N348I in HIV-1 Reverse Transcriptase Counteracts the Synergy Between Zidovudine and Nevirapine

Abstract

The efficacy of regimens that include both zidovudine and nevirapine can be explained by the synergistic interactions between these drugs. N348I in HIV-1 reverse transcriptase (RT) confers decreased susceptibility to zidovudine and nevirapine. Here we demonstrate that N348I reverses the synergistic inhibition of HIV-1 by zidovudine and nevirapine. Also, the efficiency of zidovudine-monophosphate excision in the presence of nevirapine is greater for N348I HIV-1 RT compared to the wild-type enzyme. These data help explain the frequent selection of N348I in regimens that contain zidovudine and nevirapine, and suggest that the selection of N348I should be monitored in resource-limited settings where these drugs are routinely used.

Human Immunodeficiency Virus Reverse Transcriptase

“…The net result of this diminished RNase H cleavage phenotype is that enzymes that contain the N348I mutation exhibit an increased ability to excise AZT-MP from RNA/ DNA T/Ps, but not DNA/DNA T/Ps. In addition, effi ciency of AZT-MP excision in the presence of NVP is greater for N348I HIV-1 RT compared to wild-type enzyme, which is consistent with the ability of this mutation to reverse the synergistic inhibition of HIV-1 by AZT and NVP (Huey Yap et al 2012 ). AZT-MP excision can only occur when the chain-terminating moiety resides in the N-site of the RT polymerase active site.…”

Targeting HIV-1 Reverse Transcriptase Using a Fragment-Based Approach

“…The combination analysis performed was based on the median effect principle (Chou and Talalay 1983). Data were analyzed using the CalcuSyn Version 2 software (Biosoft, Cambridge, UK) according to CalcuSyn user manual instructions for fixed-ratio combinations [ 44 ]. Nevirapine (NVP) was tested in combination with doravirine (DOR), compound B - 1 and 27 at fixed ratios of 18:1, 1:200 and 1:19, respectively.…”