Major Nucleoside RT Inhibitor (NRTI) Resistance Mutations
The table lists the most common clinically significant NRTI-resistance mutations. Mutations in bold red are associated with the highest levels of reduced susceptibility or virological response to the relevant NRTI. Mutations in bold reduce NRTI susceptibility or virological response. Mutations in plain text contribute to reduced susceptibility in combination with other NRTI-resistance mutations.
M184V/I are selected by 3TC/FTC and reduce susceptibility to these drugs >100-fold. They are also selected by and cause low-level resistance to ABC and ddI (1,2,3,4,5,6,7,8,9,10,11,12,13,14,15). In contrast, M184V/I increase susceptibility to AZT, d4T and TDF (16,17,18,19,3,20,4,5,13,21) and slows the emergence of AZT, d4T, and TDF resistance (22,23,24,17,25,26,27,28,29,30). M184V/I are associated with reduced viral replication in vitro and in vivo (31,32,33,34,35,36,37). M184I usually emerges before M184V because it results from a more common HIV-1 nucleotide substitution (38). However, M184V outcompetes M184I within several weeks of viral replication and is found in most patients with virological failure on 3TC or FTC (39,31).
K65R is selected by TDF, ABC, d4T, ddI, and rarely 3TC (40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59). It reduces TDF, ABC and ddI susceptibility ~2-fold and d4T susceptibility ~1.5-fold in the PhenoSense assay (60) –reductions that are well above the highest reductions observed in viruses from ARV-naïve patients (61,4,62,14,6,63). K65R + M184V/I appear sufficient to abrogate the NRTI activity of a regimen comprising ABC, TDF, or d4T plus a cytosine analog suggesting that despite the relatively low-levels of reduced susceptibility associated with K65R, this mutation is highly clinically relevant. K65R reduces 3TC and FTC susceptibility about 5 to 10-fold (3,64). This is considered low-level / intermediate resistance for these NRTIs because they have a much wider dynamic susceptibility range (the most resistant viruses have >200-fold reduced susceptibility to 3TC and FTC) and because K65R alone is usually not sufficient to abrogate the activity of 3TC and FTC in vivo. K65R is also selected by TAF and has a similar effect on TAF susceptibility as it does on TDF susceptibility (65).
K65R increases AZT susceptibility, except when it occurs in combination with Q151M (4,62,66,67,22,5,6,68,69,70,4). K65R rarely occurs in combination with TAMs because K65R and most TAMs exhibit bidirectional antagonism (68,71,72,73).
Several lines of evidence suggest that K65R is more likely to emerge in subtype C viruses than viruses belonging to other subtypes. First, biochemical studies have shown that the unique subtype C sequence context in the region of K65R, specifically – a span of five consecutive adenosines preceding the adenosine at the second position in the K65 codon – renders it more likely to be mutated during reverse transcription (74,75,72). Second, K65R has been reported to emerge more rapidly during in vitro passage of subtype C than subtype B viruses in the presence of TDF (76). Third, two retrospective studies have suggested that patients who develop VF on a TDF-containing regimen are at a somewhat higher risk of developing K65R if they are infected with a subtype C virus (77,78). Nonetheless, regardless of subtype, K65R is the most common NRTI-associated resistance mutation other than M184V to develop in patients receiving a TDF-containing regimen. There has also been no evidence that patients with subtype C viruses are at higher risk of developing VF on a TDF-containing regimen.
K65N is an uncommon NRTI-selected mutation that reduces susceptibility to TDF, 3TC/FTC, ABC and ddI (79,80,81,82). It has been reported primarily in patients receiving d4T or TDF plus 3TC/FTC (54,83,84,85). It also appears to increase susceptibility to AZT (80). K65E is an extremely rare, highly unfit NRTI-selected mutation (86) that usually occurs as part of an electrophoretic mixture with the wildtype K (63).
Thymidine Analog Mutations (TAMs)
TAMs are non-polymorphic mutations selected by the thymidine analogs AZT and d4T. They reduce NRTI susceptibility by facilitating primer unblocking (aka nucleotide excision, pyrophosphorolysis) (87,88,89,90,91,92,93). The classical TAMs — M41L, D67N, K70R, L210W, T215Y/F and K219Q/E — were first reported in patients receiving AZT monotherapy (94,95,96,97). Several additional mutations are selected by AZT and d4T and/or facilitate primer unblocking, including T215 revertant mutations, additional amino acid variants at the classical TAM positions, and accessory mutations at other positions that contribute to reduced NRTI susceptibility.
The TAMs occur in two distinct but overlapping patterns: Type 1, which includes M41L, L210W, and T215Y; and Type 2, which includes D67N, K70R, T215F, and K219Q/E (30,98,99,100,101). Type 1 TAMs have a greater negative impact on virological response to an ABC-, ddI-, or TDF-containing regimen than do Type 2 TAMs (8,11,7,102,30,103,104). The near-uniform development of M184V during most virological failures blunts the effects of the TAMs on AZT, d4T, and TDF susceptibility but is associated with further reductions in susceptibility to ABC and ddI.
(i) M41L usually occurs in combination with T215Y. Together, M41L and T215Y confer high-level resistance to AZT and d4T and low-to-intermediate-level resistance to ABC, ddI and TDF. (ii) D67N reduces susceptibility primarily to AZT and d4T. When present with other TAMs it is also associated with reduced susceptibility to ABC, ddI and TDF. (iii) K70R confers intermediate-level resistance to AZT and low-level resistance to d4T and TDF. (iv) L210W usually occurs in combination with M41L and T215Y. Together, M41L, L210W and T215Y confer high-level resistance to AZT and d4T and intermediate to high-level resistance to ABC, ddI and TDF. (v) T215Y/F confer intermediate-level resistance to AZT and d4T and low-level resistance to ABC, ddI and TDF. (vi) K219Q/E reduce susceptibility to AZT and d4T when present with other TAMs.
Patients primarily infected with strains containing T215Y/F often develop viruses with the following reversion mutations (105,106,107): T215C/D/S, from the mutation of TAT/C (Y) to TGT/C (C), GAT/C (D), or TCT/C (S); T215I/V, from the mutation of TTT/A (F) to ATT/A (I) or GTT/A (V); and T215E from an additional revertant mutation GAT/C (D) to GAA/G (D) (107,108,109). Some ARV–naive patients with T215 revertants may be at increased risk of developing virological failure on AZT- or d4T-containing first line regimens because in contrast to the wild type threonine (T), most revertants require just a single base-pair change to develop T215Y/F and because the presence of a revertant by standard sequencing may indicate the presence of T215Y/F as a minority variant (110,111,112,113).
Variants at TAM positions
D67G/E and K219N/R are also selected by AZT and d4T and appear to contribute to reduced NRTI susceptibility in combination with other TAMs (114,115,4). In contrast to K70R, K70E/G/Q/T/N/S are NRTI-selected mutations that appear to increase susceptibility to AZT and reduce susceptibility to the remaining NRTIs (40,116,117,118).
E40F, E44D/A and V118I contribute to reduced NRTI susceptibility primarily in combination with other TAMs (119,120,121,122,123,4). V118I is polymorphic and occurs in 2% to 3% of ARV-naive patients; E40F and E44D/A are nonpolymorphic. K43Q/N, E203K, H208Y, D218E, K223Q/E and L228H/R are poorly characterized nonpolymorphic NRTI-selected mutations that usually occur in combination with multiple other TAMs (124,125,115,126,127).
K70E/G/Q/T/N/S are an uncommon nonpolymorphic mutations selected in patients receiving d4T, TDF and ABC-containing regimens (128,129,130,131,49,48,132,133,134,116,78,117,135,136). K70E/G and possibly K70Q/T/N/S reduce susceptibility to these NRTIs and cause potentially low-level resistance to 3TC/FTC. K70E/G and possibly K70Q/T/N/S increase AZT susceptibility (40,116,118).
