Background: The dendritic cell (DC)-specific C-type lectin DC-SIGN play an important role in the HIV-1 pathogenesis. HIV-1 is efficiently captured by DC-SIGN on DC at mucosal tissues. HIV-1 escapes the DC-SIGN-mediated antigen presentation route, and hides as infectious particles in non-lysosomal compartments during transport to lymphoid tissues, where HIV-1 is efficiently transmitted by DC-SIGN to T-cells. We analyzed both the carbohydrate- and pathogen-recognition profile of DC-SIGN. We investigate how pathogens target DC-SIGN to influence the immunological function of DC, which may contribute to the pathogenesis of HIV-1.

Methods: An ELISA-based DC-SIGN binding assay was used to evaluate the interaction of DC-SIGN with different pathogens and their ability to block HIV-1 binding. Using whole GFP-labeled pathogens, we compare the internalization of HIV-1 by DC with other pathogens. Immunological responses of DC after pathogen interactions were investigated by measuring cytokines and the ability of DC to initiate immune responses.

Results: Detailed analysis of the carbohydrate-recognition profile of DC-SIGN revealed novel carbohydrate specificities, and concomitantly we identified novel pathogens that interact with DC-SIGN on DC. DC-SIGN captures and internalizes intact Mycobacterium tuberculosis through specific cell-wall components, and antibodies against DC-SIGN that block HIV-1 capture also block mycobacterial infection of DC. Strikingly, the internalization pathway is different from HIV-1, since the mycobacteria are targeted to the late endosomal compartments, whereas HIV-1 is targeted to early endosomes. Moreover, M. tuberculosis targets DC-SIGN to escape immunity by infecting DC and by suppressing DC-mediated immune responses by inducing anti-inflammatory cytokines. Furthermore, HIV-1 binding to DC-SIGN is inhibited by carbohydrates from M. tuberculosis and other pathogens such as Leishmania mexicana.

Conclusions: Tuberculosis is a major complication in HIV-1 infections and we demonstrate that infection of DC with M. tuberculosis affects the immunological function of DC, thereby inhibiting cellular immune responses against HIV-1. Moreover, our screening method identified novel carbohydrate structures that inhibit HIV-1 binding to DC-SIGN and these structures will be useful in developing strategies to combat HIV-1 dissemination.