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Reverse-transcriptase inhibitor
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===NRTI resistance=== There are two major mechanisms of NRTI resistance. The first being reduced incorporation of the nucleotide analog into DNA over the normal nucleotide. This results from mutations in the N-terminal polymerase domain of the reverse transcriptase that reduce the enzyme's affinity or ability to bind to the drug . A prime example for this mechanism is the M184V mutation that confers resistance to lamivudine (3TC) and emtricitabine (FTC).<ref>{{cite journal |last1 = Hachiya | first1 = A | last2 = Kodama | first2 = EN | last3 = Schuckmann | first3 = MM | last4 = Kirby | first4 = KA | last5 = Michailidis | first5 = E | last6 = Sakagami | first6 = Y | last7 = Oka | first7 = S | last8 = Singh | first8 = K | last9 = Sarafianos | first9 = SG | editor1-last = Ambrose | editor1-first = Zandrea |title=K70Q adds high-level tenofovir resistance to "Q151M complex" HIV reverse transcriptase through the enhanced discrimination mechanism |journal=PLOS ONE |volume=6 |issue=1 |pages=e16242 |year=2011 |pmid=21249155 |pmc=3020970 |doi=10.1371/journal.pone.0016242 | bibcode = 2011PLoSO...616242H | doi-access = free |bibcode-access=free }}</ref><ref>{{cite journal | last1 = Sarafianos | first1 = SG | last2 = Das | first2 = K | last3 = Clark Jr | first3 = AD | last4 = Ding | first4 = J | last5 = Boyer | first5 = PL | last6 = Hughes | first6 = SH | last7 = Arnold | first7 = E | title = Lamivudine (3TC) resistance in HIV-1 reverse transcriptase involves steric hindrance with beta-branched amino acids |bibcode-access=free | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 18 | pages = 10027β32 | year = 1999 | pmid = 10468556 | pmc = 17836 | doi=10.1073/pnas.96.18.10027| bibcode = 1999PNAS...9610027S | doi-access = free }}</ref> Another well characterized set of mutations is the Q151M complex found in multi-drug resistant HIV which decreases reverse transcriptase's efficiency at incorporating NRTIs, but does not affect natural nucleotide incorporation. The complex includes Q151M mutation along with A62V, V75I, F77L, and F116Y.<ref>{{cite journal | last1 = Shafer | first1 = RW | last2 = Kozal | first2 = MJ | last3 = Winters | first3 = MA | last4 = Iversen | first4 = AK | last5 = Katzenstein | first5 = DA | last6 = Ragni | first6 = MV | last7 = Meyer | first7 = WA III | last8 = Gupta | first8 = P | last9 = Rasheed | first9 = S | last10 = Coombs | first10 = R. | last11 = Katzman | first11 = M. | last12 = Fiscus | first12 = S. | last13 = Merigan | first13 = T. C. | title = Combination therapy with zidovudine and didanosine selects for drug-resistant human immunodeficiency virus type 1 strains with unique patterns of ''pol'' gene mutations | journal = The Journal of Infectious Diseases | volume = 169 | issue = 4 | pages = 722β9 | year = 1994 | pmid = 8133086 | doi = 10.1093/infdis/169.4.722 | display-authors = 8 }}</ref><ref>{{cite journal | last1 = Iversen | first1 = AK | last2 = Shafer | first2 = RW | last3 = Wehrly | first3 = K | last4 = Winters | first4 = MA | last5 = Mullins | first5 = JI | last6 = Chesebro | first6 = B | last7 = Merigan | first7 = TC | title = Multidrug-resistant human immunodeficiency virus type 1 strains resulting from combination antiretroviral therapy | journal = Journal of Virology | volume = 70 | issue = 2 | pages = 1086β90 | year = 1996 | pmid = 8551567 | pmc = 189915 | doi = 10.1128/JVI.70.2.1086-1090.1996 |doi-access=free }}</ref> A virus with Q151M alone is intermediately resistant to zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), and slightly resistant to abacavir (ABC).