L74V occurs commonly in patients receiving ABC or ddI; it also occurs occasionally in patients receiving TDF (137,83,138,78). The combination of L74V + M184V is the most common pattern of mutations to develop in patients receiving ABC/3TC (42,139,57,50,6). This combination reduces ABC susceptibility by >5-fold and ddI susceptibility >2-fold. L74V increases susceptibility to AZT and AZT treatment selects against the development of this mutation (139,140,141,4,13,142). In contrast, TDF treatment does not select against L74V even though this mutation increases susceptibility to TDF in vitro (143,141). L74V and L74I may have compensatory effects on viral fitness, particularly in the presence of NNRTI-resistance mutations, possibly explaining their occurrence even in patients receiving TDF (144,145).
L74I is selected primarily by ddI and ABC, and occasionally by TDF (146,147,114,83). It is appears less effective than L74V in reducing susceptibility to ABC and ddI in vitro. It does not appear to significantly increase AZT and TDF susceptibility (114).
Y115F is selected by ABC and TDF (42,80,148,80,1,149,51,3,47,48,49,83,138). Alone, Y115F reduces ABC susceptibility ~3-fold but has little phenotypic effect on TDF susceptibility. In combination with K65R or Q151M, Y115F synergistically reduces ABC and TDF susceptibility (14,80,4).
Multi-Nucleoside RT Inhibitor Resistance Mutations
Q151M usually occurs in combination with two or more of the following four accessory mutations: A62V, V75I, F77L, and F116Y (142,150,151,152). Q151M alone causes high-level resistance to AZT, d4T, ddI and ABC, and low-level resistance to 3TC, FTC and TDF. In combination with two or more accessory mutations it causes intermediate-level resistance to 3TC, FTC and TDF (4,65). Q151L is an extremely rare highly unfit nonpolymorphic NRTI-selected mutation. Although it does not appear to reduce NRTI susceptibility, it represents a transition between wildtype and Q151M (153).
Beta3-Beta4 Insertions and Deletions
Beta3-Beta4 insertions occurring anywhere between codons 66 and 70 are by convention assigned to position 69. These insertions usually comprise a T69S substitution followed by two additional amino acids (154,155,156,157). T69 insertions usually occur in combination with multiple TAMs, and in this context they cause intermediate-level resistance to 3TC and FTC and high-level resistance to the remaining NRTIs. T69 insertions are the mutations associated with the greatest reductions in TDF susceptibility (4,158,65).
The most common Beta3-Beta4 deletions occur at positions 67, 69, and 70. Position 67 deletions usually occur in combination with the unusual mutation T69G and either Q151M or multiple TAMs (159,160,161). Viruses with position D67 deletions usually have high-level reductions in susceptibility to most NRTIs. T69 deletions usually occur in combination with K65R and/or Q151M (54). Viruses with T69 deletions plus K65R alone contribute reduced susceptibility to all NRTIs except AZT (161,162). A recent study, in which T69 deletions were replaced with the wildtype threonine residue, suggested that their phenotypic effect is minimal (163). K70 deletions have in vitro effects that appear to be similar to those of T69 deletions. An S68 deletion has been reported to emerge during in vitro passage with an investigational NRTI and to have in vitro effects that are also similar to T69 deletions (164).
T69D is a nonpolymorphic NRTI-selected mutation that primarily reduces susceptibility to ddI and possibly d4T (165,166,11,167,168). T69N is a somewhat nonpolymorphic NRTI-selected mutation. In combination with TAMs, it appears to contribute reduced susceptibility to AZT, ddI and d4T (169) T69G is a rare nonpolymorphic mutation that usually occurs in viruses from patients with a D67 deletion (160).
V75T/M/A/S are nonpolymorphic NRTI-selected mutations (135). V75T is selected primarily by d4T and ddI and reduces susceptibility to these NRTIs (170,4,81). V75M is selected in patients receiving a regimen containing d4T and 3TC, particularly in CRF01_AE viruses (171,54). It appears to reduce susceptibility to ddI, d4T, and possibly AZT. Few data are available on the significance of V75S/A.
N348I is a nonpolymorphic accessory mutation selected by the NRTIs AZT and d4T and by the NNRTIs NVP and EFV (172,173,174). Alone, it reduces AZT susceptibility about 3-fold and NVP and EFV susceptibility by 3-fold and 2-fold, respectively (172,173,175,176). It facilitates primer unblocking by reducing the rate of RNA template degradation (172).
- 1.0 1.1 Miller V, Ait-Khaled M, Stone C, Griffin P, Mesogiti D, Cutrell A, Harrigan R, Staszewski S, Katlama C, Pearce G and Tisdale M. HIV-1 reverse transcriptase (RT) genotype and susceptibility to RT inhibitors during abacavir monotherapy and combination therapy. AIDS 2000.
- ^ Harrigan PR, Stone C, Griffin P, Najera I, Bloor S, Kemp S, Tisdale M and Larder B. Resistance profile of the human immunodeficiency virus type 1 reverse transcriptase inhibitor abacavir (1592U89) after monotherapy and combination therapy. CNA2001 Investigative Group. J.Infect.Dis. 2000.
- 3.0 3.1 3.2 3.3 Whitcomb JM, Parkin NT, Chappey C, Hellmann NS and Petropoulos CJ. Broad nucleoside reverse-transcriptase inhibitor cross-resistance in human immunodeficiency virus type 1 clinical isolates. J Infect Dis 2003.
- 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9 4.10 4.11 Melikian GL, Rhee SY, Taylor J, Fessel WJ, Kaufman D, Towner W, Troia-Cancio PV, Zolopa A, Robbins GK, Kagan R, Israelski D and Shafer RW. Standardized comparison of the relative impacts of HIV-1 reverse transcriptase (RT) mutations on nucleoside RT inhibitor susceptibility. Antimicrob Agents Chemother 2012.
- 5.0 5.1 5.2 Kulkarni R, Babaoglu K, Lansdon EB, Rimsky L, Van Eygen V, Picchio G, Svarovskaia E, Miller MD and White KL. The HIV-1 reverse transcriptase M184I mutation enhances the E138K-associated resistance to rilpivirine and decreases viral fitness. J Acquir Immune Defic Syndr 2012.
- 6.0 6.1 6.2 6.3 Lanier ER, Givens N, Stone C, Griffin P, Gibb D, Walker S, Tisdale M, Irlbeck D, Underwood M, St Clair M and Ait-Khaled M. Effect of concurrent zidovudine use on the resistance pathway selected by abacavir-containing regimens. HIV Med 2004.
- 7.0 7.1 Lanier ER, Ait-Khaled M, Scott J, Stone C, Melby T, Sturge G, St Clair M, Steel H, Hetherington S, Pearce G, Spreen W and Lafon S. Antiviral efficacy of abacavir in antiretroviral therapy-experienced adults harbouring HIV-1 with specific patterns of resistance to nucleoside reverse transcriptase inhibitors. Antivir Ther 2004.
- 8.0 8.1 Molina JM, Marcelin AG, Pavie J, Heripret L, De Boever CM, Troccaz M, Leleu G and Calvez V. Didanosine in HIV-1-infected patients experiencing failure of antiretroviral therapy: a randomized placebo-controlled trial. J Infect Dis 2005.
- ^ Winters MA, Bosch RJ, Albrecht MA and Katzenstein DA. Clinical impact of the M184V mutation on switching to didanosine or maintaining lamivudine treatment in nucleoside reverse-transcriptase inhibitor-experienced patients. J Infect Dis 2003.
- ^ Eron JJ, Jr, Bosch RJ, Bettendorf D, Petch L, Fiscus S and Frank I. The effect of lamivudine therapy and M184V on the antiretroviral activity of didanosine. J Acquir Immune Defic Syndr 2007.
- 11.0 11.1 11.2 De Luca A, Giambenedetto SD, Trotta MP, Colafigli M, Prosperi M, Ruiz L, Baxter J, Clevenbergh P, Cauda R, Perno CF and Antinori A. Improved interpretation of genotypic changes in the HIV-1 reverse transcriptase coding region that determine the virological response to didanosine. J Infect Dis 2007.
