Cryo-Electron Tomographic Structure of an Immunodeficiency Virus Envelope Complex In Situ

Abstract

The envelope glycoprotein (Env) complexes of the human and simian immunodeficiency viruses (HIV and SIV, respectively) mediate viral entry and are a target for neutralizing antibodies. The receptor binding surfaces of Env are in large part sterically occluded or conformationally masked prior to receptor binding. Knowledge of the unliganded, trimeric Env structure is key for an understanding of viral entry and immune escape, and for the design of vaccines to elicit neutralizing antibodies. We have used cryo-electron tomography and averaging to obtain the structure of the SIV Env complex prior to fusion. Our result reveals novel details of Env organisation, including tight interaction between monomers in the gp41 trimer, associated with a three-lobed, membrane-distal gp120 trimer. A cavity exists at the gp41–gp120 trimer interface. Our model for the spike structure agrees with previously predicted interactions between gp41 monomers, and furthers our understanding of gp120 interactions within an intact spike. HIV (human immunodeficiency virus) causes AIDS (acquired immunodeficiency syndrome) that is responsible for approximately 50 million infections since its first description in 1981. Antiviral therapies have made enormous progress, but a vaccine remains essential and yet elusive. The phenotypic variability of the virus (particle size varies by 3-fold) makes a structural approach difficult. Common virus surface components must be maintained to allow attachment to and penetration of host cells for infection. Reacting to these common viral components with neutralizing antibodies would allow the immune system to respond rapidly to infection and potentially serve as a basis for a vaccine. HIV (and its close relative simian immunodeficiency virus [SIV]) avoids antibody neutralization, in part by masking these essential components with flexible structural elements such as sugars and protein domains. The structural variability of the virus forced the authors to combine over a hundred electron micrographs to visualize the structure of the individual virus particles. The authors could then computationally extract the surface components and generate their average structure. This average sheds light on mechanisms of occlusion of common viral components from the immune system. This average structure could serve as a basis for effective vaccine design.