Abstract
BackgroundHIV-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.FindingsWe 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.ConclusionsThis 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.
Highlights
A curative therapy or preventive vaccine for HIV-1 infected patients remains elusive to date
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
Summary
A curative therapy or preventive vaccine for HIV-1 infected patients remains elusive to date. HIV-1 inhibitors that target different stages of virion morphogenesis demonstrated promising antiviral activity, mainly by inhibiting capsid assembly, disrupting nucleocapsid binding with viral RNA/DNA or blocking proteolytic processing of polyproteins during maturation [2,3,4,5]. Treatment failure of patients in a phase II clinical study of the maturation inhibitor bevirimat was attributed to natural polymorphisms at drug binding positions, showing up in subtype-specific patterns [8]. Studies that extensively investigate the implications of HIV-1 diversity for gagdirected drug development are lacking to date. In this large-scale analysis, we examined the distribution of naturally occurring sequence variability in full-length gag sequences of major HIV-1 subtypes. A comprehensive understanding of gag natural diversity is needed
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