• Variations in HIV-1 Gag p6 Contribute to the Amprenavir-Specific Protease I50V Resistance Pathway
  Abstract 1765
  Authored by Michael F. Maguire (GlaxoSmithKline, Stevenage, United Kingdom), S. Macmanus (GlaxoSmithKline, Stevenage, United Kingdom), P. Griffin (GlaxoSmithKline, Stevenage, United Kingdom), C. Guinea (GlaxoSmithKline, Stevenage, United Kingdom), W. Harris (GlaxoSmithKline, Stevenage, United Kingdom), N. Richards (GlaxoSmithKline, Greenford, United Kingdom), J. Wolfram (GlaxoSmithKline, Greenford, United Kingdom), M. Tisdale (GlaxoSmithKline, Stevenage, United Kingdom), W. Snowden (GlaxoSmithKline, Stevenage, United Kingdom), J. P. Kleim (GlaxoSmithKline, Stevenage, United Kingdom)
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It has been known for some time that there are at least two ways for HIV to mutate and become resistant to protease inhibitors. The best-known changes occur in the protease enzyme itself, through amino acid changes in the active site that alter how well protease inhibitors fit in the enzyme, and through so-called "compensatory mutations," which optimize the way the mutated enzyme works to process HIV proteins. The second mechanism is through alterations in the target sites, where protease cuts the long poly protein into the functioning pieces needed to assemble an infectious virus. Target sites in the gag region have been identified that can mutate and contribute to resistance.

One reason this is important is that gag cleavage mutations are not reported in commercial genotyping assays. This means that these are essentially invisible to the clinician interpreting a genotype. They may be one reason that viruses with the same genotype may have a wide range of sensitivity when tested by phenotype. It is not known, in general, whether mutations in gag cleavage sites cost the virus in terms of fitness. Protease resistance that reduces viral fitness is thought to be one reason why many people with detectable viral load and resistant viruses continue to do well, with their CD4 counts remaining stable or even increasing.

In this study Maguire and his colleagues from GlaxoSmithKline in the UK explored the role of gag p6 mutations in amprenavir resistance. They first searched for mutations in gag in viruses with different amprenavir mutations. Viruses with the I50V mutation and with I84V (important in resistance to other protease inhibitors) were more likely to have mutations in gag. In both clinical isolates and in experiments, evolution of the gag cleavage site mutations enhanced amprenavir resistance and led to moderate cross-resistance.

Perhaps the most important finding, however, was that the evolution of gag mutations partially corrected the loss of fitness that resulted from the I50V mutation (see abstract 1766). This helps our understanding of how initial resistance mutations often result in loss of fitness, but how the virus can evolve methods to compensate. The clinical utility could someday result in the ability to look at a mutant virus and predict whether it is good for the patient to maintain the mutant, or whether clinical progression is likely.