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• W2961396114 abstract "The rising prevalence of HIV drug resistance (HIVDR) could threaten gains made in combating the HIV epidemic and compromise the 90-90-90 target proposed by United Nations Programme on HIV/AIDS (UNAIDS) to have achieved virological suppression in 90% of all persons receiving antiretroviral therapy (ART) by the year 2020. HIVDR has implications for the persistence of HIV, the selection of current and future ART drug regimens, and strategies of vaccine and cure development. Focusing on drug classes that are in clinical use, this Review critically summarizes what is known about the mechanisms the virus utilizes to escape drug control. Armed with this knowledge, strategies to limit the expansion of HIVDR are proposed. The rising prevalence of HIV drug resistance (HIVDR) could threaten gains made in combating the HIV epidemic and compromise the 90-90-90 target proposed by United Nations Programme on HIV/AIDS (UNAIDS) to have achieved virological suppression in 90% of all persons receiving antiretroviral therapy (ART) by the year 2020. HIVDR has implications for the persistence of HIV, the selection of current and future ART drug regimens, and strategies of vaccine and cure development. Focusing on drug classes that are in clinical use, this Review critically summarizes what is known about the mechanisms the virus utilizes to escape drug control. Armed with this knowledge, strategies to limit the expansion of HIVDR are proposed. Enormous gains have been made since the advent of combined antiretroviral therapy (ART), resulting in reduced HIV-associated mortality and morbidity. 36.9 million people are living with HIV, of whom 21.7 million receive ART (UNAIDS, 2018UNAIDSGlobal HIV & AIDS statistics — 2018 fact sheet.https://www.unaids.org/en/resources/fact-sheetDate: 2018Google Scholar). Over the past two decades, non-nucleoside reverse transcriptase (RT) inhibitor (NNRTI)-based triple-combination therapy has been the predominant first-line treatment. NNRTIs were initially combined with nucleoside/tide RT inhibitors (NRTIs), including lamivudine (3TC), zidovudine (AZT), or stavudine (D4T). The thymidine analogs were subsequently replaced with tenofovir (TDF) (World Health Organization, 2013World Health Organization (2013). Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection.Google Scholar). The rate of virological failure (VF) among individuals in low- and middle-income countries (LMICs) on first-line ART is around 20% (Boender et al., 2015Boender T.S. Sigaloff K.C. McMahon J.H. Kiertiburanakul S. Jordan M.R. Barcarolo J. Ford N. Rinke de Wit T.F. Bertagnolio S. Long-term Virological Outcomes of First-Line Antiretroviral Therapy for HIV-1 in Low- and Middle-Income Countries: A Systematic Review and Meta-analysis.Clin. Infect. Dis. 2015; 61: 1453-1461Crossref PubMed Scopus (52) Google Scholar). Although poor adherence is implicated as the initial cause for VF, resuppression can occur on the same regimen, even with drug resistance mutations (Gupta et al., 2014Gupta R.K. Goodall R.L. Ranopa M. Kityo C. Munderi P. Lyagoba F. Mugarura L. Gilks C.F. Kaleebu P. Pillay D. DART Virology Group and Trial TeamHigh rate of HIV resuppression after viral failure on first-line antiretroviral therapy in the absence of switch to second-line therapy.Clin. Infect. Dis. 2014; 58: 1023-1026Crossref PubMed Google Scholar). HIV drug resistance (HIVDR) accumulates as VF continues and necessitates a treatment switch to second-line, protease inhibitor (PI)-based triple-combination therapy (Boender et al., 2016Boender T.S. Kityo C.M. Boerma R.S. Hamers R.L. Ondoa P. Wellington M. Siwale M. Nankya I. Kaudha E. Akanmu A.S. et al.Accumulation of HIV-1 drug resistance after continued virological failure on first-line ART in adults and children in sub-Saharan Africa.J. Antimicrob. Chemother. 