Editing Reverse-transcriptase inhibitor (section)

===NNRTI resistance===
NNRTIs do not bind to the active site of the polymerase but in a less conserved pocket near the active site in the p66 subdomain. Their binding results in a conformational change in the reverse transcriptase that distorts the positioning of the residues that bind DNA, inhibiting polymerization.<ref>{{cite journal | last1 = De Clercq | first1 = E | title = The role of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection | journal = Antiviral Research | volume = 38 | issue = 3 | pages = 153–79 | year = 1998 | pmid = 9754886 | doi = 10.1016/S0166-3542(98)00025-4 }}</ref> Mutations in response to NNRTIs decrease the binding of the drug to this pocket. Treatment with a regimen including efavirenz (EFV) and nevirapine (NVP) typically results in mutations L100I, Y181C/I, K103N, V106A/M, V108I, Y188C/H/L and G190A/S.<ref>{{cite journal | last1 = Johnson | first1 = VA | last2 = Brun-Vezinet | first2 = F | last3 = Clotet | first3 = B | last4 = Gunthard | first4 = HF | last5 = Kuritzkes | first5 = DR|author5-link=Daniel Kuritzkes | last6 = Pillay | first6 = D | last7 = Schapiro | first7 = JM | last8 = Richman | first8 = DD | title = Update of the drug resistance mutations in HIV-1: December 2009 | journal = Topics in HIV Medicine | volume = 17 | issue = 5 | pages = 138–45 | year = 2009 | pmid = 20068260 }}</ref>
There are three main mechanisms of NNRTI resistance. In the first NRTI mutations disrupt specific contacts between the inhibitor and the NNRTI binding pocket. An example of this is K103N and K101E which sit at the entrance of the pocket,<ref>{{cite journal | doi = 10.1016/j.jmb.2006.08.097 | last1 = Das | first1 =   Kalyan| year = 2007 | last2 = Sarafianos | first2 = SG | last3 = Clark Jr | first3 = AD | last4 = Boyer | first4 = PL | last5 = Hughes | first5 = SH | last6 = Arnold | first6 = E | title = Crystal structures of clinically relevant Lys103Asn/Tyr181Cys double mutant HIV-1 reverse transcriptase in complexes with ATP and non-nucleoside inhibitor HBY 097 | journal = J Mol Biol | volume = 365 | issue = 1| pages = 77–89 | pmid = 17056061 }}</ref><ref>{{cite journal | last1 = Hsiou | first1 = Y | last2 = Ding | first2 = J | last3 = Das | first3 = K | last4 = Clark Jr | first4 = AD | last5 = Boyer | first5 = PL | last6 = Lewi | first6 = P | last7 = Janssen | first7 = PA | last8 = Kleim | first8 = JP | last9 = Rösner | first9 = M | last10 = Hughes | first10 = Stephen H | last11 = Arnold | first11 = Edward | title = The Lys103Asn mutation of HIV-1 RT: a novel mechanism of drug resistance | journal = Journal of Molecular Biology | volume = 309 | issue = 2 | pages = 437–45 | year = 2001 | pmid = 11371163 | doi = 10.1006/jmbi.2001.4648 | s2cid = 3109889 | display-authors = 8 }}</ref> blocking the entrance/binding of the drug. A second mechanism is the disruption of important interactions on the inside of the pocket. For example, Y181C and Y188L result in the loss of important aromatic rings involved in NNRTI binding.<ref>{{cite journal | last1 = Ren | first1 = J | last2 = Nichols | first2 = C | last3 = Bird | first3 = L | last4 = Chamberlain | first4 = P | last5 = Weaver | first5 = K | last6 = Short | first6 = S | last7 = Stuart | first7 = DI | last8 = Stammers | first8 = DK | title = Structural mechanisms of drug resistance for mutations at codons 181 and 188 in HIV-1 reverse transcriptase and the improved resilience of second generation non-nucleoside inhibitors | journal = Journal of Molecular Biology | volume = 312 | issue = 4 | pages = 795–805 | year = 2001 | pmid = 11575933 | doi = 10.1006/jmbi.2001.4988 }}</ref><ref>{{cite journal | last1 = Das | first1 = K | last2 = Ding | first2 = J | last3 = Hsiou | first3 = Y | last4 = Clark Jr | first4 = AD | last5 = Moereels | first5 = H | last6 = Koymans | first6 = L | last7 = Andries | first7 = K | last8 = Pauwels | first8 = R | last9 = Janssen | first9 = PA | last10 = Boyer | first10 = Paul L. | last11 = Clark | first11 = Patrick | last12 = Smith | first12 = Richard H. | last13 = Kroeger Smith | first13 = Marilyn B. | last14 = Michejda | first14 = Christopher J. | last15 = Hughes | first15 = Stephen H. | last16 = Arnold | first16 = Edward | title = Crystal structures of 8-Cl and 9-Cl TIBO complexed with wild-type HIV-1 RT and 8-Cl TIBO complexed with the Tyr181Cys HIV-1 RT drug-resistant mutant | journal = Journal of Molecular Biology | volume = 264 | issue = 5 | pages = 1085–100 | year = 1996 | pmid = 9000632 | doi=10.1006/jmbi.1996.0698| display-authors = 8 }}</ref> The third type of mutations result in changes in the overall conformation or the size of the NNRTI binding pocket. An example is G190E, which creates a steric bulk in the pocket, leaving little or no room for an NNRTI to tightly bind.<ref>{{cite journal | last1 = Hsiou | first1 = Y | last2 = Das | first2 = K | last3 = Ding | first3 = J | last4 = Clark Jr | first4 = AD | last5 = Kleim | first5 = JP | last6 = Rösner | first6 = M | last7 = Winkler | first7 = I | last8 = Riess | first8 = G | last9 = Hughes | first9 = SH | last10 = Arnold | first10 = Edward | title = Structures of Tyr188Leu mutant and wild-type HIV-1 reverse transcriptase complexed with the non-nucleoside inhibitor HBY 097: inhibitor flexibility is a useful design feature for reducing drug resistance | journal = Journal of Molecular Biology | volume = 284 | issue = 2 | pages = 313–23 | year = 1998 | pmid = 9813120 | doi = 10.1006/jmbi.1998.2171 | display-authors = 8 }}</ref><ref>{{cite journal | last1 = Ren | first1 = J | last2 = Esnouf | first2 = R | last3 = Garman | first3 = E | last4 = Somers | first4 = D | last5 = Ross | first5 = C | last6 = Kirby | first6 = I | last7 = Keeling | first7 = J | last8 = Darby | first8 = G | last9 = Jones | first9 = Y | last10 = Stuart | first10 = David | last11 = Stammers | first11 = David | title = High resolution structures of HIV-1 RT from four RT-inhibitor complexes | journal = Nature Structural Biology | volume = 2 | issue = 4 | pages = 293–302 | year = 1995 | pmid = 7540934 | doi = 10.1038/nsb0495-293 | s2cid = 34618424 | display-authors = 8 }}</ref>