Expression of the C-type lectin receptor CD205 on B cells mediates HIV-1 binding and trans infection of CD4+ T cells

HIV-1 is a virus that has learned to hide inside the human body, specifically within a resting state inside certain immune cells called CD4+ T cells. Even when powerful medicines suppress the virus so it cannot be detected in the blood, these hidden reservoirs remain, waiting to restart the infection if treatment stops. A major place where this hiding happens is deep inside the lymph nodes, in specialized areas known as B cell follicles. Here, two types of immune cells, B cells and CD4+ T cells, constantly meet and talk to one another to coordinate the body's defense. While B cells are excellent at catching and holding onto viruses to show them to other cells, they cannot be infected by HIV-1 themselves because they lack the specific doorways the virus needs to enter. However, scientists have long suspected that this very act of holding the virus might be dangerous, allowing B cells to act as a bridge, picking up the virus and handing it directly to a nearby T cell in a highly efficient transfer that bypasses the body's usual defenses.

For years, researchers knew this transfer happened, but they did not know the molecular keys that unlocked the door. They understood that in the lymph nodes, B cells receive various chemical signals from their environment, such as proteins called CD40 ligand, interleukin-4, and interferon-gamma, which tell them how to behave. The question was whether any of these specific signals turned the B cell into a super-efficient virus catcher. In a new study, scientists at the University of Pittsburgh set out to find the answer. They took B cells from human donors and exposed them to different combinations of these chemical signals in the laboratory. They then introduced a fluorescent version of HIV-1 to see which cells would grab the virus and how well they could pass it on to CD4+ T cells.

The results were clear and specific. When B cells were stimulated with a combination of CD40 ligand and interleukin-4, they became remarkably good at binding the virus. These cells did not just catch a few viral particles; they grabbed them with such efficiency that they could transfer the virus to CD4+ T cells far better than any other condition tested. In contrast, B cells stimulated with other signals, such as those involving interferon-gamma, barely caught any virus at all. The researchers also checked to see if this ability was simply a side effect of the cells becoming generally active or "awake." They found that while all the different signals made the B cells more active, only the specific combination of CD40 ligand and interleukin-4 made them sticky for the virus. This proved that general activation was not the cause; something specific had to change on the surface of the cell.

To find out what that specific change was, the team looked at the genetic instructions inside the B cells. They used a technique that reads the activity of thousands of genes at once to see which ones were turned on by the different signals. They discovered that the combination of CD40 ligand and interleukin-4 caused a massive increase in the production of a protein called CD205. This protein is a type of receptor, a structure on the cell surface that acts like a hand reaching out to grab specific things. The researchers confirmed that this protein was indeed present in much higher numbers on the surface of the cells that were good at catching the virus. They then used a microscope to watch the virus and the CD205 protein in the same cell. They saw that the virus particles and the CD205 protein were sitting right next to each other, confirming that the virus was physically attaching to this receptor.

To be absolutely certain that CD205 was the key, the scientists performed a blocking experiment. They added a special antibody, a type of protein designed to stick to CD205, to the B cells before introducing the virus. This antibody covered the CD205 receptors, effectively putting a cap on the cell's hands. When they did this, the B cells lost their ability to grab the virus. The virus could no longer bind to the cell surface, and the transfer to the T cells stopped. This experiment confirmed that CD205 is the critical receptor that allows B cells to catch HIV-1. The study also ruled out other known virus-catching proteins that are found on different immune cells, showing that B cells do not use those same tools. Instead, they rely on this specific receptor, which is boosted by the natural signals found in lymph nodes.

This discovery changes how we understand the hidden reservoir of HIV-1. It suggests that in the lymph nodes, the natural conversation between B cells and T cells, driven by signals like CD40 ligand and interleukin-4, inadvertently creates a perfect environment for the virus to hitch a ride. The virus uses the B cell's own machinery to move from one cell to another with high efficiency, helping it stay hidden and persistent. By identifying CD205 as the specific tool the virus uses, this work points to a new target for future therapies. If scientists can find a way to block this specific interaction in the lymph nodes, they might be able to stop the virus from spreading within these hidden reservoirs, offering a new path toward controlling or potentially curing the infection.