2016; 71: 2918-2927Crossref PubMed Scopus (27) Google Scholar, Goodall et al., 2017Goodall R.L. Dunn D.T. Nkurunziza P. Mugarura L. Pattery T. Munderi P. Kityo C. Gilks C. Kaleebu P. Pillay D. Gupta R.K. DART Virology GroupRapid accumulation of HIV-1 thymidine analogue mutations and phenotypic impact following prolonged viral failure on zidovudine-based first-line ART in sub-Saharan Africa.J. Antimicrob. Chemother. 2017; 72: 1450-1455Crossref PubMed Scopus (5) Google Scholar). This acquired drug resistance (ADR) in individuals failing first-line ART is high in various regions of the world. Up to half of patients in sub-Saharan Africa (SSA) failing TDF-containing ART have resistance to all three drugs in the regimen (Gregson et al., 2017Gregson J. Kaleebu P. Marconi V.C. van Vuuren C. Ndembi N. Hamers R.L. Kanki P. Hoffmann C.J. Lockman S. Pillay D. et al.Occult HIV-1 drug resistance to thymidine analogues following failure of first-line tenofovir combined with a cytosine analogue and nevirapine or efavirenz in sub Saharan Africa: a retrospective multi-centre cohort study.Lancet Infect. Dis. 2017; 17: 296-304Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, TenoRes Study Group, 2016TenoRes Study GroupGlobal epidemiology of drug resistance after failure of WHO recommended first-line regimens for adult HIV-1 infection: a multicentre retrospective cohort study.Lancet Infect. Dis. 2016; 16: 565-575Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar). Transmission of these drug-resistant HIV strains has inevitably resulted in infected individuals presenting with transmitted drug resistance (TDR) (Gupta et al., 2012Gupta R.K. Jordan M.R. Sultan B.J. Hill A. Davis D.H. Gregson J. Sawyer A.W. Hamers R.L. Ndembi N. Pillay D. Bertagnolio S. Global trends in antiretroviral resistance in treatment-naive individuals with HIV after rollout of antiretroviral treatment in resource-limited settings: a global collaborative study and meta-regression analysis.Lancet. 2012; 380: 1250-1258Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Gupta et al., 2018Gupta R.K. Gregson J. Parkin N. Haile-Selassie H. Tanuri A. Andrade Forero L. Kaleebu P. Watera C. Aghokeng A. Mutenda N. et al.HIV-1 drug resistance before initiation or re-initiation of first-line antiretroviral therapy in low-income and middle-income countries: a systematic review and meta-regression analysis.Lancet Infect. Dis. 2018; 18: 346-355Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, Rhee et al., 2015Rhee S.Y. Blanco J.L. Jordan M.R. Taylor J. Lemey P. Varghese V. Hamers R.L. Bertagnolio S. Rinke de Wit T.F. Aghokeng A.F. et al.Geographic and temporal trends in the molecular epidemiology and genetic mechanisms of transmitted HIV-1 drug resistance: an individual-patient- and sequence-level meta-analysis.PLoS Med. 2015; 12: e1001810Crossref PubMed Scopus (0) Google Scholar). In LMICs where drug-resistance testing is not available routinely, pre-treatment drug resistance is associated with an increased risk of VF (Ávila-Ríos et al., 2016Ávila-Ríos S. García-Morales C. Matías-Florentino M. Romero-Mora K.A. Tapia-Trejo D. Quiroz-Morales V.S. Reyes-Gopar H. Ji H. Sandstrom P. Casillas-Rodríguez J. et al.HIVDR MexNet GroupPretreatment HIV-drug resistance in Mexico and its impact on the effectiveness of first-line antiretroviral therapy: a nationally representative 2015 WHO survey.Lancet HIV. 2016; 3: e579-e591Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, Hamers et al., 2012Hamers R.L. Schuurman R. Sigaloff K.C. Wallis C.L. Kityo C. Siwale M. Mandaliya K. Ive P. Botes M.E. Wellington M. et al.PharmAccess African