HIV-1 Gag protein assembles at the plasma membrane of infected cells for viral particle formation. Gag targets lipids, mainly PI(4,5)P2, at the inner leaflet of this membrane. Here, we address the question whether Gag is able to trap specifically PI(4,5)P2 or other lipids during HIV-1 assembly in the host CD4+ T lymphocytes. Lipid dynamics within and away from HIV-1 assembly sites were determined using super-resolution microscopy coupled with scanning fluorescence correlation spectroscopy in living cells. Analysis of HIV-1–infected cells revealed that, upon assembly, HIV-1 is able to specifically trap PI(4,5)P2 and cholesterol, but not phosphatidylethanolamine or sphingomyelin. Furthermore, our data showed that Gag is the main driving force to restrict the mobility of PI(4,5)P2 and cholesterol at the cell plasma membrane. This is the first direct evidence highlighting that HIV-1 creates its own specific lipid environment by selectively recruiting PI(4,5)P2 and cholesterol as a membrane nanoplatform for virus assembly.

https://advances.sciencemag.org/content/advances/5/10/eaaw8651.full.pdf

HIV-1 Gag specifically restricts PI(4,5)P2 and cholesterol mobility in living cells creating a nanodomain platform for virus assembly.

Gag, the primary structural protein of HIV-1, is recruited to the plasma membrane for virus assembly by its matrix (MA) domain. Gag is subsequently cleaved into its component domains, causing structural maturation to repurpose the virion for cell entry. We determined the structure and arrangement of MA within immature and mature HIV-1 through cryo-electron tomography. We found that MA rearranges between two different hexameric lattices upon maturation. In mature HIV-1, a lipid extends out of the membrane to bind with a pocket in MA. Our data suggest that proteolytic maturation of HIV-1 not only assembles the viral capsid surrounding the genome but also repurposes the membrane-bound MA lattice for an entry or postentry function and results in the partial removal of up to 2500 lipids from the viral membrane.

Maturation of the matrix and viral membrane of HIV-1.

The self-assembly of HIV-1 Gag polyprotein at the inner leaflet of the cell host plasma membrane is the key orchestrator of virus assembly. The binding between Gag and the plasma membrane is mediated by specific interaction of the Gag matrix domain and the PI(4,5)P2 lipid (PIP2). It is unknown whether this interaction could lead to local reorganization of the plasma membrane lipids. In this study, using model membranes, we examined the ability of Gag to segregate specific lipids upon self-assembly. We show for the first time that Gag self-assembly is responsible for the formation of PIP2 lipid nanoclusters, enriched in cholesterol but not in sphingomyelin. We also show that Gag mainly partition into liquid-disordered domains of these lipid membranes. Our work strongly suggests that, instead of targeting pre-existing plasma membrane lipid domains, Gag is more prone to generate PIP2/Cholesterol lipid nanodomains at the inner leaflet of the plasma membrane during early events of virus assembly.

/pdf/self-assembly-of-hiv-1-gag-protein-on-lipid-membranes-4y4jc9g2k4.pdf

Self assembly of HIV-1 Gag protein on lipid membranes generates PI(4,5)P 2 /Cholesterol nanoclusters

The Ebola virus is a lipid-enveloped virus that obtains its lipid coat from the plasma membrane of the host cell it infects during the budding process. The Ebola virus protein VP40 localizes to the inner leaflet of the plasma membrane and forms the viral matrix, which provides the major structure for the Ebola virus particles. VP40 is initially a dimer that rearranges to a hexameric structure that mediates budding. VP40 hexamers and larger filaments have been shown to be stabilized by PI(4,5)P2 in the plasma membrane inner leaflet. Reduction in the plasma membrane levels of PI(4,5)P2 significantly reduce formation of VP40 oligomers and virus-like particles. We investigated the lipid–protein interactions in VP40 hexamers at the plasma membrane. We quantified lipid–lipid self-clustering by calculating the fractional interaction matrix and found that the VP40 hexamer significantly enhances the PI(4,5)P2 clustering. The radial pair distribution functions suggest a strong interaction between PI(4,5)P2 and the VP40 hexamer. The cationic Lys side chains are found to mediate the PIP2 clustering around the protein, with cholesterol filling the space between the interacting PIP2 molecules. These computational studies support recent experimental data and provide new insights into the mechanisms by which VP40 assembles at the plasma membrane inner leaflet, alters membrane curvature, and forms new virus-like particles.

/pdf/the-ebola-virus-protein-vp40-hexamer-enhances-the-clustering-5ff6j85r9x.pdf

The Ebola virus protein VP40 hexamer enhances the clustering of PI(4,5)P2 lipids in the plasma membrane.

Viruses are parasites that must infect the living cell of a host in order to grow and replicate To do so, the virus attaches to the host’s cell and transfers its genetic material to the inside The virus then hijacks the cell and forces it to build proteins and more genetic material that will assemble into new copies of the virus, and the completed virus particles are released to infect new cells The HIV-1 virus encodes a protein called Gag that coordinates the assembly of new copies of this virus Thousands of Gag proteins accumulate into a lattice at the inside of the host cell membrane by an unknown mechanism, where they gather all essential components to form a new infectious virus Once completed, the virus particle detaches itself from the host cell and Gag gives the virus its structure Previous research by several groups has shown that a lipid molecule found in cell membranes called PIP2 can bind to Gag and helps the virus to assemble However, until now, it was unclear if PIP2 anchors Gag to the cell membrane of living cells and if it plays any other roles in the later stages of assembly Now, Mucksch et al have developed a new approach to study this question by rapidly manipulating the levels of PIP2 in living cells and monitoring Gag assembly through a fluorescent marker The experiments showed that PIP2 was needed to initiate the assembly process, but also to maintain the partially assembled Gag lattice at the membrane When PIP2 was removed, Gag proteins could not gather at the cell membrane and the already assembled Gag lattices broke down When PIP2 levels were increased again, the Gag proteins that had disappeared from the membrane formed new lattices This suggests that PIP2 has a much broader role in HIV-1 particle formation than previously assumed A next step will be to use this new experimental approach to study how particles of HIV are assembled and released This knowledge may help scientists to develop antiviral drugs that interfere with the assembly step of the virus that could be used to prevent or treat HIV infections

Synchronized HIV assembly by tunable PIP2 changes reveals PIP2 requirement for stable Gag anchoring

Structural and Molecular Determinants of Membrane Binding by the HIV-1 Matrix Protein.

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Structural and Molecular Determinants of Membrane Binding by the HIV-1 Matrix Protein.