Conformational Plasticity of HIV-1 Env and Implications for Vaccine Design

Citation

Yang, Zhi (2022) Conformational Plasticity of HIV-1 Env and Implications for Vaccine Design. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/99hp-y284. https://resolver.caltech.edu/CaltechTHESIS:01222022-001845303

Abstract

The human immunodeficiency virus (HIV) envelope glycoprotein (Env), a (gp120/gp41)₃ trimer, is present on the surface of the viral envelope membrane. Env binding to the host cell receptor, CD4, and the co-receptor, CCR5 or CXCR4, triggers a cascade of Env conformational changes and structural rearrangements which ultimately leads to the viral and host cell membrane fusion, marking the initiation of a viral infection. In this work, we present findings of the conformational changes of an Env trimer from a closed, pre-fusion state to an asymmetrically open state when bound to receptor CD4 and a co-receptor mimicking antibody, E51. We showed the importance of tyrosine sulfation in gp120 binding. The EM structures also indicate the existence of Env’s multiple conformational states. Based on the structural information, we modeled the order of conformations on the path to co-receptor binding and viral-host cell membrane fusion.

As the sole viral protein present on the virion surface, the Env acts as the target for anti-HIV antibodies. Using various types of engineered Env as the immunogen, researchers made attempts to elicit anti-HIV neutralizing antibodies in animals. In this work, we identified and analyzed two neutralizing antibodies, Ab1303 and Ab1573, that target the Env CD4 binding site (CD4bs), one of the conserved epitopes on the Env gp120 surface. Using biophysical and structural methods, we described a novel recognition mechanism of these antibodies and proposed a model about the unique behavior of Env under physiological conditions. This study proved that CD4bs Abs that recognize an "occluded open" Env can be raised by sequential animal immunizations, thereby guiding the future immunogen design and therapeutic applications.

Thesis Files