Studies to Evaluate Resistance (PASER) InvestigatorsEffect of pretreatment HIV-1 drug resistance on immunological, virological, and drug-resistance outcomes of first-line antiretroviral treatment in sub-Saharan Africa: a multicentre cohort study.Lancet Infect. Dis. 2012; 12: 307-317Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar), cessation of treatment (World Health Organization, 2017aWorld Health OrganizationGuidelines on the public health response to pretreatment HIV drug resistance, July 2017. World Health Organization, 2017Google Scholar), and death (Cambiano et al., 2013Cambiano V. Bertagnolio S. Jordan M.R. Lundgren J.D. Phillips A. Transmission of drug resistant HIV and its potential impact on mortality and treatment outcomes in resource-limited settings.J. Infect. Dis. 2013; 207: S57-S62Crossref PubMed Scopus (0) Google Scholar, Pinoges et al., 2015Pinoges L. Schramm B. Poulet E. Balkan S. Szumilin E. Ferreyra C. Pujades-Rodríguez M. Risk factors and mortality associated with resistance to first-line antiretroviral therapy: multicentric cross-sectional and longitudinal analyses.J. Acquir. Immune Defic. Syndr. 2015; 68: 527-535Crossref PubMed Scopus (8) Google Scholar). Surveillance reveals that the prevalence of pre-treatment drug resistance is rising, and NNRTI resistance has exceed 15% in a number of countries (Gupta et al., 2012Gupta R.K. Jordan M.R. Sultan B.J. Hill A. Davis D.H. Gregson J. Sawyer A.W. Hamers R.L. Ndembi N. Pillay D. Bertagnolio S. Global trends in antiretroviral resistance in treatment-naive individuals with HIV after rollout of antiretroviral treatment in resource-limited settings: a global collaborative study and meta-regression analysis.Lancet. 2012; 380: 1250-1258Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Gupta et al., 2018Gupta R.K. Gregson J. Parkin N. Haile-Selassie H. Tanuri A. Andrade Forero L. Kaleebu P. Watera C. Aghokeng A. Mutenda N. et al.HIV-1 drug resistance before initiation or re-initiation of first-line antiretroviral therapy in low-income and middle-income countries: a systematic review and meta-regression analysis.Lancet Infect. Dis. 2018; 18: 346-355Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, World Health Organization, 2012World Health OrganizationThe HIV drug resistance report - 2012. World Health Organization, 2012Google Scholar, World Health Organization, 2017bWorld Health OrganizationHIV drug resistance report 2017. World Health Organization, 2017Google Scholar). HIVDR has now been recognized as a threat to combating the HIV epidemic and an impediment to the Joint United Nations Programme on HIV/AIDS 90-90-90 by the 2020 target to achieve virological suppression in 90% of all persons receiving ART by the year 2020 (UNAIDS, 2014UNAIDS90-90-90 An ambitious treatment target to help end the AIDS epidemic.https://www.unaids.org/en/resources/909090Date: 2014Google Scholar). In this Review, we (1) examine how HIVDR is acquired under drug pressure, exploring the mechanisms of drug escape for all drug classes currently in clinical use, (2) describe other mechanisms of drug escape, (3) explore the contribution of HIV persistence and anatomical compartments to HIVDR, (4) discuss what the rise of HIVDR means for future treatment options and the landscape of HIV infections, and (5) suggest next steps to achieve HIVDR control and to limit the expansion of HIVDR to even further lines of treatment. HIV-1 evolution is driven by the need to evade host immunity. HIV has vast genetic diversity within and between individuals (Kearney et al., 2009Kearney M. Maldarelli F. Shao W. Margolick J.B. Daar E.S. Mellors J.W. Rao V. Coffin J.M. Palmer S. Human immunodeficiency virus type 1 population genetics and adaptation in newly infected individuals.J. Virol. 