- ^ Miller V, Sturmer M, Staszewski S, Groschel B, Hertogs K, de Bethune MP, Pauwels R, Harrigan PR, Bloor S, Kemp SD and Larder BA. The M184V mutation in HIV-1 reverse transcriptase (RT) conferring lamivudine resistance does not result in broad cross-resistance to nucleoside analogue RT inhibitors. AIDS 1998.
- 13.0 13.1 13.2 Rhee SY, Taylor J, Wadhera G, Ben-Hur A, Brutlag DL and Shafer RW. Genotypic predictors of human immunodeficiency virus type 1 drug resistance. Proc Natl Acad Sci U S A 2006.
- 14.0 14.1 14.2 Vermeiren H, Van Craenenbroeck E, Alen P, Bacheler L, Picchio G and Lecocq P. Prediction of HIV-1 drug susceptibility phenotype from the viral genotype using linear regression modeling. J Virol Methods 2007.
- ^ Sproat M, Pozniak AL, Peeters M, Winters B, Hoetelmans R, Graham NM and Gazzard BG. The influence of the M184V mutation in HIV-1 reverse transcriptase on the virological outcome of highly active antiretroviral therapy regimens with or without didanosine. Antivir Ther 2005.
- ^ Larder BA, Kemp SD and Harrigan PR. Potential mechanism for sustained antiretroviral efficacy of AZT-3TC combination therapy. Science 1995.
- 17.0 17.1 Masquelier B, Descamps D, Carriere I, Ferchal F, Collin G, Denayrolles M, Ruffault A, Chanzy B, Izopet J, Buffet-Janvresse C, Schmitt MP, Race E, Fleury HJ, Aboulker JP, Yeni P and Brun-Vezinet F. Zidovudine resensitization and dual HIV-1 resistance to zidovudine and lamivudine in the delta lamivudine roll-over study. Antivir Ther 1999.
- ^ Gotte M, Arion D, Parniak MA and Wainberg MA. The M184V mutation in the reverse transcriptase of human immunodeficiency virus type 1 impairs rescue of chain-terminated DNA synthesis. J Virol 2000.
- ^ Boyer PL, Sarafianos SG, Arnold E and Hughes SH. The M184V mutation reduces the selective excision of zidovudine 5'-monophosphate (AZTMP) by the reverse transcriptase of human immunodeficiency virus type 1. J Virol 2002.
- ^ Ross L, Parkin N, Chappey C, Fisher R, Clair MS, Bates M, Tisdale M and Lanier ER. Phenotypic impact of HIV reverse transcriptase M184I/V mutations in combination with single thymidine analog mutations on nucleoside reverse transcriptase inhibitor resistance. AIDS 2004.
- ^ Wolf K, Walter H, Beerenwinkel N, Keulen W, Kaiser R, Hoffmann D, Lengauer T, Selbig J, Vandamme AM, Korn K and Schmidt B. Tenofovir resistance and resensitization. Antimicrob Agents Chemother 2003.
- 22.0 22.1 Kuritzkes DR, Quinn JB, Benoit SL, Shugarts DL, Griffin A, Bakhtiari M, Poticha D, Eron JJ, Fallon MA and Rubin M. Drug resistance and virologic response in NUCA 3001, a randomized trial of lamivudine (3TC) versus zidovudine (ZDV) versus ZDV plus 3TC in previously untreated patients. AIDS 1996.
- ^ Nijhuis M, Schuurman R, de Jong D, van Leeuwen R, Lange J, Danner S, Keulen W, de Groot T and Boucher CA. Lamivudine-resistant human immunodeficiency virus type 1 variants (184V) require multiple amino acid changes to become co-resistant to zidovudine in vivo. J Infect Dis 1997.
- ^ Kuritzkes DR, Shugarts D, Bakhtiari M, Poticha D, Johnson J, Rubin M, Gingeras TR, Kennedy M and Eron JJ. Emergence of dual resistance to zidovudine and lamivudine in HIV-1-infected patients treated with zidovudine plus lamivudine as initial therapy. J Acquir Immune Defic Syndr 2000.
- ^ Catucci M, Venturi G, Romano L, Riccio ML, De Milito A, Valensin PE and Zazzi M. Development and significance of the HIV-1 reverse transcriptase M184V mutation during combination therapy with lamivudine, zidovudine, and protease inhibitors. J Acquir Immune Defic Syndr 1999.
- ^ Maguire M, Gartland M, Moore S, Hill A, Tisdale M, Harrigan R and Kleim JP. Absence of zidovudine resistance in antiretroviral-naive patients following zidovudine/lamivudine/protease inhibitor combination therapy: virological evaluation of the AVANTI 2 and AVANTI 3 studies. AIDS 2000.
- ^ Averbuch D, Schapiro JM, Lanier ER, Gradstein S, Gottesman G, Kedem E, Einhorn M, Grisaru-Soen G, Ofir M, Engelhard D and Grossman Z. Diminished selection for thymidine-analog mutations associated with the presence of M184V in Ethiopian children infected with HIV subtype C receiving lamivudine-containing therapy. Pediatr Infect Dis J 2006.
- ^ Mouroux M, Descamps D, Izopet J, Yvon A, Delaugerre C, Matheron S, Coutellier A, Valantin MA, Bonmarchand M, Agut H, Massip P, Costagliola D, Katlama C, Brun-Vezinet F and Calvez V. Low-rate emergence of thymidine analogue mutations and multi-drug resistance mutations in the HIV-1 reverse transcriptase gene in therapy-naive patients receiving stavudine plus lamivudine combination therapy. Antivir Ther 2001.
- ^ Picard V, Angelini E, Maillard A, Race E, Clavel F, Chene G, Ferchal F and Molina JM. Comparison of genotypic and phenotypic resistance patterns of human immunodeficiency virus type 1 isolates from patients treated with stavudine and didanosine or zidovudine and lamivudine. J Infect Dis 2001.
- 30.0 30.1 30.2 Miller MD, Margot N, Lu B, Zhong L, Chen SS, Cheng A and Wulfsohn M. Genotypic and phenotypic predictors of the magnitude of response to tenofovir disoproxil fumarate treatment in antiretroviral-experienced patients. J Infect Dis 2004.
- 31.0 31.1 Frost SD, Nijhuis M, Schuurman R, Boucher CA and Brown AJ. Evolution of lamivudine resistance in human immunodeficiency virus type 1-infected individuals: the relative roles of drift and selection. J Virol 2000.
- ^ Eron JJ, Benoit SL, Jemsek J, MacArthur RD, Santana J, Quinn JB, Kuritzkes DR, Fallon MA and Rubin M. Treatment with lamivudine, zidovudine, or both in HIV-positive patients with 200 to 500 CD4+ cells per cubic millimeter. North American HIV Working Party. N Engl J Med 1995.
- ^ Zaccarelli M, Perno CF, Forbici F, Cingolani A, Liuzzi G, Bertoli A, Trotta MP, Bellocchi MC, Di Giambenedetto S, Tozzi V, Gori C, D'Arrigo R, De Longis P, Noto P, Girardi E, De Luca A and Antinori A. Using a database of HIV patients undergoing genotypic resistance test after HAART failure to understand the dynamics of M184V mutation. Antivir Ther 2003.
- ^ Diallo K, Gotte M and Wainberg MA. Molecular impact of the M184V mutation in human immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents Chemother 2003.
- ^ Pluda JM, Cooley TP, Montaner JS, Shay LE, Reinhalter NE, Warthan SN, Ruedy J, Hirst HM, Vicary CA, Quinn JB and et al. A phase I/II study of 2'-deoxy-3'-thiacytidine (lamivudine) in patients with advanced human immunodeficiency virus infection. J Infect Dis 1995.
