Project Report

A major obstacle to generating a successful human immunodeficiency virus-1 (HIV-1) vaccine is the inability to induce broadly reactive neutralizing antibodies (NAbs) after immunization. The human monoclonal NAbs, 2F5 and 4E10, represent rare antibodies with broadly neutralizing activity made from B cells of HIV-1 infected humans. Their neutralizing mechanism represents a promising framework for the design of new HIV-1 liposomal vaccine candidates, yet this mechanism is only poorly understood. Recently, Alam et al. has demonstrated that 2F5 and 4E10 associate with HIV-1 lipids as part of an essential first step in neutralization before binding to the viral membrane-proximal external region (MPER) of gp41. This lipid reactivity is thought to facilitate NAb localization and diffusion within the viral membrane, positioning NAbs so that they are more likely to encounter sparse and transient HIV-1 antigens. Thus, vaccine immunogens must elicit antibodies that also interact with the viral membrane; however, the role of specific membrane properties that facilitate NAb interactions has not been clearly defined. Our research thus focuses on understanding how membrane properties, such as composition, lipid domain organization, and lipid diffusivity contribute to the neutralizing mechanism of 2F5 and 4E10. To this end, 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 preliminary 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. Because current 2F5/4E10 immunogens have not yet elicited antibodies with the required membrane reactivity, our research is important in that it will reveal molecular details of the role of lipids underlying 2F5/4E10 antigen binding. This information will help determine how vaccines can induce antibodies with the required antigen and membrane reactivity.

National Science Foundation (NSF)
Office of International and Integrative Activities (IIA)
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Carter Kimsey
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Hardy Gregory J
United States
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