Impact of drug resistance mutation on non B HIV-1 clades

Markus Bickel, University of California, Los Angeles
Molecular Biology

HIV-1 treatment with antiretroviral drugs can fail because the virus can develop resistance mutations against the drugs. However, it has been noted that some patients still have clinical benefits from treatment even when their viruses have resistance mutations. Research has shown that this benefit is related to the fact that the virus grows more poorly when it has mutations (with a reduced replicative capacity, RC). Thus, understanding the effect of resistance mutations on RC could be very important in treatment strategies where fully suppressive drug treatment is difficult or impossible. Furthermore, the persistence of drug resistance mutations also depends on RC; mutations that cause reduced RC are less likely to be spread from one person to another. This is pertinent to understanding the risk of drug resistant virus spread population-wide.

A particular drug resistance mutation that is important is K103N, which makes HIV resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs). An NNRTI (nevirapine) is the basis of HIV-1 therapies being distributed in resource poor areas of the world. Although data suggest that K103N doesn't cause reduced RC, all these data are based on a single family of HIV-1 (clade B). However, some clinical data from areas of the world where non clade B viruses predominate indicate the RC could be higher for those viruses. Understanding the impact of K103N on other strains of HIV-1 is therefore important.

We hypothesize that the effect of K103N on HIV RC depends on the sequence of the virus, which differs dramatically across different strains and clades. Surprisingly, measurements of K103N effects on RC have been performed with a single strain of clade B HIV only. For this project, we plan to experimentally measure the impact of K103N on several viruses from clade B and other clades from strains circulating worldwide.

The results of our experiment could be of clinical significance, since nevirapine is the most commonly used antiretroviral drug in countries with limited resources. Therefore patients who have acquired the K103N mutation are nevertheless likely to be treated with NVP since there are very limited options. If the viral fitness of non B clades is significantly decreased due to the K103N mutation, this finding could argue for continued clinical benefit despite existing drug resistance. Furthermore, if K103N causes loss of RC, this would suggest that the spread of this mutation could be a lesser problem than currently believed.