Abstract
Evidence suggests that lipid membrane interactions with rare, broadly neutralizing antibodies (NAbs), 2F5 and 4E10, play a critical role in HIV-1 neutralization. The objective of this research is to understand how lipid membrane properties, such as lipid domain organization contribute to 2F5/4E10 membrane interactions and antigen localization at the membrane interface, with the ultimate vision of guiding immunogen designs. Recent immunization studies have shown that induction of antibodies that avidly bind the gp41-MPER antigen is not sufficient for neutralization. Rather, it is required that antigen designs induce polyreactive antibodies that recognize MPER antigens as well as the viral lipid membrane. However, the mechanistic details of how membrane properties influence NAb-lipid and NAb-antigen interactions remain unknown. Furthermore, it is well established that the native viral membrane is heterogeneous, representing a mosaic of lipid rafts and protein clustering. However, the size, physical properties, and dynamics of these regions are poorly characterized and their potential roles in HIV-1 neutralization are also unknown. Methods: To understand how membrane properties contribute to 2F5/4E10 membrane interactions, we have engineered biomimetic supported lipid bilayers (SLBs) and are able to use atomic force microscopy to visualize membrane domains, antigen clustering, and antibody-membrane interactions.Our results showed that lipid domains were easily observed for simple binary membrane constructs and for complex, biomimetic HIV-1 model membranes. Localized binding of HIV-1 antigens (MPER656) and NAbs were observed to interact preferentially with the most fluid membrane domain. This supports the theory that NAbs may interact with regions of low lateral lipid forces that allow antibody insertion into the bilayer. NAbs were also observed to cluster at the edge of certain domain interfaces suggesting NAbs affinity for high interfacial energy regions of the lipid membrane.
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