Escape of HIV-1 from a small molecule CCR5 inhibitor is not associated with a fitness loss
When human immunodeficiency virus type 1 (HIV-1) develops resistance in vitro or in vivo to antiretroviral drugs such as reverse transcriptase or protease inhibitors, its replicative fitness is often impaired (i.e., it grows at a lower rate or to a lesser extent than the parental, inhibitor-sensitive virus). We investigated whether resistance development in vitro to a new class of antiretroviral drugs, the CCR5 inhibitors, has an associated fitness cost. These inhibitors are small molecules that bind CCR5, a cell surface protein that HIV-1 uses as a co-receptor during the process of cellular entry. We found that resistance was not associated with a fitness loss. Furthermore, when the escape mutant was cultured for 20 passages without the small molecule CCR5 inhibitor (AD101), it remained resistant to the compound. Specific amino acid substitutions conferring AD101 resistance did cause a fitness loss when experimentally introduced into a sensitive clone, but in the naturally selected escape mutant they are probably compensated for by other changes. This work may help understand the development and management of resistance to CCR5 inhibitors now being evaluated clinically to treat HIV-1 infection.
