Abstract
SummaryHIV-1 Env mediates viral entry into host cells and is the sole target for neutralizing antibodies. However, Env structure and organization in its native virion context has eluded detailed characterization. Here, we used cryo-electron tomography to analyze Env in mature and immature HIV-1 particles. Immature particles showed distinct Env positioning relative to the underlying Gag lattice, providing insights into long-standing questions about Env incorporation. A 9.1-Å sub-tomogram-averaged reconstruction of virion-bound Env in conjunction with structural mass spectrometry revealed unexpected features, including a variable central core of the gp41 subunit, heterogeneous glycosylation between protomers, and a flexible stalk that allows Env tilting and variable exposure of neutralizing epitopes. Together, our results provide an integrative understanding of HIV assembly and structural variation in Env antigen presentation.
Highlights
Human immunodeficiency virus-1 (HIV-1) continues to infect nearly two million people worldwide each year, with no vaccine available against the virus (Pandey and Galvani, 2019)
(Stano et al, 2017). hVLPs assemble around a functional Gag layer that undergoes proteolytic maturation and have the composition of authentic HIV-1 virions but are replication incompetent because the packaged genome lacks the envelope glycoprotein (Env) gene (Leaman and Zwick, 2013; Stano et al, 2017)
Despite the lack of infectivity of AT-2-treated hVLPs, they induced syncytia formation and cytotoxicity in cells, similar to non-AT-2-treated hVLPs, in accordance with a previous report (Rossio et al, 1998), showing that AT-2-treated HIV-1 virions bear functional Envs that are capable of mediating cell entry (Figure S2)
Summary
Human immunodeficiency virus-1 (HIV-1) continues to infect nearly two million people worldwide each year, with no vaccine available against the virus (Pandey and Galvani, 2019). The envelope glycoprotein (Env) on the surface of HIV-1 is an essential viral entry machine that mediates binding to host cell receptors and subsequent membrane fusion. Env is translated as a precursor gp160 protein, which trimerizes and is cleaved into gp120 and gp subunits that are primarily responsible for receptor binding and fusion, respectively. The gp120 and gp subunits remain as non-covalently associated heterodimers with gp embedded in the viral membrane via its transmembrane domain (TMD) and the C-terminal cytoplasmic domain (CTD) in the viral lumen. Upon incorporation into budding virions, Env CTD interacts with the matrix domain (MA) of immature Gag polyprotein, which assembles as a membrane-associated lattice on the inner side of the viral bilayer (Checkley et al, 2011; Tedbury and Freed, 2014)
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