- ^ Castagna A, Danise A, Menzo S, Galli L, Gianotti N, Carini E, Boeri E, Galli A, Cernuschi M, Hasson H, Clementi M and Lazzarin A. Lamivudine monotherapy in HIV-1-infected patients harbouring a lamivudine-resistant virus: a randomized pilot study (E-184V study). AIDS 2006.
- ^ Campbell TB, Shulman NS, Johnson SC, Zolopa AR, Young RK, Bushman L, Fletcher CV, Lanier ER, Merigan TC and Kuritzkes DR. Antiviral activity of lamivudine in salvage therapy for multidrug-resistant HIV-1 infection. Clin Infect Dis 2005.
- ^ Keulen W, Back NK, van Wijk A, Boucher CA and Berkhout B. Initial appearance of the 184Ile variant in lamivudine-treated patients is caused by the mutational bias of human immunodeficiency virus type 1 reverse transcriptase. J Virol 1997.
- ^ Keulen W, Boucher C and Berkhout B. Nucleotide substitution patterns can predict the requirements for drug-resistance of HIV-1 proteins. Antiviral Res 1996.
- 40.0 40.1 40.2 Wainberg MA, Miller MD, Quan Y, Salomon H, Mulato AS, Lamy PD, Margot NA, Anton KE and Cherrington JM. In vitro selection and characterization of HIV-1 with reduced susceptibility to PMPA. Antivir Ther 1999.
- ^ Garcia-Lerma JG, MacInnes H, Bennett D, Reid P, Nidtha S, Weinstock H, Kaplan JE and Heneine W. A novel genetic pathway of human immunodeficiency virus type 1 resistance to stavudine mediated by the K65R mutation. J Virol 2003.
- 42.0 42.1 42.2 Tisdale M, Alnadaf T and Cousens D. Combination of mutations in human immunodeficiency virus type 1 reverse transcriptase required for resistance to the carbocyclic nucleoside 1592U89. Antimicrob.Agents Chemother. 1997.
- ^ Squires K, Pozniak AL, Pierone G, Jr, Steinhart CR, Berger D, Bellos NC, Becker SL, Wulfsohn M, Miller MD, Toole JJ, Coakley DF and Cheng A. Tenofovir disoproxil fumarate in nucleoside-resistant HIV-1 infection: a randomized trial. Ann Intern Med 2003.
- ^ Gallant JE, Staszewski S, Pozniak AL, DeJesus E, Suleiman JM, Miller MD, Coakley DF, Lu B, Toole JJ and Cheng AK. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA 2004.
- ^ McColl DJ, Margot NA, Wulfsohn M, Coakley DF, Cheng AK and Miller MD. Patterns of resistance emerging in HIV-1 from antiretroviral-experienced patients undergoing intensification therapy with tenofovir disoproxil fumarate. J Acquir Immune Defic Syndr 2004.
- ^ Margot NA, Lu B, Cheng A and Miller MD. Resistance development over 144 weeks in treatment-naive patients receiving tenofovir disoproxil fumarate or stavudine with lamivudine and efavirenz in Study 903. HIV Med 2006.
- 47.0 47.1 Wirden M, Marcelin AG, Simon A, Kirstetter M, Tubiana R, Valantin MA, Paris L, Bonmarchand M, Conan F, Kalkias L, Katlama C and Calvez V. Resistance mutations before and after tenofovir regimen failure in HIV-1 infected patients. J Med Virol 2005.
- 48.0 48.1 48.2 Hawkins CA, Chaplin B, Idoko J, Ekong E, Adewole I, Gashau W, Murphy RL and Kanki P. Clinical and genotypic findings in HIV-infected patients with the K65R mutation failing first-line antiretroviral therapy in Nigeria. J Acquir Immune Defic Syndr 2009.
- 49.0 49.1 49.2 Sunpath H, Wu B, Gordon M, Hampton J, Johnson B, Moosa MY, Ordonez C, Kuritzkes DR and Marconi VC. High rate of K65R for antiretroviral therapy-naive patients with subtype C HIV infection failing a tenofovir-containing first-line regimen. AIDS 2012.
- 50.0 50.1 Sax PE, Tierney C, Collier AC, Daar ES, Mollan K, Budhathoki C, Godfrey C, Jahed NC, Myers L, Katzenstein D, Farajallah A, Rooney JF, Ha B, Woodward WC, Feinberg J, Tashima K, Murphy RL and Fischl MA. Abacavir/lamivudine versus tenofovir DF/emtricitabine as part of combination regimens for initial treatment of HIV: final results. J Infect Dis 2011.
- 51.0 51.1 Gulick RM, Ribaudo HJ, Shikuma CM, Lustgarten S, Squires KE, Meyer WA, 3rd Acosta EP, Schackman BR, Pilcher CD, Murphy RL, Maher WE, Witt MD, Reichman RC, Snyder S, Klingman KL and Kuritzkes DR. Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. N Engl J Med 2004.
- ^ Ait-Khaled M, Rakik A, Griffin P, Cutrell A, Fischl MA, Clumeck N, Greenberg SB, Rubio R, Peters BS, Pulido F, Gould J, Pearce G, Spreen W, Tisdale M and Lafon S. Mutations in HIV-1 reverse transcriptase during therapy with abacavir, lamivudine and zidovudine in HIV-1-infected adults with no prior antiretroviral therapy. Antivir Ther 2002.
- ^ Trotta MP, Bonfigli S, Ceccherini-Silberstein F, Bellagamba R, D'Arrigo R, Soldani F, Zaccarelli M, Concetta Bellocchi M, Lorenzini P, Marconi P, Boumis E, Forbici F, Comandini UV, Tozzi V, Narciso P, Federico Perno C and Antinori A. Clinical and genotypic correlates of mutation K65R in HIV-infected patients failing regimens not including tenofovir. J Med Virol 2006.
- 54.0 54.1 54.2 54.3 Tang MW, Rhee SY, Bertagnolio S, Ford N, Holmes S, Sigaloff KC, Hamers RL, de Wit TF, Fleury HJ, Kanki PJ, Ruxrungtham K, Hawkins CA, Wallis CL, Stevens W, van Zyl GU, Manosuthi W, Hosseinipour MC, Ngo-Giang-Huong N, Belec L, Peeters M, Aghokeng A, Bunupuradah T, Burda S, Cane P, Cappelli G, Charpentier C, Dagnra AY, Deshpande AK, El-Katib Z, Eshleman SH, Fokam J, Gody JC, Katzenstein D, Koyalta DD, Kumwenda JJ, Lallemant M, Lynen L, Marconi VC, Margot NA, Moussa S, Ndung'u T, Nyambi PN, Orrell C, Schapiro JM, Schuurman R, Sirivichayakul S, Smith D, Zolfo M, Jordan MR and Shafer RW. Nucleoside reverse transcriptase inhibitor resistance mutations associated with first-line stavudine-containing antiretroviral therapy: programmatic implications for countries phasing out stavudine. J Infect Dis 2013.
- ^ Winters MA, Shafer RW, Jellinger RA, Mamtora G, Gingeras T and Merigan TC. Human immunodeficiency virus type 1 reverse transcriptase genotype and drug susceptibility changes in infected individuals receiving dideoxyinosine monotherapy for 1 to 2 years. Antimicrob Agents Chemother 1997.
- ^ Sosa N, Hill-Zabala C, Dejesus E, Herrera G, Florance A, Watson M, Vavro C and Shaefer M. Abacavir and lamivudine fixed-dose combination tablet once daily compared with abacavir and lamivudine twice daily in HIV-infected patients over 48 weeks (ESS30008, SEAL). J Acquir Immune Defic Syndr 2005.
- 57.0 57.1 Moyle GJ, DeJesus E, Cahn P, Castillo SA, Zhao H, Gordon DN, Craig C and Scott TR. Abacavir once or twice daily combined with once-daily lamivudine and efavirenz for the treatment of antiretroviral-naive HIV-infected adults: results of the Ziagen Once Daily in Antiretroviral Combination Study. J Acquir Immune Defic Syndr 2005.
