Organization of Cellular Receptors into a Nanoscale Junction during HIV-1 Adhesion

The fusion of the human immunodeficiency virus type 1 (HIV-1) with its host cell is the target for new antiretroviral therapies. Viral particles interact with the flexible plasma membrane via viral surface protein gp120 which binds its primary cellular receptor CD4 and subsequently the coreceptor CCR5. However, whether and how these receptors become organized at the adhesive junction between cell and virion are unknown. Here, stochastic modeling predicts that, regarding binding to gp120, cellular receptors CD4 and CCR5 form an organized, ring-like, nanoscale structure beneath the virion, which locally deforms the plasma membrane. This organized adhesive junction between cell and virion, which we name the viral junction, is reminiscent of the well-characterized immunological synapse, albeit at much smaller length scales. The formation of an organized viral junction under multiple physiopathologically relevant conditions may represent a novel intermediate step in productive infection.Author Summary: The entry of human immunodeficiency virus (HIV) into cells is the target for new therapies preventing HIV infection. While intermediate steps of viral entry have been characterized, the progression between these steps and how they result in productive infection are not well understood. By using stochastic modeling, we examine the initial interaction of a single viral particle with a flexible plasma membrane populated with viral receptors. The model predicts the formation of an organized receptor ultrastructure beneath the viral particle, which we name viral junction and which may contribute to productive viral infection. The organization of the viral junction depends on receptor density, CD4 bond stability, membrane mechanical flexibility, as well as viral protein organization and density.