Journal Article

Human Immunodeficiency Virus gag and protease: partners in resistance

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

2012

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Amino acids / Antibodies / Binding Sites / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cross-resistance / Drug Resistance, Viral / Enzymes / Evolution, Molecular / gag Gene Products, Human Immunodeficiency Virus - metabolism / Gag mutations / Genetic aspects / Genetic Variation / Health aspects / HIV / HIV (Viruses) / HIV Infections - virology / HIV Protease - genetics / HIV Protease - metabolism / HIV Protease Inhibitors - pharmacology / HIV-1 - drug effects / HIV-1 - enzymology / HIV-1 - physiology / Human immunodeficiency virus / Humans / Infectious Diseases / Maturation inhibitors / Mutation / Particle maturation / Physiological aspects / pol Gene Products, Human Immunodeficiency Virus - genetics / pol Gene Products, Human Immunodeficiency Virus - metabolism / Protease inhibitors / Proteases / Protein Structure / Proteins / Resistance / Review / Selection, Genetic / Vaccine / Viral proteins / Virology / Virus Replication