- ^ Green H, Gibb DM, Walker AS, Pillay D, Butler K, Candeias F, Castelli-Gattinara G, Compagnucci A, Della Negra M, de Rossi A, Feiterna-Sperling C, Giaquinto C, Harper L, Levy J, Saidi Y, Wintergerst U and Paediatric European Network for the Treatment of, Aids. Lamivudine/abacavir maintains virological superiority over zidovudine/lamivudine and zidovudine/abacavir beyond 5 years in children. AIDS 2007.
- ^ Inzaule SC, Weidle PJ, Yang C, Ndiege K, Hamers RL, Rinke de Wit TF, Thomas T and Zeh C. Prevalence and dynamics of the K65R drug resistance mutation in HIV-1-infected infants exposed to maternal therapy with lamivudine, zidovudine and either nevirapine or nelfinavir in breast milk. J Antimicrob Chemother 2016.
- ^ Petropoulos CJ, Parkin NT, Limoli KL, Lie YS, Wrin T, Huang W, Tian H, Smith D, Winslow GA, Capon DJ and Whitcomb JM. A novel phenotypic drug susceptibility assay for human immunodeficiency virus type 1. Antimicrob Agents Chemother 2000.
- ^ Parkin NT, Hellmann NS, Whitcomb JM, Kiss L, Chappey C and Petropoulos CJ. Natural variation of drug susceptibility in wild-type human immunodeficiency virus type 1. Antimicrob Agents Chemother 2004.
- 62.0 62.1 Svarovskaia ES, Feng JY, Margot NA, Myrick F, Goodman D, Ly JK, White KL, Kutty N, Wang R, Borroto-Esoda K and Miller MD. The A62V and S68G mutations in HIV-1 reverse transcriptase partially restore the replication defect associated with the K65R mutation. J Acquir Immune Defic Syndr 2008.
- 63.0 63.1 Rhee SY, Gonzales MJ, Kantor R, Betts BJ, Ravela J and Shafer RW. Human immunodeficiency virus reverse transcriptase and protease sequence database. Nucleic Acids Res 2003.
- ^ Borroto-Esoda K, Parkin N and Miller MD. A comparison of the phenotypic susceptibility profiles of emtricitabine and lamivudine. Antivir Chem Chemother 2007.
- 65.0 65.1 65.2 Margot NA, Johnson A, Miller MD and Callebaut C. Characterization of HIV-1 Resistance to Tenofovir Alafenamide In Vitro. Antimicrob Agents Chemother 2015.
- ^ Boucher CA, Cammack N, Schipper P, Schuurman R, Rouse P, Wainberg MA and Cameron JM. High-level resistance to (-) enantiomeric 2'-deoxy-3'-thiacytidine in vitro is due to one amino acid substitution in the catalytic site of human immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents Chemother 1993.
- ^ Tisdale M, Kemp SD, Parry NR and Larder BA. Rapid in vitro selection of human immunodeficiency virus type 1 resistant to 3'-thiacytidine inhibitors due to a mutation in the YMDD region of reverse transcriptase. Proc Natl Acad Sci U S A 1993.
- 68.0 68.1 Parikh UM, Bacheler L, Koontz D and Mellors JW. The K65R mutation in human immunodeficiency virus type 1 reverse transcriptase exhibits bidirectional phenotypic antagonism with thymidine analog mutations. J Virol 2006.
- ^ Ross L, Elion R, Lanier R, Dejesus E, Cohen C, Redfield RR, Gathe JC, Hsu RK, Yau L, Paulsen D and Ha B. Modulation of K65R selection by zidovudine inclusion: analysis of HIV resistance selection in subjects with virologic failure receiving once-daily abacavir/lamivudine/zidovudine and tenofovir DF (study COL40263). AIDS Res Hum Retroviruses 2009.
- ^ Stephan C, Dauer B, Bickel M, Haberl A, Locher L, Muller A, Klauke S, Berger A, Doerr HW, Sturmer M and Staszewski S. Intensification of a failing regimen with zidovudine may cause sustained virologic suppression in the presence of resensitising mutations including K65R. J Infect 2010.
- ^ Das K, Bandwar RP, White KL, Feng JY, Sarafianos SG, Tuske S, Tu X, Clark AD, Jr, Boyer PL, Hou X, Gaffney BL, Jones RA, Miller MD, Hughes SH and Arnold E. Structural basis for the role of the K65R mutation in HIV-1 reverse transcriptase polymerization, excision antagonism, and tenofovir resistance. J Biol Chem 2009.
- 72.0 72.1 Garforth SJ, Lwatula C and Prasad VR. The lysine 65 residue in HIV-1 reverse transcriptase function and in nucleoside analog drug resistance. Viruses 2014.
- ^ White KL, Chen JM, Feng JY, Margot NA, Ly JK, Ray AS, Macarthur HL, McDermott MJ, Swaminathan S and Miller MD. The K65R reverse transcriptase mutation in HIV-1 reverses the excision phenotype of zidovudine resistance mutations. Antivir Ther 2006.
- ^ Coutsinos D, Invernizzi CF, Xu H, Moisi D, Oliveira M, Brenner BG and Wainberg MA. Template usage is responsible for the preferential acquisition of the K65R reverse transcriptase mutation in subtype C variants of human immunodeficiency virus type 1. J Virol 2009.
- ^ Invernizzi CF, Coutsinos D, Oliveira M, Moisi D, Brenner BG and Wainberg MA. Signature nucleotide polymorphisms at positions 64 and 65 in reverse transcriptase favor the selection of the K65R resistance mutation in HIV-1 subtype C. J Infect Dis 2009.
- ^ Brenner BG, Oliveira M, Doualla-Bell F, Moisi DD, Ntemgwa M, Frankel F, Essex M and Wainberg MA. HIV-1 subtype C viruses rapidly develop K65R resistance to tenofovir in cell culture. AIDS 2006.
- ^ Theys K, Vercauteren J, Snoeck J, Zazzi M, Camacho RJ, Torti C, Schulter E, Clotet B, Sonnerborg A, De Luca A, Grossman Z, Struck D, Vandamme AM and Abecasis AB. HIV-1 subtype is an independent predictor of reverse transcriptase mutation K65R in HIV-1 patients treated with combination antiretroviral therapy including tenofovir. Antimicrob Agents Chemother 2013.
- 78.0 78.1 78.2 and TenoRes Study, Group. Global 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.
- ^ Ross LL, Dretler R, Gerondelis P, Rouse EG, Lim ML and Lanier ER. A rare HIV reverse transcriptase mutation, K65N, confers reduced susceptibility to tenofovir, lamivudine and didanosine. AIDS 2006.
- 80.0 80.1 80.2 80.3 80.4 Margot NA, Waters JM and Miller MD. In vitro human immunodeficiency virus type 1 resistance selections with combinations of tenofovir and emtricitabine or abacavir and lamivudine. Antimicrob Agents Chemother 2006.
- 81.0 81.1 van Westen GJ, Hendriks A, Wegner JK, Ijzerman AP, van Vlijmen HW and Bender A. Significantly Improved HIV Inhibitor Efficacy Prediction Employing Proteochemometric Models Generated From Antivirogram Data. PLoS Comput Biol 2013.
- ^ Chunduri H, Crumpacker C and Sharma PL. Reverse transcriptase mutation K65N confers a decreased replication capacity to HIV-1 in comparison to K65R due to a decreased RT processivity. Virology 2011.
- 83.0 83.1 83.2 83.3 Van Zyl GU, Liu TF, Claassen M, Engelbrecht S, de Oliveira T, Preiser W, Wood NT, Travers S and Shafer RW. Trends in Genotypic HIV-1 Antiretroviral Resistance between 2006 and 2012 in South African Patients Receiving First- and Second-Line Antiretroviral Treatment Regimens. PLoS One 2013.
