Mutations/drug resistance

Acquired resistance has been observed by constitutive upregulation of mdr efflux pump expression due to a mutation inactivating a respective repressor or inducibly, caused by molecules transiently inactivating repressor molecules upon binding. Depending upon the substrate spectra of the respective subset of efflux pumps upregulated, a multiple drug resistance (mdr) phenotype is expressed, which in combination with a specific resistance mechanism can contribute to a clinically relevant level of resistance. 

Class of drug/compound Mutation Fold-resistance Cross-resistance Comments Reference... 

Johnston E, Winters MA, Rhee SY, Merigan TC, Schiffer CA, Shafer RW (2004) Association of a novel human immunodeficiency virus type 1 protease substrate cleft mutation, L23I, with protease inhibitor therapy and in vitro drug resistance. Antimicrob Agents Chemother 48 4864 868... 

Fig. 2 The HBV polymerase and envelope proteins, whose reading frames overlap each other, and position of the main HBV drug-resistant mutations...

As for HIV, the selection of HCV drug resistant variants can be accompanied by a decrease in RC. For HCV protease inhibitor resistant variants, the level of resistance seems to be inversely related to viral fitness (Sarrazin et al. 2007 Tong et al. 2006 Yi et al. 2006). There is some evidence that viral RC can be restored by the selection of compensatory mutations within the protease gene (Sarrazin et al. 2007 Tong et al. 2006 Yi et al. 2006). However, further research is warranted to investigate to what extent viral fitness can be restored and by which mutations. Also for the nucleoside and non-nucleoside inhibitors, the selection of resistance results in a fitness defect. It remains to be investigated whether or not compensatory mutations can be selected. 

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