Day 31: Another player for infection in trans?

You would think that after 25+ years of research, we would have some sort of handle on how HIV infection is actually established. But as far as I can tell, there is still a considerable amount of debate on the subject. Quick, which is more infectious—cell-associated virus or free virus? Which is more important in establishing infection—genital tract infection or spread in the lymph nodes?

 

One of the widely regarded hypotheses is that HIV “hitchhikes” its way to the lymph nodes, where it gains easy access to CD4 cells. It has been shown that viral particles can attach to dendritic cells (and possibly infect, but that’s another story), which make their way to the lymph nodes when activated. Dendritic cells are professional antigen presenting cells, meaning that they do a lot of T-cell activation. They are designed to interact and stimulate CD4 cells. So, you can easily see how a virus attached to or hiding in a dendritic cell would be able to successfully infect an activated CD4 cell. The DCs pick up the virus, the DCs travel to the lymph nodes, stimulate some CD4 cells and, at the same time, HIV infects these cells.

 

The main protein on DCs that has been identified in this trans-infection is DC-SIGN, an adhesion molecule. A new paper in PNAS has also identified another player, syndecan-3. Most of the figures in the paper are supportive that syndecan-3 is a player, but they are not conclusive. However, the authors use siRNA to knockdown syndecan-3 and show that this results in less HIV attachment, which is fairly strong evidence. The authors showed that syndecan-3 knockdown did not affect DC-SIGN expression by flow cytometry, but it did not say in the paper whether this was surface expression or intracellular expression. They also did not show whether DC-SIGN trafficking was altered by syndecan-3 knockdown. Obviously, if syndecan-3 knockdown prevents DC-SIGN from reaching the cell surface or changes the molecule’s conformation, then knockdown of syndecan-3 would affect binding mediated through DC-SIGN. It would have been nice if they had incubated virus (both wild-type and virus without gp120) with DC lysate, pelleted the virus, and then done a western blot for syndecan-3. Still, the paper shows that syndecan-3 knockdown affects both HIV binding and also transmission of the virus to T cells, so it has to be doing something.

If syndecan-3 and DC-SIGN are important players for infection in trans, then small molecules that target these interactions may be good candidates for microbicides.

M. Linde