<ref>{{cite journal | last1 = Maeda | first1 = Y | last2 = Venzon | first2 = DJ | last3 = Mitsuya | first3 = H | title = Altered drug sensitivity, fitness, and evolution of human immunodeficiency virus type 1 with pol gene mutations conferring multi-dideoxynucleoside resistance | journal = The Journal of Infectious Diseases | volume = 177 | issue = 5 | pages = 1207β13 | year = 1998 | pmid = 9593005 | doi = 10.1086/515282 | doi-access = }}</ref><ref name="Pmid">{{cite journal | last1 = Matsumi | first1 = S | last2 = Kosalaraksa | first2 = P | last3 = Tsang | first3 = H | last4 = Kavlick | first4 = MF | last5 = Harada | first5 = S | last6 = Mitsuya | first6 = H | title = Pathways for the emergence of multi-dideoxynucleoside-resistant HIV-1 variants | journal = AIDS | volume = 17 | issue = 8 | pages = 1127β37 | year = 2003 | pmid = 12819513 | doi = 10.1097/00002030-200305230-00003| s2cid = 21484628 | doi-access = free }}</ref> A virus with Q151M complexed with the other four mutations becomes highly resistant to the above drugs, and is additionally resistant to lamivudine (3TC) and emtricitabine (FTC).<ref name="Pmid" /><ref>{{cite journal | last1 = Gao | first1 = HQ | last2 = Boyer | first2 = PL | last3 = Sarafianos | first3 = SG | last4 = Arnold | first4 = E | last5 = Hughes | first5 = SH | title = The role of steric hindrance in 3TC resistance of human immunodeficiency virus type-1 reverse transcriptase | journal = Journal of Molecular Biology | volume = 300 | issue = 2 | pages = 403β18 | year = 2000 | pmid = 10873473 | doi = 10.1006/jmbi.2000.3823 | url = https://zenodo.org/record/1229892 }}</ref> The second mechanism is the excision or the hydrolytic removal of the incorporated drug or [[pyrophosphate|pyrophosphorolysis]]. This is a reverse of the polymerase reaction in which the pyrophosphate/PPI released during nucleotide incorporation reacts with the incorporated drug (monophosphate) resulting in the release of the triphosphate drug. This 'unblocks' the DNA chain, allowing it to be extended, and replication to continue.<ref name="Pmid_a">{{cite journal | last1 = Meyer | first1 = PR | last2 = Matsuura | first2 = SE | last3 = Mian | first3 = AM | last4 = So | first4 = AG | last5 = Scott | first5 = WA | title = A mechanism of AZT resistance: an increase in nucleotide-dependent primer unblocking by mutant HIV-1 reverse transcriptase | journal = Molecular Cell | volume = 4 | issue = 1 | pages = 35β43 | year = 1999 | pmid = 10445025 |doi = 10.1016/S1097-2765(00)80185-9 | doi-access = free }}</ref> Excision enhancement mutations, typically M41L, D67N, K70R, L210W, T215Y/F, and K219E/Q, are selected for by thymidine analogs AZT and D4T; and are therefore called thymidine analog mutations (TAMs).<ref name="Pmid_a" /><ref>{{cite journal | last1 = Boyer | first1 = PL | last2 = Sarafianos | first2 = SG | last3 = Arnold | first3 = E | last4 = Hughes | first4 = SH | title = Selective excision of AZTMP by drug-resistant human immunodeficiency virus reverse transcriptase | journal = Journal of Virology | volume = 75 | issue = 10 | pages = 4832β42 | year = 2001 | pmid = 11312355 | pmc = 114238 | doi = 10.1128/JVI.75.10.4832-4842.2001 }}</ref><ref>{{cite journal | last1 = Arion | first1 = D | last2 = Kaushik | first2 = N | last3 = McCormick | first3 = S | last4 = Borkow | first4 = G | last5 = Parniak | first5 = MA | title = Phenotypic mechanism of HIV-1 resistance to 3'-azido-3'-deoxythymidine (AZT): increased polymerization processivity and enhanced sensitivity to pyrophosphate of the mutant viral reverse transcriptase | journal = Biochemistry | volume = 37 | issue = 45 | pages = 15908β17 | year = 1998 | pmid = 9843396 | doi = 10.1021/bi981200e }}</ref> Other mutations including insertions and deletions in the background of the above mutations also confer resistance via enhanced excision.<ref name="Pmid" />
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