- ^ Coetzer M, Westley B, Delong A, Tray C, Sophearin D, Nerrienet E, Schreier L and Kantor R. Extensive drug resistance in HIV-infected Cambodian children who are undetected as failing first-line antiretroviral therapy by WHO 2010 guidelines. AIDS Res Hum Retroviruses 2013.
- ^ Mollan K, Daar ES, Sax PE, Balamane M, Collier AC, Fischl MA, Lalama CM, Bosch RJ, Tierney C and Katzenstein D. HIV-1 amino acid changes among participants with virologic failure: associations with first-line efavirenz or atazanavir plus ritonavir and disease status. J Infect Dis 2012.
- ^ Fourati S, Visseaux B, Armenia D, Morand-Joubert L, Artese A, Charpentier C, Van Den Eede P, Costa G, Alcaro S, Wirden M, Perno CF, Ceccherini Silberstein F, Descamps D, Calvez V and Marcelin AG. Identification of a rare mutation at reverse transcriptase Lys65 (K65E) in HIV-1-infected patients failing on nucleos(t)ide reverse transcriptase inhibitors. J Antimicrob Chemother 2013.
- ^ and Menendez-Arias L. A structural frame for understanding the role of thymidine analogue resistance mutations in resistance to zidovudine and other nucleoside analogues. Antivir Ther 2011.
- ^ Arion D, Sluis-Cremer N and Parniak MA. Mechanism by which phosphonoformic acid resistance mutations restore 3'-azido-3'-deoxythymidine (AZT) sensitivity to AZT-resistant HIV-1 reverse transcriptase. J Biol Chem 2000.
- ^ Meyer PR, Matsuura SE, So AG and Scott WA. Unblocking of chain-terminated primer by HIV-1 reverse transcriptase through a nucleotide-dependent mechanism. Proc Natl Acad Sci U S A 1998.
- ^ Meyer PR, Matsuura SE, Mian AM, So AG and Scott WA. A mechanism of AZT resistance: an increase in nucleotide-dependent primer unblocking by mutant HIV-1 reverse transcriptase. Mol Cell 1999.
- ^ Meyer PR, Matsuura SE, Schinazi RF, So AG and Scott WA. Differential removal of thymidine nucleotide analogues from blocked DNA chains by human immunodeficiency virus reverse transcriptase in the presence of physiological concentrations of 2'-deoxynucleoside triphosphates. Antimicrob Agents Chemother 2000.
- ^ Meyer PR, Matsuura SE, Tolun AA, Pfeifer I, So AG, Mellors JW and Scott WA. Effects of specific zidovudine resistance mutations and substrate structure on nucleotide-dependent primer unblocking by human immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents Chemother 2002.
- ^ Boyer PL, Sarafianos SG, Arnold E and Hughes SH. Selective excision of AZTMP by drug-resistant human immunodeficiency virus reverse transcriptase. J Virol 2001.
- ^ Larder BA and Kemp SD. Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to zidovudine (AZT). Science 1989.
- ^ Kellam P, Boucher CA and Larder BA. Fifth mutation in human immunodeficiency virus type 1 reverse transcriptase contributes to the development of high-level resistance to zidovudine. Proc Natl Acad Sci U S A 1992.
- ^ Harrigan PR, Kinghorn I, Bloor S, Kemp SD, Najera I, Kohli A and Larder BA. Significance of amino acid variation at human immunodeficiency virus type 1 reverse transcriptase residue 210 for zidovudine susceptibility. J Virol 1996.
- ^ Hooker DJ, Tachedjian G, Solomon AE, Gurusinghe AD, Land S, Birch C, Anderson JL, Roy BM, Arnold E and Deacon NJ. An in vivo mutation from leucine to tryptophan at position 210 in human immunodeficiency virus type 1 reverse transcriptase contributes to high-level resistance to 3'-azido-3'-deoxythymidine. J Virol 1996.
- ^ Cozzi-Lepri A, Ruiz L, Loveday C, Phillips AN, Clotet B, Reiss P, Ledergerber B, Holkmann C, Staszewski S, Lundgren JD and Euro, Sida Study Group. Thymidine analogue mutation profiles: factors associated with acquiring specific profiles and their impact on the virological response to therapy. Antivir Ther 2005.
- ^ De Luca A, Di Giambenedetto S, Romano L, Gonnelli A, Corsi P, Baldari M, Di Pietro M, Menzo S, Francisci D, Almi P, Zazzi M and Antiretroviral Resistance Cohort Analysis Study, Group. Frequency and treatment-related predictors of thymidine-analogue mutation patterns in HIV-1 isolates after unsuccessful antiretroviral therapy. J Infect Dis 2006.
- ^ Yahi N, Tamalet C, Tourres C, Tivoli N and Fantini J. Mutation L210W of HIV-1 reverse transcriptase in patients receiving combination therapy. Incidence, association with other mutations, and effects on the structure of mutated reverse transcriptase. J Biomed Sci 2000.
- ^ Rhee SY, Liu T, Ravela J, Gonzales MJ and Shafer RW. Distribution of human immunodeficiency virus type 1 protease and reverse transcriptase mutation patterns in 4,183 persons undergoing genotypic resistance testing. Antimicrob Agents Chemother 2004.
- ^ Brun-Vezinet F, Descamps D, Ruffault A, Masquelier B, Calvez V, Peytavin G, Telles F, Morand-Joubert L, Meynard JL, Vray M and Costagliola D. Clinically relevant interpretation of genotype for resistance to abacavir. AIDS 2003.
- ^ Masquelier B, Tamalet C, Montes B, Descamps D, Peytavin G, Bocket L, Wirden M, Izopet J, Schneider V, Ferre V, Ruffault A, Palmer P, Trylesinski A, Miller M, Brun-Vezinet F and Costagliola D. Genotypic determinants of the virological response to tenofovir disoproxil fumarate in nucleoside reverse transcriptase inhibitor-experienced patients. Antivir Ther 2004.
- ^ Barrios A, de Mendoza C, Martin-Carbonero L, Ribera E, Domingo P, Galindo MJ, Galvez J, Estrada V, Dalmau D, Asensi V and Soriano V. Role of baseline human immunodeficiency virus genotype as a predictor of viral response to tenofovir in heavily pretreated patients. J Clin Microbiol 2003.
- ^ Goudsmit J, De Ronde A, Ho DD and Perelson AS. Human immunodeficiency virus fitness in vivo: calculations based on a single zidovudine resistance mutation at codon 215 of reverse transcriptase. J Virol 1996.
- ^ Yerly S, Rakik A, De Loes SK, Hirschel B, Descamps D, Brun-Vezinet F and Perrin L. Switch to unusual amino acids at codon 215 of the human immunodeficiency virus type 1 reverse transcriptase gene in seroconvertors infected with zidovudine-resistant variants. J Virol 1998.
- 107.0 107.1 Garcia-Lerma JG, Nidtha S, Blumoff K, Weinstock H and Heneine W. Increased ability for selection of zidovudine resistance in a distinct class of wild-type HIV-1 from drug-naive persons. Proc Natl Acad Sci U S A 2001.
- ^ Wensing AM, van de Vijver DA, Angarano G, Asjo B, Balotta C, Boeri E, Camacho R, Chaix ML, Costagliola D, De Luca A, Derdelinckx I, Grossman Z, Hamouda O, Hatzakis A, Hemmer R, Hoepelman A, Horban A, Korn K, Kucherer C, Leitner T, Loveday C, MacRae E, Maljkovic I, de Mendoza C, Meyer L, Nielsen C, Op de Coul EL, Ormaasen V, Paraskevis D, Perrin L, Puchhammer-Stockl E, Ruiz L, Salminen M, Schmit JC, Schneider F, Schuurman R, Soriano V, Stanczak G, Stanojevic M, Vandamme AM, Van Laethem K, Violin M, Wilbe K, Yerly S, Zazzi M, Boucher CA and Programme, Spread. Prevalence of drug-resistant HIV-1 variants in untreated individuals in Europe: implications for clinical management. J Infect Dis 2005.
