The HIV-1 Gag Protein Displays Extensive Functional and Structural Roles in Virus Replication and Infectivity

Abstract

Once merely thought of as the protein responsible for the overall physical nature of the human immunodeficiency virus type 1 (HIV-1), the Gag polyprotein has since been elucidated to have several roles in viral replication and functionality. Over the years, extensive research into the polyproteins’ structure has revealed that Gag can mediate its own trafficking to the plasma membrane, it can interact with several host factors and can even aid in viral genome packaging. Not surprisingly, Gag has also been associated with HIV-1 drug resistance and even treatment failure. Therefore, this review provides an extensive overview of the structural and functional roles of the HIV-1 Gag domains in virion integrity, functionality and infectivity.

Engineering RNA export for measurement and manipulation of living cells

“…We focused on the well-characterized sequence-specific RNA binding protein, MS2 bacteriophage coat protein (MCP), which binds to a cognate RNA hairpin aptamer 31 . To facilitate engineering, we replaced the MMLV Gag capsid with the HIV Gag capsid, which has better annotated functional domains 32 and tolerates protein fusions without compromising VLP assembly and release 22 , 33 . We fused MCP to HIV Gag, forming Gag-MCP, and tagged cargo RNA with twelve tandem MS2 hairpins in its 3’ UTR ( Figure 1F ).…”

“…Despite functioning well, the viral exporter designs described so far had limited potential for further engineering. Rational design of viral proteins is difficult because their architectures are not modular 32 , as highlighted by the dual role of nucleocapsid domains in RNA binding and particle assembly in diverse retroviruses 27 , 28 , 37 , 38 . In addition, fusing proteins to viral capsids can disrupt VLP assembly in an unpredictable manner 39 .…”

Determinants in the HTLV-1 capsid major homology region that are critical for virus particle assembly

“…Within the HIV-1 CA CTD , this configuration is stabilized by a network of hydrogen bonds and salt bridges between the side chains of glutamine, glutamate, and arginine. This network appears to be absolutely conserved within the retroviral MHR motif [40-42]. Moreover, conserved positions are occupied by large hydrophobic side chains — typically phenylalanine, tyrosine, or leucine — which constitute part of the hydrophobic core of CA CTD .…”

“…While a number of studies have been conducted on the MHR, there remains many unanswered questions regarding the evolutionary conservation and function of the MHR [26, 40]. Models have been previously proposed to help explain MHR conservation and function.…”

HIV-1 Gag Binds the Multi-Aminoacyl-tRNA Synthetase Complex via the EPRS Subunit

“…In addition to functions in protein translation and priming of retroviral reverse transcription, cellular tRNAs are also involved in regulating HIV-1 Gag assembly at the plasma membrane (PM) [ 21 , 22 ]. The Gag polyprotein consists of the myristoylated membrane-binding matrix (MA) domain, the capsid (CA) domain, which mediates Gag oligomerization and assembly, the nucleocapsid (NC), which facilitates gRNA packaging, tRNA primer annealing and reverse transcription, and the C-terminal p6 domain, which plays a role in viral budding from the host cell [ 22 ]. The MA domain of Gag encodes a lysine/arginine-rich highly basic region (HBR), which interacts with negatively charged lipid membranes [ 23 , 24 , 25 ].…”