than only capturing and protecting HIV-1, but the original mechanism remains valid. Furthermore, several other proteins have been shown to function in a similar way. Our work has paved the road for a group of virus attachment receptors.
It was a very exciting time for me and the co-authors: it was my first contact with HIV-1 research and I became fascinated by this kind of research. It is the main reason why I am now studying host-pathogen interactions with a main focus on HIV-1.

About the author: Teunis B.H. Geijtenbeek is Professor of Cellular and Molecular Immunology at the Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

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