2009; 83: 2715-2727Crossref PubMed Scopus (107) Google Scholar). This is driven by a high replication rate, the absence of a proof-reading mechanism during reverse transcription (Mansky and Temin, 1995Mansky L.M. Temin H.M. Lower in vivo mutation rate of human immunodeficiency virus type 1 than that predicted from the fidelity of purified reverse transcriptase.J. Virol. 1995; 69: 5087-5094Crossref PubMed Google Scholar), and a high recombination rate that also propagates drug-resistance mutations and contributes to HIV-1 persistence and immunopathogenesis (Song et al., 2018Song H. Giorgi E.E. Ganusov V.V. Cai F. Athreya G. Yoon H. Carja O. Hora B. Hraber P. Romero-Severson E. et al.Tracking HIV-1 recombination to resolve its contribution to HIV-1 evolution in natural infection.Nat. Commun. 2018; 9: 1928Crossref PubMed Scopus (3) Google Scholar). HIV-1 recombination among parent viruses that are each resistant to a single drug can generate multidrug-resistant variants (Rawson et al., 2018Rawson J.M.O. Nikolaitchik O.A. Keele B.F. Pathak V.K. Hu W.S. Recombination is required for efficient HIV-1 replication and the maintenance of viral genome integrity.Nucleic Acids Res. 2018; 46: 10535-10545PubMed Google Scholar). Additionally, genetic diversity is broader in the presence of ART compared to drug-naive individuals. A cross-sectional study investigating HIV genetic sequences found greater diversity in ART-treated participants compared with ART-naive individuals (Haddad et al., 2000Haddad D.N. Birch C. Middleton T. Dwyer D.E. Cunningham A.L. Saksena N.K. Evidence for late stage compartmentalization of HIV-1 resistance mutations between lymph node and peripheral blood mononuclear cells.AIDS. 2000; 14: 2273-2281Crossref PubMed Scopus (30) Google Scholar). This inherent diversity has implications for the persistence of HIV, the selection of drug resistance mutations, and strategies of vaccine and cure development. NRTIs are purine/pyrimidine analogs and therefore competitive inhibitors of incoming deoxynucleotide triphosphates (dNTPs) that constitute the viral nucleic acid (NA). Most NRTIs lack a 3′-OH and act as chain terminators when they are incorporated into viral DNA by RT. RT has two enzymatic activities, a DNA polymerase that can copy either a DNA or an RNA template and a RNase H that cleaves RNA when complexed with DNA. RT is a heterodimer with two subunits: p66 and p51 (Figure 1A). The NA binding cleft or binding pocket is formed primarily by the p66 fingers, palm, thumb, connection and RNase H subdomains of p66. The connection and thumb subdomains of p51 form the floor of the binding cleft. Within the p66 subunit is the DNA primer grip, which helps to position the 3′-OH end of the primer strand at the polymerase active site (Sarafianos et al., 2001Sarafianos S.G. Das K. Tantillo C. Clark Jr., A.D. Ding J. Whitcomb J.M. Boyer P.L. Hughes S.H. Arnold E. Crystal structure of HIV-1 reverse transcriptase in complex with a polypurine tract RNA:DNA.EMBO J. 2001; 20: 1449-1461Crossref PubMed Scopus (330) Google Scholar). Also within the polymerase active site in the p66 palm subunit is the YMDD loop, which coordinates the catalytic carboxylates (D110, D185, and D186) that bind to divalent metal ions required for catalysis (Hsiou et al., 1996Hsiou Y. Ding J. Das K. Clark Jr., A.D. Hughes S.H. Arnold E. Structure of unliganded HIV-1 reverse transcriptase at 2.7 A resolution: implications of conformational changes for polymerization and inhibition mechanisms.Structure. 1996; 4: 853-860Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Rodgers et al., 1995Rodgers D.W. Gamblin S.J. Harris B.A. Ray S. Culp J.S. Hellmig B. Woolf D.J. Debouck C. Harrison S.C. The structure of unliganded reverse transcriptase from the human immunodeficiency virus type 1.Proc. Natl. Acad. Sci. USA. 1995; 92: 1222-1226Crossref PubMed Scopus (0) Google Scholar). Mechanisms of resistance are as follows.