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Published on: March 8, 2012
Inhibition of human immunodeficiency virus type 1 Env-mediated fusion by DC-SIGN
Cinzia Nobile1, Arnaud Moris, Françoise Porrot
1Virus and Immunity Group, URA CNRS 1930, Institut Pasteur, 75724 Paris Cedex 15, France.
Insights
DC-SIGN enhances human immunodeficiency virus (HIV) capture and internalization by immune cells. However, this lectin inhibits viral fusion and syncytium formation, impacting HIV-1 replication dynamics.
Area of Science:
- Immunology
- Virology
- Cell Biology
Background:
- Dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN) is a lectin found on immune cells.
- DC-SIGN binds to human immunodeficiency virus (HIV) envelope glycoproteins, facilitating viral capture.
- The precise role of DC-SIGN in HIV infection and cell-to-cell transmission remains unclear.
Purpose of the Study:
- To investigate the effects of DC-SIGN on HIV entry and Env-induced syncytium formation.
- To elucidate the cellular mechanisms by which DC-SIGN influences early HIV-1 replication steps.
Main Methods:
- Analysis of viral entry and syncytium formation in DC-SIGN expressing cells.
- Quantification of virion internalization and intracellular trafficking.
- Assessment of the impact of CD4 surface levels and fusion inhibitors on DC-SIGN function.
Main Results:
- DC-SIGN expression enhanced HIV susceptibility and virion internalization.
- Captured virions accumulated in vesicular compartments with altered cytosolic access.
- DC-SIGN inhibited syncytium formation, an effect partially reversed by increased CD4 levels.
- The fusion inhibitor T-20 remained effective in DC-SIGN expressing cells.
Conclusions:
- DC-SIGN plays a complex role in early HIV-1 replication, facilitating viral capture and internalization.
- DC-SIGN inhibits viral fusion and syncytium formation, potentially through competition with CD4 for Env binding.
- These findings offer insights into DC-SIGN's intricate modulation of HIV infection pathways.
Abstract:
DC-SIGN, a lectin expressed on dendritic cell and macrophage subsets, binds to human immunodeficiency virus Env glycoproteins, allowing capture of viral particles. Captured virions either infect target cells or are efficiently transmitted to lymphocytes. Cellular mechanisms underlying the effects of DC-SIGN remain poorly understood. Here we have analyzed the effects of DC-SIGN on viral entry and on syncytium formation induced by Env glycoproteins. The lectin enhanced susceptibility to viral infection and dramatically increased virion internalization. Captured virions accumulated in the vesicular pathway, and their access to the cytosol was altered. Strikingly, the presence of DC-SIGN on target cells inhibited their ability to form syncytia with Env-expressing cells. However, increasing CD4 surface levels on target cells alleviated this inhibitory effect of DC-SIGN. Moreover, the potency of the viral fusion inhibitor T-20 was not affected in DC-SIGN-expressing cells. Altogether, our results indicate that DC-SIGN exerts subtle and complex effects during early steps of HIV type 1 replication. DC-SIGN facilitates capture and accumulation of viral particles in a vesicular compartment and inhibits viral fusion. Competition between CD4 and DC-SIGN for Env binding likely affects virus access to the cytosol and syncytium formation.
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