A monomeric envelope glycoprotein cytoplasmic tail is sufficient for HIV-1 Gag lattice trapping and incorporation

TL;DR

This study shows that a single piece of the HIV-1 envelope protein can be enough to get incorporated into new virus particles, even without forming the usual three-part structure.

Contribution

The study reveals that a monomeric Env cytoplasmic tail can replace the trimeric Env for virus incorporation, offering a new target for antiviral drugs.

Findings

A monomeric Env-CT is sufficient for lattice trapping and incorporation into HIV-1 particles.

Env-CT monomers can restrict the incorporation of native Env trimers and glycoproteins from distant HIV-1 isolates.

The mechanism of Env incorporation via Env-CT is conserved across different HIV-1 clades.

Abstract

To become infectious, assembling enveloped viruses must acquire viral glycoproteins to mediate downstream infection events. Human immunodeficiency virus-1 (HIV-1) envelope glycoproteins (Env) are well characterized to function as trimers for membrane fusion and entry; however, we sought to understand whether the trimeric structure of Env is required for incorporation into virus particles. Using superresolution live-cell imaging and biochemical assays, we demonstrate that a monomeric receptor chimera containing the Env cytoplasmic tail (Env-CT), known to regulate Env incorporation, is sufficient for lattice trapping and incorporation into virus assembly sites. We also demonstrate that these Env-CT monomers can restrict the incorporation of native Env trimers, competing for an apparently limited number of interaction sites in each assembling particle. Furthermore, this monomeric construct can restrict the incorporation of Env glycoproteins from an evolutionarily distant HIV-1 primary isolate. Our findings support a model where a monomeric Env-CT mediates Env incorporation, with this mechanism of Env incorporation being conserved between distant clades of HIV-1.

To combat the prevalence of HIV-1 and antiviral resistance, new classes of antivirals are needed. An attractive target for new classes includes virus assembly because released virus particles unable to obtain Env glycoproteins are non-infectious and unable to propagate HIV-1 infection. One requisite to the development of an antiviral targeting Gag-Env coalescence is the need to define the functional units constituting this molecular interface. Although Env functions as an obligatory trimer for virus entry, we demonstrate that a monomeric Env-CT is sufficient for Env incorporation into HIV-1 particles. Monomeric Env-CT displayed saturability in viral lattices and the ability to compete with native Env trimers for particle incorporation. These results suggest a less complex Env-CT structure mediates virus incorporation and that Env-CT mimetics could yield broad competitive activity against HIV-1 infection.

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