(1)Exclusion. These mutations are in the finger or palm of RT and affect the binding of an incoming dNTP. M184V and K65R increase discrimination between the dNTP and NRTIs, thereby reducing incorporation of the NRTI into the growing DNA chain. M184V/I selectively reduces the incorporation of 3TC and emtricitabine (FTC) by steric hindrance (Gao et al., 2000Gao H.Q. Boyer P.L. Sarafianos S.G. Arnold E. Hughes S.H. The role of steric hindrance in 3TC resistance of human immunodeficiency virus type-1 reverse transcriptase.J. Mol. Biol. 2000; 300: 403-418Crossref PubMed Scopus (0) Google Scholar, Sarafianos et al., 1999Sarafianos S.G. Das K. Clark Jr., A.D. Ding J. Boyer P.L. Hughes S.H. Arnold E. Lamivudine (3TC) resistance in HIV-1 reverse transcriptase involves steric hindrance with beta-branched amino acids.Proc. Natl. Acad. Sci. USA. 1999; 96: 10027-10032Crossref PubMed Scopus (0) Google Scholar). K65R reduces the rate of both nucleotide and TDF incorporation (Gu et al., 1995Gu Z. Arts E.J. Parniak M.A. Wainberg M.A. Mutated K65R recombinant reverse transcriptase of human immunodeficiency virus type 1 shows diminished chain termination in the presence of 2′,3′-dideoxycytidine 5′-triphosphate and other drugs.Proc. Natl. Acad. Sci. USA. 1995; 92: 2760-2764Crossref PubMed Scopus (70) Google Scholar, White et al., 2006White K.L. Chen J.M. Feng J.Y. Margot N.A. Ly J.K. Ray A.S. Macarthur H.L. McDermott M.J. Swaminathan S. Miller M.D. The K65R reverse transcriptase mutation in HIV-1 reverses the excision phenotype of zidovudine resistance mutations.Antivir. Ther. (Lond.). 2006; 11: 155-163PubMed Google Scholar) but also increases susceptibility to AZT by decreasing AZT excision (Parikh et al., 2007Parikh U.M. Zelina S. Sluis-Cremer N. Mellors J.W. Molecular mechanisms of bidirectional antagonism between K65R and thymidine analog mutations in HIV-1 reverse transcriptase.AIDS. 2007; 21: 1405-1414Crossref PubMed Scopus (0) Google Scholar, White et al., 2005White K.L. Margot N.A. Ly J.K. Chen J.M. Ray A.S. Pavelko M. Wang R. McDermott M. Swaminathan S. Miller M.D. A combination of decreased NRTI incorporation and decreased excision determines the resistance profile of HIV-1 K65R RT.AIDS. 2005; 19: 1751-1760Crossref PubMed Google Scholar). L74V causes resistance by disrupting the hydrogen-bonding network that involves 3-OH and is specific for didanosine (ddI) and abacavir (ABC) (Deval et al., 2004Deval J. Navarro J.M. Selmi B. Courcambeck J. Boretto J. Halfon P. Garrido-Urbani S. Sire J. Canard B. A loss of viral replicative capacity correlates with altered DNA polymerization kinetics by the human immunodeficiency virus reverse transcriptase bearing the K65R and L74V dideoxynucleoside resistance substitutions.J. Biol. Chem. 2004; 279: 25489-25496Crossref PubMed Scopus (73) Google Scholar, Martin et al., 1993Martin J.L. Wilson J.E. Haynes R.L. Furman P.A. Mechanism of resistance of human immunodeficiency virus type 1 to 2′,3′-dideoxyinosine.Proc. Natl. Acad. Sci. USA. 1993; 90: 6135-6139Crossref PubMed Scopus (67) Google Scholar, Miranda et al., 2005Miranda L.R. Götte M. Liang F. Kuritzkes D.R. The L74V mutation in human immunodeficiency virus type 1 reverse transcriptase counteracts enhanced excision of zidovudine monophosphate associated with thymidine analog resistance mutations.Antimicrob. Agents Chemother. 2005; 49: 2648-2656Crossref PubMed Scopus (48) Google Scholar).