Validation of HIV-1 MA Shell Structural Arrangements and Env Protein Interactions Predict a Role of the MA Shell in Viral Maturation.

The molecular structure of the type 1 human immunodeficiency virus (HIV-1) is tightly linked to the mechanism of viral entry. The spike envelope (Env) glycoproteins and their interaction with the underlying matrix (MA) shell have emerged as key components of the entry mechanism. Microscopy evidence suggests that the MA shell does not span the entire inner lipid surface of the virus, producing a region of the virus that completely lacks an MA shell. Interestingly, evidence also suggests that Env proteins cluster during viral maturation and, thus, it is likely that this event takes place in the region of the virus that lacks an MA shell. We have previously called this part of the virus a fusion hub to highlight its importance during viral entry. While the structure of the MA shell is in contention due to the unaddressed inconsistencies between its reported hexagonal arrangement and the physical plausibility of such a structure, it is possible that a limited number of MA hexagons could form. In this study, we measured the size of the fusion hub by analysing the cryo-EM maps of eight HIV-1 particles and measured the size of the MA shell gap to be 66.3 nm ± 15.0 nm. We also validated the feasibility of the hexagonal MA shell arrangement in six reported structures and determined the plausible components of these structures that do not violate geometrical limitations. We also examined the cytosolic domain of Env proteins and discovered a possible interaction between adjacent Env proteins that could explain the stability of cluster formation. We present an updated HIV-1 model and postulate novel roles of the MA shell and Env structure.

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

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.

Mathematical determination of the HIV-1 matrix shell structure and its impact on the biology of HIV-1.

Since its discovery in the early 1980s, there has been significant progress in understanding the biology of type 1 human immunodeficiency virus (HIV-1). Structural biologists have made tremendous contributions to this challenge, guiding the development of current therapeutic strategies. Despite our efforts, there are unresolved structural features of the virus and consequently, significant knowledge gaps in our understanding. The superstructure of the HIV-1 matrix (MA) shell has not been elucidated. Evidence by various high-resolution microscopy techniques support a model composed of MA trimers arranged in a hexameric configuration consisting of 6 MA trimers forming a hexagon. In this manuscript we review the mathematical limitations of this model and propose a new model consisting of a 6-lune hosohedra structure, which aligns with available structural evidence. We used geometric and rotational matrix computation methods to construct our model and predict a new mechanism for viral entry that explains the increase in particle size observed during CD4 receptor engagement and the most common HIV-1 ellipsoidal shapes observed in cryo-EM tomograms. A better understanding of the HIV-1 MA shell structure is a key step towards better models for viral assembly, maturation and entry. Our new model will facilitate efforts to improve understanding of the biology of HIV-1.