- ^ Wheeler WH, Ziebell RA, Zabina H, Pieniazek D, Prejean J, Bodnar UR, Mahle KC, Heneine W, Johnson JA, Hall HI, Variant, Atypical and Resistant HIVSurveillance Group. Prevalence of transmitted drug resistance associated mutations and HIV-1 subtypes in new HIV-1 diagnoses, U.S.-2006. AIDS 2010.
- ^ Violin M, Cozzi-Lepri A, Velleca R, Vincenti A, D'Elia S, Chiodo F, Ghinelli F, Bertoli A, d'Arminio Monforte A, Perno CF, Moroni M and Balotta C. Risk of failure in patients with 215 HIV-1 revertants starting their first thymidine analog-containing highly active antiretroviral therapy. AIDS 2004.
- ^ Van Laethem K, De Munter P, Schrooten Y, Verbesselt R, Van Ranst M, Van Wijngaerden E and Vandamme AM. No response to first-line tenofovir+lamivudine+efavirenz despite optimization according to baseline resistance testing: impact of resistant minority variants on efficacy of low genetic barrier drugs. J Clin Virol 2007.
- ^ Mitsuya Y, Varghese V, Wang C, Liu TF, Holmes SP, Jayakumar P, Gharizadeh B, Ronaghi M, Klein D, Fessel WJ and Shafer RW. Minority human immunodeficiency virus type 1 variants in antiretroviral-naive persons with reverse transcriptase codon 215 revertant mutations. J Virol 2008.
- ^ Pingen M, van der Ende ME, Wensing AM, el Barzouhi A, Simen BB, Schutten M and Boucher CA. Deep sequencing does not reveal additional transmitted mutations in patients diagnosed with HIV-1 variants with single nucleoside reverse transcriptase inhibitor resistance mutations. HIV Med 2013.
- 114.0 114.1 114.2 Berkhout B, Back NK, de Ronde A, Jurriaans S, Bakker M, Parkin NT and van der Hoek L. Identification of alternative amino acid substitutions in drug-resistant variants of the HIV-1 reverse transcriptase. AIDS 2006.
- 115.0 115.1 Rhee SY, Liu TF, Holmes SP and Shafer RW. HIV-1 subtype B protease and reverse transcriptase amino acid covariation. PLoS Comput Biol 2007.
- 116.0 116.1 116.2 Bradshaw D, Malik S, Booth C, Van Houtte M, Pattery T, Waters A, Ainsworth J and Geretti AM. Novel drug resistance pattern associated with the mutations K70G and M184V in human immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents Chemother 2007.
- 117.0 117.1 Rhee SY, Sankaran K, Varghese V, Winters M, Hurt CB, Eron JJ, Parkin N, Holmes SP, Holodniy M and Shafer RW. HIV-1 Protease, Reverse Transcriptase, and Integrase Variation. J Virol 2016.
- 118.0 118.1 Hachiya A, Kodama EN, Schuckmann MM, Kirby KA, Michailidis E, Sakagami Y, Oka S, Singh K and Sarafianos SG. K70Q adds high-level tenofovir resistance to "Q151M complex" HIV reverse transcriptase through the enhanced discrimination mechanism. PLoS One 2011.
- ^ Huigen MC, van Ham PM, de Graaf L, Kagan RM, Boucher CA and Nijhuis M. Identification of a novel resistance (E40F) and compensatory (K43E) substitution in HIV-1 reverse transcriptase. Retrovirology 2008.
- ^ Hertogs K, Bloor S, De Vroey V, van Den Eynde C, Dehertogh P, van Cauwenberge A, Sturmer M, Alcorn T, Wegner S, van Houtte M, Miller V and Larder BA. A novel human immunodeficiency virus type 1 reverse transcriptase mutational pattern confers phenotypic lamivudine resistance in the absence of mutation 184V. Antimicrob Agents Chemother 2000.
- ^ Girouard M, Diallo K, Marchand B, McCormick S and Gotte M. Mutations E44D and V118I in the reverse transcriptase of HIV-1 play distinct mechanistic roles in dual resistance to AZT and 3TC. J Biol Chem 2003.
- ^ Delaugerre C, Mouroux M, Yvon-Groussin A, Simon A, Angleraud F, Huraux JM, Agut H, Katlama C and Calvez V. Prevalence and conditions of selection of E44D/A and V118I human immunodeficiency virus type 1 reverse transcriptase mutations in clinical practice. Antimicrob Agents Chemother 2001.
- ^ Montes B and Segondy M. Prevalence of the mutational pattern E44D/A and/or V118I in the reverse transcriptase (RT) gene of HIV-1 in relation to treatment with nucleoside analogue RT inhibitors. J Med Virol 2002.
- ^ Svicher V, Sing T, Santoro MM, Forbici F, Rodriguez-Barrios F, Bertoli A, Beerenwinkel N, Bellocchi MC, Gago F, d'Arminio Monforte A, Antinori A, Lengauer T, Ceccherini-Silberstein F and Perno CF. Involvement of novel human immunodeficiency virus type 1 reverse transcriptase mutations in the regulation of resistance to nucleoside inhibitors. J Virol 2006.
- ^ Gonzales MJ, Wu TD, Taylor J, Belitskaya I, Kantor R, Israelski D, Chou S, Zolopa AR, Fessel WJ and Shafer RW. Extended spectrum of HIV-1 reverse transcriptase mutations in patients receiving multiple nucleoside analog inhibitors. AIDS 2003.
- ^ Betancor G, Nevot M, Mendieta J, Gomez-Puertas P, Martinez MA and Menendez-Arias L. Molecular basis of the association of H208Y and thymidine analogue resistance mutations M41L, L210W and T215Y in the HIV-1 reverse transcriptase of treated patients. Antiviral Res 2014.
- ^ Nebbia G, Sabin CA, Dunn DT, Geretti AM, Resistance UKCollaborative Group on HIV Drug and Group UKCollaborative HIV Cohort Study. Emergence of the H208Y mutation in the reverse transcriptase (RT) of HIV-1 in association with nucleoside RT inhibitor therapy. J Antimicrob Chemother 2007.
- ^ Sluis-Cremer N, Sheen CW, Zelina S, Torres PS, Parikh UM and Mellors JW. Molecular mechanism by which the K70E mutation in human immunodeficiency virus type 1 reverse transcriptase confers resistance to nucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother 2007.
- ^ Delaugerre C, Flandre P, Marcelin AG, Descamps D, Tamalet C, Cottalorda J, Schneider V, Yerly S, LeGoff J, Morand-Joubert L, Chaix ML, Costagliola D and Calvez V. National survey of the prevalence and conditions of selection of HIV-1 reverse transcriptase K70E mutation. J Med Virol 2008.
- ^ Sigaloff KC, Hamers RL, Wallis CL, Kityo C, Siwale M, Ive P, Botes ME, Mandaliya K, Wellington M, Osibogun A, Stevens WS, van Vugt M and de Wit TF. Unnecessary antiretroviral treatment switches and accumulation of HIV resistance mutations; two arguments for viral load monitoring in Africa. J Acquir Immune Defic Syndr 2011.
- ^ Hosseinipour MC, van Oosterhout JJ, Weigel R, Phiri S, Kamwendo D, Parkin N, Fiscus SA, Nelson JA, Eron JJ and Kumwenda J. The public health approach to identify antiretroviral therapy failure: high-level nucleoside reverse transcriptase inhibitor resistance among Malawians failing first-line antiretroviral therapy. AIDS 2009.
- ^ Gallant JE, Rodriguez AE, Weinberg WG, Young B, Berger DS, Lim ML, Liao Q, Ross L, Johnson J and Shaefer MS. Early virologic nonresponse to tenofovir, abacavir, and lamivudine in HIV-infected antiretroviral-naive subjects. J Infect Dis 2005.
