Polymorphisms in Gag spacer peptide 1 confer varying levels of resistance to the HIV- 1maturation inhibitor bevirimat

Catherine S Adamson,Michael Sakalian,Eric O Freed,Karl Salzwedel

doi:10.1186/1742-4690-7-36

Catherine S Adamson, Michael Sakalian + Show 2 more

Open Access

https://doi.org/10.1186/1742-4690-7-36

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Abstract

BackgroundThe maturation inhibitor bevirimat (BVM) potently inhibits human immunodeficiency virus type 1 (HIV-1) replication by blocking capsid-spacer peptide 1 (CA-SP1) cleavage. Recent clinical trials demonstrated that a significant proportion of HIV-1-infected patients do not respond to BVM. A patient's failure to respond correlated with baseline polymorphisms at SP1 residues 6-8.ResultsIn this study, we demonstrate that varying levels of BVM resistance are associated with point mutations at these residues. BVM susceptibility was maintained by SP1-Q6A, -Q6H and -T8A mutations. However, an SP1-V7A mutation conferred high-level BVM resistance, and SP1-V7M and T8Δ mutations conferred intermediate levels of BVM resistance.ConclusionsFuture exploitation of the CA-SP1 cleavage site as an antiretroviral drug target will need to overcome the baseline variability in the SP1 region of Gag.

Highlights

The maturation inhibitor bevirimat (BVM) potently inhibits human immunodeficiency virus type 1 (HIV-1)replication by blocking capsid-spacer peptide 1 (CA-SP1) cleavage
Human immunodeficiency virus type 1 (HIV-1) infectivity is dependent on virion maturation, a morphological rearrangement of the viral core that occurs concomitant with virus particle release [1,2]
Gag polymorphisms at SP1 residues 6-8 (SP1/6-8) and BVM susceptibility, we employed a quantitative biochemical CA-SP1 processing assay that we have previously used to analyze in vitroselected BVM-resistance mutations [22,24]

Summary

Introduction

The maturation inhibitor bevirimat (BVM) potently inhibits human immunodeficiency virus type 1 (HIV-1). Replication by blocking capsid-spacer peptide 1 (CA-SP1) cleavage. Recent clinical trials demonstrated that a significant proportion of HIV-1-infected patients do not respond to BVM. Human immunodeficiency virus type 1 (HIV-1) infectivity is dependent on virion maturation, a morphological rearrangement of the viral core that occurs concomitant with virus particle release [1,2]. HIV-1 maturation is triggered by cleavage of the Gag polyprotein, catalyzed by the viral protease (PR), into the matrix (MA), capsid (CA), spacer peptide 1 (SP1), nucleocapsid (NC), spacer peptide (SP2) and p6 constituents. Morphological rearrangement of the viral core is triggered by the release of the mature CA domain, which reassembles into a hexameric lattice to form a condensed conical core

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