(2)Excision. This resistance mechanism involves pyrophosphorolysis, a hydrolysis reaction that removes the chain-terminating residue and enables reverse transcription and DNA synthesis to resume. Thymidine analog mutations enhance removal of drug from its attachment at the end of the DNA chain (Table 1). Combinations of these mutations give rise to high levels of resistance to AZT and also resistance to other NRTIs (Boyer et al., 2001Boyer P.L. Sarafianos S.G. Arnold E. Hughes S.H. Selective excision of AZTMP by drug-resistant human immunodeficiency virus reverse transcriptase.J. Virol. 2001; 75: 4832-4842Crossref PubMed Scopus (0) Google Scholar, Meyer et al., 1999Meyer P.R. Matsuura S.E. Mian A.M. So A.G. Scott W.A. A mechanism of AZT resistance: an increase in nucleotide-dependent primer unblocking by mutant HIV-1 reverse transcriptase.Mol. Cell. 1999; 4: 35-43Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar).Table 1Mechanism of HIV Drug Resistance to ARTs in Clinical UseDrug ClassActionDrug and Associated MutationsResistance MechanismNucleotide/side reverse transcription inhibitorCompetitive inhibitor of viral nucleic acid. Drugs lack a 3′-OH and act as chain terminators when they are incorporated into elongating viral DNA by RT.3TC and FTC -M184VTDF and ddI- K65RExclusion. Causes a conformational change in the NA binding cleft that allows better discrimination of incoming dNTPs over drug.AZT, d4T, ddI-Q151M complex ddI and ABC- L74VExclusion. Alters the hydrogen bonding networks between RT and incoming deoxyribose, allowing better discrimination of dNTP over drug.AZT-TAMs: M41L, D67N, K70R, L210W, T215F/Y, and K219E/QT69 insertionExcision. Pyrophosphorolysis: RT enzyme-mediated reaction that removes the chain-terminating residue and allow reverse transcription to continue.AZT- T369V/IAZT- N348IConnection domain mutations. Decreases RNase H activity through poorly defined mechanism.AZT and D4T-D549N, H539NAZT, 3TC and ABC- Q509LRNase H mutations. Decreases RNase H activity and thus reduces RNA template degradation, allowing more efficient excision of AZT. Q509L alters the RNase primer grip, which affects the proximity of the RNA/DNA complex to the RNase H and thus degradation efficiency.Non-nucleotide reverse transcription inhibitorsAllosteric inhibition of RT. The binding pocket is located ∼10 Å from the polymerase active site.All- Y181CEFV, NVP, RPV-Y188LRPV- F227LLoss/change of key hydrophobic interactions. Causes loss of loss of the aromatic ring interactions with NNRTIs.All- K100IEFV and NVP- G190ASteric hindrance. Changes the shape of the binding pocketEFV - K103NETR and RPV- K101EETR and RPV- E138KPocket entrance mutations. Affect the binding pocket and interferes with the entry/exit of NNRTIs in and out of the pocketProtease inhibitorsCompetitive inhibitors of the protease enzyme. Bind at the catalytic site of the protease enzyme with high affinity, thus blocking activity.ATV- I50L, I84V, N88SDRV- I47V, I50V, I54M/L, I84V, LPV- V32I, I47V/A, L76V, V82A/F/T/SMajor mutations. Amino acid mutations that arise within or proximal to the catalytic binding site to the drug. Enlarge the binding cleft, thus reducing the affinity of the PI. The drugs also affect the protease flap dynamicsATV- L10I/F/V/C, G16E, K20R/M/I/T/V, L24I, L33I/F/V, E34Q, M36I/L/V, M46I/L, F53L/Y, D60E, I62V, I64L/M/V, A71V/I/T/L, G73C/S/T/A, V82A/T/F/I, I85V, L90M, I93L/MDRV- V11I, L33F, T74P, L89VLPV- L10F/I/R/V, K20M/R, L24I, L33F, M46I/L, I50V, F53L, I54V/L/A/M/T/S, L63P, A71V/T, G73S, I84V, L90MMinor mutations. Affect PI susceptibility through complementary mechanisms. Refer to main text.NC/p1 site- A431V, K436E, I437T/VP1/p6 site- L449FGag cleavage site mutations. Enhance efficiency of gag cleavage.Envelope gp41 mutationsUnknown mechanism.Integrase strand transfer inhibitorsSelectively inhibit strand transfer that integrates the proviral DNA into the host’s genome.RAL