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The Structure of HIV-1 Membrane Anchor and Its Implication to Vaccine Design
Chou James J1,2*, Fu Qingshan2, Liu Zhijun1
1National Center for Protein Science Shanghai, Shanghai Institute of Biochemistry and Cell Biology,Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China;
2Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
2Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
Abstract: HIV (human immunodeficiency virus) envelope spike (Env) is a transmembrane protein that mediates fusion of viral and cell membranes. As the sole antigens on the HIV virion surface， the mature HIV envelope protein has been the primary target of vaccine development. A vast amount of structural information is available for the ectodomain of Env， the primary target by the host immune system， but much less is known about its transmembrane domain (TMD) in the context of lipid bilayer. We used the latest NMR technologies and determined the structure of the TMD of HIV-1Env reconstituted in bicelles that mimic a lipid bilayer. It forms a well-ordered trimer that protects a conserved arginine， buried in the membrane. An N-terminal coiled coil and a C-terminal hydrophilic core stabilize the trimer; the latter is structurally coupled to the cytoplasmic domain.Functional studies showed that mutations destabilizing the TMD trimer severely attenuated the sensitivity of the functional Env to trimer-specific antibodies. Specifically， the trimer-specific broadly neutralizing antibody，which neutralize by stabilizing the native trimeric conformation of Env， do not recognize the Env spike when its TMD has been destabilized. We thus conclude that the TMD plays an important role in maintaining the native conformation of Env and that the influence of TMD on the Env ectodomain is an important consideration for HIV immunogen design.
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