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.

Keywords: Gag molecular structure; p17 Gag; p2 and p1 Gag; p24 Gag; p6 Gag; p7 Gag.

Figure 1

Schematic representation of a rod-shaped HIV-1 Gag polyprotein obtained by the concatenation of previously resolved structures of individual Gag domains. PDB IDs: matrix (2h3i; [12]); capsid (3nte; [13]); SP1 (1u57; [14]); nucleocapsid (1a1t; [15]); p6 (2c55; [16]). Note: The matrix-capsid linker and SP2 are hypothetical representations.

Figure 2

Proposed HIV-1 myristoylation at the molecular level. (A) Full length Gag polyprotein with a myristoylated MA at the N-terminal domain. (B) Sequestered (S) and Exposed (E) transition states in different MA conformations [37]. (C) The sequestered myristic acid switches to exposed upon PIP₂ binding at the plasma membrane. The PIP₂ fatty acid is then sequestered into the vacant hydrophobic pocket (adapted from [38]).