So, if I'm reading this right, leronlimab's ability to to

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So, if I'm reading this right, leronlimab's ability to to stabilize surface expression of CCR5 and prevent it's internalization is what makes it more effective than maraviroc. And the way my Neanderthal brain works--stable CCR5 expression Good!... preventing internalization Good! But why is preventing internalization good? I'd have thought that internalizing CCR5 would limit RANTES and the other ligands from activating the CCR5/CCL5 axis, but clearly, I'm missing something here. Ohm... can I ask you to clarify?

The ligands CCL3, CCL4 and CCL5 preferentially bind to CCR5. When the ligands bind to CCR5 they trigger b-arrestin which starts the process of internalization into the cell. CCR5 blockers like maraviroc and leronlimab do not trigger b-arrestin so CCR5 remains on the cell surface. If maraviroc is sometimes allowing binding of ligands of course those cells will internalize.

If internalization was stable then it would be effective against ligands binding it. In fact, with the CCR5 delta 32 double allele gene mutation CCR5 receptors actually exist. The gene mutation simply doesn't allow them to appear on the cell surface. The problem is that after the ligand causes CCR5 to internalize the ligand degrades and the CCR5 receptor returns to the cell surface to once again be bound by a ligand. It's not the surface stabilization by maraviroc and leronlimab that is causing benefit, it's the ability to block the ligands from binding and activating the cascade of negative events that follow. Of course, the 100% occupancy by leronlimab vs. 84% by maraviroc is also in leronlimab's favor.