Email updates

Keep up to date with the latest news and content from Retrovirology and BioMed Central.

Open Access Highly Accessed Short report

Functional conservation of HIV-1 Gag: implications for rational drug design

Guangdi Li1, Jens Verheyen2, Soo-Yon Rhee13, Arnout Voet4, Anne-Mieke Vandamme15 and Kristof Theys1*

Author Affiliations

1 Rega Institute for Medical Research, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium

2 Institute of Virology, University hospital, University Duisburg-Essen, Essen, Germany

3 Division of Infectious Diseases, Department of Medicine, Stanford University, Stanford, CA, USA

4 Zhang IRU, RIKEN Institute Laboratories, Hirosawa 2-1, Wako-shi, Saitama, Japan

5 Centro de Malária e Outras Doenças Tropicais and Unidade de Microbiologia, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Lisbon, Portugal

For all author emails, please log on.

Retrovirology 2013, 10:126  doi:10.1186/1742-4690-10-126

Published: 31 October 2013

Abstract

Background

HIV-1 replication can be successfully blocked by targeting gag gene products, offering a promising strategy for new drug classes that complement current HIV-1 treatment options. However, naturally occurring polymorphisms at drug binding sites can severely compromise HIV-1 susceptibility to gag inhibitors in clinical and experimental studies. Therefore, a comprehensive understanding of gag natural diversity is needed.

Findings

We analyzed the degree of functional conservation in 10862 full-length gag sequences across 8 major HIV-1 subtypes and identified the impact of natural variation on known drug binding positions targeted by more than 20 gag inhibitors published to date. Complete conservation across all subtypes was detected in 147 (29%) out of 500 gag positions, with the highest level of conservation observed in capsid protein. Almost half (41%) of the 136 known drug binding positions were completely conserved, but all inhibitors were confronted with naturally occurring polymorphisms in their binding sites, some of which correlated with HIV-1 subtype. Integration of sequence and structural information revealed one drug binding pocket with minimal genetic variability, which is situated at the N-terminal domain of the capsid protein.

Conclusions

This first large-scale analysis of full-length HIV-1 gag provided a detailed mapping of natural diversity across major subtypes and highlighted the considerable variation in current drug binding sites. Our results contribute to the optimization of gag inhibitors in rational drug design, given that drug binding sites should ideally be conserved across all HIV-1 subtypes.

Keywords:
HIV subtype; Gag inhibitor; Matrix; Capsid; Nucleocapsid; Drug binding site; Natural polymorphism; Amino acid conservation