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Sexual transmission of HIV-1 requires the crossing of mucosal tissue, and the precise mechanism of HIV-1 transmission across this barrier is poorly understood. One of the cell types first encountered by HIV-1 are intraepithelial and submucosal dendritic cells (DC). DC are professional antigen presenting cells that sample the environment at sites of pathogen entry. Sentinel immature DC develop into mature effector DC upon activation by microorganisms, and migrate to the draining lymph nodes where they stimulate naïve Th cells. HIV-1 has been proposed to make use of this migratory process, being captured by the DC and delivered to the lymph node where the virus is transmitted to CD4+ T cells. The lymph node then becomes the principal site of virus production. DC capture HIV-1 through C-type lectin receptors, of which the best studied example is DC-SIGN (CD209) that mediates HIV-1 internalization such that the virus remains infectious for several days. Subsequent transmission to T cells takes place via an ‘infectious synapse’, but virus that has not been internalized can also be transmitted to T cells. We previously investigated the ability of different subsets of mature DC to mediate HIV-1 transmission. Not all mature DC subsets are equally efficient in transmitting HIV-1 to T cells. A higher ICAM-1 expression on certain DC subsets plays an important role. The ICAM-1-LFA-1 interaction is important for immunological cross talk between DC and T cells, and HIV-1 exploits this process for efficient transmission.Recently we have identified a very potent transmission inhibitor. In a single cycle transmission assay, we screened a large set of proteins from milk and serum for their ability to block HIV-1 transmission by DC. Proteins that were chemically altered to be negatively charged can inhibit transmission, likely because they bind the positively charged envelop protein of HIV-1. Interestingly, bovine lactoferrin inhibits DC-mediated HIV-1 transmission in its native form. This suggests a more specific mechanism: we found that lactoferrin binds to DC-SIGN, thus preventing HIV-1 capture and subsequent transmission to T cells. Interestingly, bovine LF is a much more efficient inhibitor of transmission than human LF. Since LF is non-toxic and easy to purify in large quantities from cow milk, it forms an interesting candidate microbicide against HIV-1. Our current research focuses on the impact HIV-1 has on DC functioning. We try to identify which immunological processes of DC are altered by HIV-1 and how this is achieved. Relevant publications Groot F, Geijtenbeek TB, Sanders RW, Baldwin CE, Sanchez-Hernandez M, Floris R, van Kooyk Y, de Jong EC, Berkhout B. Lactoferrin Prevents Dendritic Cell-Mediated Human Immunodeficiency Virus Type 1 Transmission by Blocking the DC-SIGN--gp120 Interaction. J Virol. 2005 Mar;79(5):3009-15.
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