N-Glycans Modulate HIV-1 Env Conformational Plasticity

Human immunodeficiency virus-1 (HIV-1) remains a global health crisis, with over 39 million people living with the virus and no effective vaccine available. Central to HIV infection and immune evasion is the envelope glycoprotein (Env), a heavily glycosylated class I fusion protein that mediates viral entry and is the sole immunogenic target. Despite the recent advancements provided by imaging techniques, the characterization of Env’s structure and dynamics within its native membrane environment remains incomplete. Here, we present microsecond-long, all-atom molecular dynamics simulations of the full-length Env glycoprotein embedded in a biologically relevant lipid bilayer with a complete glycosylation profile. Our simulations reveal a pronounced tilting motion of Env relative to the membrane, with supporting evidence from cryo-electron tomography, which also captures Env tilting within the native membrane. Importantly, we identify a critical role for N-linked glycans at N88 and N611 in modulating the tilting transition. These findings highlight the dual role of Env’s glycan shield as both a protective barrier against neutralizing antibodies and a structural modulator of conformational plasticity. While providing an atomically detailed view of Env in a native membrane environment and advancing the general understanding of its glycan shield and its vulnerabilities, this work also suggests a possible strategy to modulate Env’s conformational plasticity.