Controlling Spatial Organization of HIV Coreceptor CCR5

CC chemokine receptor type 5 (CCR5) functions as a key coreceptor facilitating HIV entry into host cells. Recent experimental findings suggest that CCR5 preferentially localizes at lipid domain boundaries within the host cell membrane, where its positioning enhances viral fusion efficiency by allowing the HIV fusion peptide gp41 to exploit the mechanically weaker interface regions. In this study, we employ coarse-grained molecular dynamics simulations to investigate the spatial organization of CCR5 within domain forming model membranes. Our results reveal a molecular mechanism by which CCR5 preferentially migrates and stabilizes at domain boundaries. Additionally, we show that lysophosphatidylcholine (lysoPC) lipids, acting as linactants, accumulate at domain interfaces, reduce line tension, and ultimately disrupt membrane domain organization. This disruption leads to a delocalization of CCR5, potentially impairing the ability of gp41 to target membrane boundaries for fusion. Together, our findings suggest that linactants may be employed to disrupt the spatial organization of CCR5, potentially hindering HIV's ability to initiate membrane fusion and entry.