Human Immunodeficiency Virus gag and protease: partners in resistance

Axel Fun,Jens Verheyen,Annemarie Mj Wensing,Monique Nijhuis

doi:10.1186/1742-4690-9-63

Axel Fun, Jens Verheyen + Show 2 more

Open Access

https://doi.org/10.1186/1742-4690-9-63

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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.

Highlights

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
The level of Gag processing of a Protease inhibitor (PI) resistant isolate may impact the development of bevirimat resistance
Clinical perspective This review highlights the complex interactions between the viral protease and its Gag substrates and how mutations in Gag can affect PI and maturation inhibitor susceptibility

Summary

Introduction

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. Selection of Gag non-cleavage site mutations during protease inhibitor exposure Besides HIV-1 CS mutations, accumulation of non-CS mutations during PI therapy has been observed in all Gag proteins (MA, CA, NC, p6) as well as in spacer peptide p2 (Table 2). Capsid Mutations in CA have not been associated with virological failure to PI therapy, but substitutions M200I (with GS-8374 [64]) and H219Q/P (with GS-8374 [64] and APV [59,60]) have been selected during PI exposure in vitro.

Results

Conclusion