Figure 4.

Mechanism of C-terminal domain NNRTI resistance. During reverse transcription, an NNRTI binds RT and forms a stalled complex. (A) In the case of a wild-type RT with wild-type RNase H activity, the stalled complex leads to a sensitive phenotype as RNase H cleavage causes minimal stretches of homology to be retained between the RNA/DNA hybrid. (B) In the case of RT mutations that reduce the affinity of the NNRTI for RT, the NNRTI has time to dissociate from the template-primer, forming a polymerization-competent complex and a resistant phenotype. (C) In the case of an RT with reduced RNase H activity, the reduction in template cleavage allows longer stretches of RNA/DNA hybrids to be retained, allowing more time for the NNRTI to dissociate and enable re-initiation of polymerization, leading to a resistant phenotype. Labels as in Figure 3; gray cylinder, NNRTI.