and EVGE92QV/N155HMutations in the CCD-.Around the catalytic triad that coordinate two Mg2+ required for IN catalyzes. N155 is not in direct contact with INSTIs but leads to conformational change of the catalytic pocket.RAL, EVG, DTG and BIC- G140CS/Q148HKRConfers cross-resistance to all INSTIs in clinical use. Q148 mutations affect conformational change of the catalytic pocket.RAL- T97A/Y143CHRY143 is in direct contact with RAL in the catalytic pocket. Mutation affects binding of RAL to the catalytic pocket.RAL-T66IR/S153/F121Mutations in the CCD around the catalytic triad that coordinate the two Mg2+ required for IN catalyzes.DTG and BIC- R263K/S153/F121Mutations in the CTD. Involved in acetylation regulation, which enhances DNA binding. The mechanism is incompletely understood.3ʹ-polypurine tract mutationsPrevents plus strand syntheses by interfering with RNA primer binding.four 5′ terminal bases of the LTRDecreases binding of INSTIs to integrase.Entry inhibitors (fusion inhibitors, CCR5 co-receptor antagonist)Peptide mimetics of HR2. Selectively inhibit the function of gp41. Allosteric inhibitors of CCR5.ENF- HR1 mutations: G36D/S, V38A, Q40H, N42T/E/S, N43D/S/K, L44M, L45MMVC-tropism shiftMVC-Gp120 mutations: P13S/G15GA, I20F/A25D/I26V, T2I/G11S/I26V/V34A, and N13H/I2T/R18K/T22AMechanism not fully understood. Drug-resistant mutation disrupts HR1- HR2 interaction, which may increase discrimination between the fusion inhibitors and the native HR2 from CCR5 to CXCR4 or dual tropic. Mechanism not fully understood. Virus gp120 is able to bind to the drug-bound form of CCR5.RT, reverse transcriptase; dNTP, deoxynucleotide triphosphate; CCD, catalytic core domain; CTD, C-terminal domain; NRTI, nucleotide/side reverse transcription inhibitor; NNRTI, non-nucleotide reverse transcription inhibitor; PI, protease inhibitor; INSTI, integrase strand transfer inhibitor; 3TC, lamivudine; FTC, emtricitabine; TDF, tenofovir; ddI, didanosine; AZT, zidovudine; D4T, stavudine; TAMs, thymidine analog mutations; EFV, efavirenz; NVP, nevirapine; ETR, etravirine; RPV, rilpivirine; RAL, raltegravir; EVG, elvitegravir; DTG, dolutegravir; HR1; heptad repeat 1, HR2; heptad repeat 2. Open table in a new tab (3)Connection domain mutations. The connection domain (CN) is one of five subdomains of RT and acts as a tether between polymerase and RNase H. CN mutations in the context of thymidine analog mutations increase resistance to AZT by 500-fold (Nikolenko et al., 2007Nikolenko G.N. Delviks-Frankenberry K.A. Palmer S. Maldarelli F. Fivash Jr., M.J. Coffin J.M. Pathak V.K. Mutations in the connection domain of HIV-1 reverse transcriptase increase 3′-azido-3′-deoxythymidine resistance.Proc. Natl. Acad. Sci. USA. 2007; 104: 317-322Crossref PubMed Scopus (0) Google Scholar).(4)RNase H mutations. These mutations decrease RNase H activity and RNA template degradation, allowing more time for AZT-MP to be excised from the terminated primer (Nikolenko et al., 2005Nikolenko G.N. Palmer S. Maldarelli F. Mellors J.W. Coffin J.M. Pathak V.K. Mechanism for nucleoside analog-mediated abrogation of HIV-1 replication: balance between RNase H activity and nucleotide excision.Proc. Natl. Acad. Sci. USA. 2005; 102: 2093-2098Crossref PubMed Scopus (0) Google Scholar). RT, reverse transcriptase; dNTP, deoxynucleotide triphosphate; CCD, catalytic core domain; CTD, C-terminal domain; NRTI, nucleotide/side reverse transcription inhibitor; NNRTI, non-nucleotide reverse transcription inhibitor; PI, protease inhibitor; INSTI, integrase strand transfer inhibitor; 3TC, lamivudine; FTC, emtricitabine; TDF, tenofovir; ddI, didanosine; AZT, zidovudine; D4T, stavudine; TAMs, thymidine analog