Challenging the Existing Model of the Hexameric HIV-1 Gag Lattice and MA Shell Superstructure: Implications for Viral Entry.

Joy Ramielle L Santos,Eduardo Reyes-Serratos,Tarana A Mangukia,Marcelo Marcet-Palacios,Weijie Sun

doi:10.3390/v13081515

Joy Ramielle L Santos, Eduardo Reyes-Serratos + Show 3 more

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https://doi.org/10.3390/v13081515

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Abstract

Despite type 1 human immunodeficiency virus (HIV-1) being discovered in the early 1980s, significant knowledge gaps remain in our understanding of the superstructure of the HIV-1 matrix (MA) shell. Current viral assembly models assume that the MA shell originates via recruitment of group-specific antigen (Gag) polyproteins into a hexagonal lattice but fails to resolve and explain lattice overlapping that occurs when the membrane is folded into a spherical/ellipsoidal shape. It further fails to address how the shell recruits, interacts with and encompasses the viral spike envelope (Env) glycoproteins. These Env glycoproteins are crucial as they facilitate viral entry by interacting with receptors and coreceptors located on T-cells. In our previous publication, we proposed a six-lune hosohedral structure, snowflake-like model for the MA shell of HIV-1. In this article, we improve upon the six-lune hosohedral structure by incorporating into our algorithm the recruitment of complete Env glycoproteins. We generated the Env glycoprotein assembly using a combination of predetermined Env glycoprotein domains from X-ray crystallography, nuclear magnetic resonance (NMR), cryoelectron tomography, and three-dimensional prediction tools. Our novel MA shell model comprises 1028 MA trimers and 14 Env glycoproteins. Our model demonstrates the movement of Env glycoproteins in the interlunar spaces, with effective clustering at the fusion hub, where multiple Env complexes bind to T-cell receptors during the process of viral entry. Elucidating the HIV-1 MA shell structure and its interaction with the Env glycoproteins is a key step toward understanding the mechanism of HIV-1 entry.

Highlights

The outer surface of HIV-1 is surrounded by a lipid bilayer containing the viral spike envelope (Env) glycoproteins
We proposed a new MA shell model consisting of a six-lune MA hosohedron that explained a number of microscopy observations, including HIV-1 viral expansion during entry [15], rearrangement of Env glycoproteins to form clusters during maturation [16,17,18], the pleomorphic nature of viral structures including spherical and ellipsoidal shapes [19], and the correct number of MA trimers per viral particle [20]
We propose a novel interaction between the CT domains of Env glycoproteins and the MA trimers, which provides a mechanism of HIV viral maturation

Summary

Introduction

The outer surface of HIV-1 is surrounded by a lipid bilayer containing the viral spike envelope (Env) glycoproteins. 14 copies of the mature Env glycoprotein are found per viral particle, clustered together in patterns that resemble underlying “trenches” created by internal structural components of the virus [2]. Inside the virus, embedded into the inner lipid layer, matrix (MA) proteins arrange themselves into a shell with a superstructure that has not been elucidated. MA have been resolved into trimers by X-ray crystallography [3]. These trimers have been observed to form hexagonal arrangements [4] when placed onto flat two-dimensional surfaces.

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