Controlling Spatial Organization of HIV Coreceptor CCR5

Area of Science:

• Biophysics
• Cellular Biology
• Virology

Background:

• CC chemokine receptor type 5 (CCR5) is a primary coreceptor for HIV entry into host cells.
• CCR5 localization at lipid domain boundaries enhances HIV fusion efficiency by facilitating gp41 interaction with membrane interfaces.
• Understanding CCR5's spatial organization is key to developing strategies against HIV entry.

Purpose of the Study:

• To investigate the spatial organization of CCR5 in domain-forming model membranes using molecular dynamics simulations.
• To elucidate the molecular mechanism of CCR5 localization at membrane domain boundaries.
• To explore the effect of lysophosphatidylcholine (lysoPC) lipids on CCR5 organization and membrane properties.

Main Methods:

• Coarse-grained molecular dynamics simulations were employed to model CCR5 within heterogeneous lipid membranes.
• Analysis focused on the preferential localization and stabilization of CCR5 at lipid domain interfaces.
• The impact of lysoPC, acting as a linactant, on membrane domain organization and CCR5 distribution was simulated.

Main Results:

• Simulations revealed that CCR5 preferentially migrates to and stabilizes at the boundaries of lipid domains.
• Lysophosphatidylcholine (lysoPC) lipids were observed to accumulate at domain interfaces, reducing line tension.
• This accumulation of lysoPC disrupted membrane domain organization, leading to CCR5 delocalization.

Conclusions:

• CCR5's preferential localization at membrane domain boundaries is a key factor in facilitating HIV fusion.
• Linactants like lysoPC can disrupt membrane organization and delocalize CCR5, potentially hindering HIV entry.
• Targeting CCR5 organization via linactants presents a potential therapeutic strategy to inhibit HIV fusion and entry.