mutations; EFV, efavirenz; NVP, nevirapine; ETR, etravirine; RPV, rilpivirine; RAL, raltegravir; EVG, elvitegravir; DTG, dolutegravir; HR1; heptad repeat 1, HR2; heptad repeat 2. NNRTIs are allosteric inhibitors of RT. Although the NNRTIs in clinical use—nevirapine (NVP), efavirenz (EFV), etravirine (ETR), and rilpivirine (RPV)—are chemically diverse, they all bind the same hydrophobic pocket, distinct from the polymerase active site (Das et al., 2005Das K. Lewi P.J. Hughes S.H. Arnold E. Crystallography and the design of anti-AIDS drugs: conformational flexibility and positional adaptability are important in the design of non-nucleoside HIV-1 reverse transcriptase inhibitors.Prog. Biophys. Mol. Biol. 2005; 88: 209-231Crossref PubMed Scopus (0) Google Scholar) (Figure 1B). Structural studies show that RT bound to NVP causes a conformational change in the primer grip within the p66 thumb subunit, leaving it in a locked, hyperextended position. This alters the alignment of the DNA primer with the polymerase active site and impairs polymerase activity (Hsiou et al., 1996Hsiou Y. Ding J. Das K. Clark Jr., A.D. Hughes S.H. Arnold E. Structure of unliganded HIV-1 reverse transcriptase at 2.7 A resolution: implications of conformational changes for polymerization and inhibition mechanisms.Structure. 1996; 4: 853-860Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). In addition, binding of RT with NNRTI distorts the YMDD loop of the polymerase active site such that its catalytic carboxylates cannot bind the metal cofactors, which affects translocation of the NA that normally occurs after the incorporation of each nucleotide (Das et al., 2007Das K. Sarafianos S.G. Clark Jr., A.D. Boyer P.L. Hughes S.H. Arnold E. Crystal structures of clinically relevant Lys103Asn/Tyr181Cys double mutant HIV-1 reverse transcriptase in complexes with ATP and non-nucleoside inhibitor HBY 097.J. Mol. Biol. 2007; 365: 77-89Crossref PubMed Scopus (0) Google Scholar). NMR studies demonstrate that the NNRTI binding site is highly plastic in the ligand-free enzyme. However, this conformational plasticity is reduced upon RT/`NNRTI binding, with the NNRTI binding pocket becoming more rigid (Sharaf et al., 2016Sharaf N.G. Ishima R. Gronenborn A.M. Conformational Plasticity of the NNRTI-Binding Pocket in HIV-1 Reverse Transcriptase: A Fluorine Nuclear Magnetic Resonance Study.Biochemistry. 2016; 55: 3864-3873Crossref PubMed Scopus (9) Google Scholar). Drug-resistant variants—K103N, V108I, and E138K—modulate this conformational plasticity, with K103N having the biggest effect (Sharaf et al., 2016Sharaf N.G. Ishima R. Gronenborn A.M. Conformational Plasticity of the NNRTI-Binding Pocket in HIV-1 Reverse Transcriptase: A Fluorine Nuclear Magnetic Resonance Study.Biochemistry. 2016; 55: 3864-3873Crossref PubMed Scopus (9) Google Scholar). Mechanisms of resistance are as follows.(1)Loss/change of key hydrophobic interactions. Y181C, Y188L and F227L cause loss of the aromatic ring interactions with NNRTIs (Das et al., 1996Das K. Ding J. Hsiou Y. Clark Jr., A.D. Moereels H. Koymans L. Andries K. Pauwels R. Janssen P.A. Boyer P.L. et al.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.J. Mol. Biol. 1996; 264: 1085-1100Crossref PubMed Scopus (0) Google Scholar, Ren et al., 2001Ren J. Nichols C. Bird L. Chamberlain P. Weaver K. Short S. Stuart D.I. Stammers D.K. Structural mech" @default.
• W2961396114 created "2019-07-23" @default.
• W2961396114 creator A5036869978 @default.
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• W2961396114 creator A5062153742 @default.
• W2961396114 date "2019-07-01" @default.
• W2961396114 modified "2023-10-11" @default.
• W2961396114 title "The Impact of HIV-1 Drug Escape on the Global Treatment Landscape" @default.
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