Human Immunodeficiency Virus Gag and protease: partners in resistance

Abstract

Human Immunodeficiency Virus (HIV) maturation plays an essential role in the viral life cycle by enabling the generation of mature infectious virus particles through proteolytic processing of the viral Gag and GagPol precursor proteins. An impaired polyprotein processing results in the production of non-infectious virus particles. Consequently, particle maturation is an excellent drug target as exemplified by inhibitors specifically targeting the viral protease (protease inhibitors; PIs) and the experimental class of maturation inhibitors that target the precursor Gag and GagPol polyproteins. Considering the different target sites of the two drug classes, direct cross-resistance may seem unlikely. However, coevolution of protease and its substrate Gag during PI exposure has been observed both in vivo and in vitro. This review addresses in detail all mutations in Gag that are selected under PI pressure. We evaluate how polymorphisms and mutations in Gag affect PI therapy, an aspect of PI resistance that is currently not included in standard genotypic PI resistance testing. In addition, we consider the consequences of Gag mutations for the development and positioning of future maturation inhibitors.

Figure 1

A schematic representation of HIV particle maturation. At the top, the viral GagPol polyprotein is depicted. On the left, the 5 sequential proteolytic processing steps of Gag are shown. In the middle, the 5 Gag cleavage sites (CS) and their nucleotide and corresponding amino acid sequences are shown. The numbers above the residues correspond to their position in the Gag polyprotein. At the top of the middle panel, the location of the p5-p5’ positions is indicated. On the right are schematic representations and electron-microscopy images of an HIV particle. Top: the immature, non-infectious particle with its granulated core. Bottom: the fully mature and infectious virion with its characteristic electron-dense conical core. The pacman figure represents the viral protease enzyme.