Abstract

Cleavage of Gag and Gag-Pol precursors by the viral protease is an essential step in the replication cycle of HIV. Protease inhibitors, which compete with natural cleavage sites, strongly impair viral infectivity and have proven to be highly valuable in the treatment of HIV-infected subjects. However, as with all other antiretroviral drugs, the clinical benefit of protease inhibitors can be compromised by resistance. One key feature of HIV resistance to protease inhibitors is that the mutations that promote resistance are not only located in the protease itself, but also in some of its natural substrates. The best documented resistance-associated substrate mutations are located in, or near, the cleavage sites in the NC/SP2/p6 region of Gag. These mutations improve interactions between the substrate and the mutated enzyme and correspondingly increase cleavage. Initially described as compensatory mutations able to partially correct the loss of viral fitness that results from protease mutations, changes in Gag are now recognized as being directly involved in resistance. Besides NC/SP2/p6 mutations, polymorphisms in other regions of Gag have been found to exert various effects on viral fitness and or resistance, but their importance deserves further evaluation.

Highlights

  • Protease inhibitors (PIs) are among the most active antiretroviral drugs currently used in the treatment of HIV infection

  • A unique feature of HIV resistance to PIs is the fact that resistance mutations arise in the protease itself – the direct target of the inhibitors – and in some of the natural substrates of the protease – the Gag cleavage sites

  • We will review here the evidence that Gag cleavage site mutations are an important element of HIV resistance to PIs and discuss the mechanisms and implications of this phenomenon

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Summary

Introduction

Protease inhibitors (PIs) are among the most active antiretroviral drugs currently used in the treatment of HIV infection. These compounds, which mimic the natural Gag and Gag-Pol substrates of the HIV protease, inhibit the proteolytic activity of the enzyme and exert a powerful inhibitory effect on HIV replication both in vitro and in vivo. A unique feature of HIV resistance to PIs is the fact that resistance mutations arise in the protease itself – the direct target of the inhibitors – and in some of the natural substrates of the protease – the Gag cleavage sites. We will review here the evidence that Gag cleavage site mutations are an important element of HIV resistance to PIs and discuss the mechanisms and implications of this phenomenon

The HIV-1 protease and its natural substrates
HIV resistance to PIs: protease mutations
HIV resistance to protease inhibitors and viral fitness
Cleavage site mutations as resistance mutations
Mechanisms of action of Gag cleavage site mutations
Findings
Role of other mutations or polymorphisms in Gag in HIV resistance to PIs
Full Text
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