- ^ Delaunay C, Brun-Vezinet F, Landman R, Collin G, Peytavin G, Trylesinski A, Flandre P, Miller M and Descamps D. Comparative selection of the K65R and M184V/I mutations in human immunodeficiency virus type 1-infected patients enrolled in a trial of first-line triple-nucleoside analog therapy (Tonus IMEA 021). J Virol 2005.
- ^ Kagan RM, Lee TS, Ross L, Lloyd RM, Jr, Lewinski MA and Potts SJ. Molecular basis of antagonism between K70E and K65R tenofovir-associated mutations in HIV-1 reverse transcriptase. Antiviral Res 2007.
- 135.0 135.1 Shahriar R, Rhee SY, Liu TF, Fessel WJ, Scarsella A, Towner W, Holmes SP, Zolopa AR and Shafer RW. Nonpolymorphic human immunodeficiency virus type 1 protease and reverse transcriptase treatment-selected mutations. Antimicrob Agents Chemother 2009.
- ^ Megens S, De Wit S, Bernatchez J, Dekeersmaeker N, Vinken L, Covens K, Theys K, Camacho RJ, Vandamme AM, Gotte M and Van Laethem K. Characterization of amino acids Arg, Ser and Thr at position 70 within HIV-1 reverse transcriptase. Acta Clin Belg 2014.
- ^ Tamalet C, Tomei C, Henry M, Solas C, Villacian J and Colson P. Selection of L74V mutation in reverse transcriptase of HIV-1 subtype D by a tenofovir DF-lamivudine based regimen. AIDS 2007.
- 138.0 138.1 Rhee SY, Jordan MR, Raizes E, Chua A, Parkin N, Kantor R, Van Zyl GU, Mukui I, Hosseinipour MC, Frenkel LM, Ndembi N, Hamers RL, Rinke de Wit TF, Wallis CL, Gupta RK, Fokam J, Zeh C, Schapiro JM, Carmona S, Katzenstein D, Tang M, Aghokeng AF, De Oliveira T, Wensing AM, Gallant JE, Wainberg MA, Richman DD, Fitzgibbon JE, Schito M, Bertagnolio S, Yang C and Shafer RW. HIV-1 Drug Resistance Mutations: Potential Applications for Point-of-Care Genotypic Resistance Testing. PLoS One 2015.
- 139.0 139.1 St Clair MH, Martin JL, Tudor-Williams G, Bach MC, Vavro CL, King DM, Kellam P, Kemp SD and Larder BA. Resistance to ddI and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase. Science 1991.
- ^ Miranda LR, Gotte M, Liang F and Kuritzkes DR. 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.
- 141.0 141.1 Trivedi V, Von Lindern J, Montes-Walters M, Rojo DR, Shell EJ, Parkin N, O'Brien WA and Ferguson MR. Impact of human immunodeficiency virus type 1 reverse transcriptase inhibitor drug resistance mutation interactions on phenotypic susceptibility. AIDS Res Hum Retroviruses 2008.
- 142.0 142.1 Shafer RW, Kozal MJ, Winters MA, Iversen AK, Katzenstein DA, Ragni MV, Meyer WA, 3rd Gupta P, Rasheed S, Coombs R and et al. Combination therapy with zidovudine and didanosine selects for drug-resistant human immunodeficiency virus type 1 strains with unique patterns of pol gene mutations. J Infect Dis 1994.
- ^ Parkin N, Chappey C, Petropoulos C and Hellmann N. HIV-1 reverse transcriptase mutations that suppress zidovudine resistance also increase in vitro susceptibility to tenofovir, but not stavudine. XII International HIV Drug Resistance Workshop. Los Cabos, Mexico. 2003.
- ^ Kleim JP, Rosner M, Winkler I, Paessens A, Kirsch R, Hsiou Y, Arnold E and Riess G. Selective pressure of a quinoxaline nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) on HIV-1 replication results in the emergence of nucleoside RT-inhibitor-specific (RT Leu-74-->Val or Ile and Val-75-->Leu or Ile) HIV-1 mutants. Proc Natl Acad Sci U S A 1996.
- ^ Wang J, Li D, Bambara RA, Yang H and Dykes C. L74V increases the reverse transcriptase content of HIV-1 virions with non-nucleoside reverse transcriptase drug-resistant mutations L100I+K103N and K101E+G190S, which results in increased fitness. J Gen Virol 2013.
- ^ Wirden M, Roquebert B, Derache A, Simon A, Duvivier C, Ghosn J, Dominguez S, Boutonnet V, Ait-Arkoub Z, Katlama C, Calvez V and Marcelin AG. Risk factors for selection of the L74I reverse transcriptase mutation in human immunodeficiency virus type 1-infected patients. Antimicrob Agents Chemother 2006.
- ^ Wirden M, Lambert-Niclot S, Marcelin AG, Schneider L, Ait-Mohand H, Brunet C, Angleraud F, Amard S, Katlama C and Calvez V. Antiretroviral combinations implicated in emergence of the L74I and L74V resistance mutations in HIV-1-infected patients. Aids 2009.
- ^ Stone C, Ait-Khaled M, Craig C, Griffin P and Tisdale M. Human immunodeficiency virus type 1 reverse transcriptase mutation selection during in vitro exposure to tenofovir alone or combined with abacavir or lamivudine. Antimicrob Agents Chemother 2004.
- ^ Ndembi N, Goodall RL, Dunn DT, McCormick A, Burke A, Lyagoba F, Munderi P, Katundu P, Kityo C, Robertson V, Yirrell DL, Walker AS, Gibb DM, Gilks CF, Kaleebu P and Pillay D. Viral rebound and emergence of drug resistance in the absence of viral load testing: a randomized comparison between zidovudine-lamivudine plus Nevirapine and zidovudine-lamivudine plus Abacavir. J Infect Dis 2010.
- ^ Shafer RW, Iversen AK, Winters MA, Aguiniga E, Katzenstein DA and Merigan TC. Drug resistance and heterogeneous long-term virologic responses of human immunodeficiency virus type 1-infected subjects to zidovudine and didanosine combination therapy. The AIDS Clinical Trials Group 143 Virology Team. J Infect Dis 1995.
- ^ Shirasaka T, Kavlick MF, Ueno T, Gao WY, Kojima E, Alcaide ML, Chokekijchai S, Roy BM, Arnold E, Yarchoan R and et al. Emergence of human immunodeficiency virus type 1 variants with resistance to multiple dideoxynucleosides in patients receiving therapy with dideoxynucleosides. Proc Natl Acad Sci U S A 1995.
- ^ Iversen AK, Shafer RW, Wehrly K, Winters MA, Mullins JI, Chesebro B and Merigan TC. Multidrug-resistant human immunodeficiency virus type 1 strains resulting from combination antiretroviral therapy. J Virol 1996.
- ^ Garcia-Lerma JG, Gerrish PJ, Wright AC, Qari SH and Heneine W. Evidence of a role for the Q151L mutation and the viral background in development of multiple dideoxynucleoside-resistant human immunodeficiency virus type 1. J Virol 2000.
- ^ Van Vaerenbergh K, Van Laethem K, Albert J, Boucher CA, Clotet B, Floridia M, Gerstoft J, Hejdeman B, Nielsen C, Pannecouque C, Perrin L, Pirillo MF, Ruiz L, Schmit JC, Schneider F, Schoolmeester A, Schuurman R, Stellbrink HJ, Stuyver L, Van Lunzen J, Van Remoortel B, Van Wijngaerden E, Vella S, Witvrouw M, Yerly S, De Clercq E, Destmyer J and Vandamme AM. Prevalence and characteristics of multinucleoside-resistant human immunodeficiency virus type 1 among European patients receiving combinations of nucleoside analogues. Antimicrob Agents Chemother 2000.
- ^ Winters MA, Coolley KL, Girard YA, Levee DJ, Hamdan H, Shafer RW, Katzenstein DA and Merigan TC. A 6-basepair insert in the reverse transcriptase gene of human immunodeficiency virus type 1 confers resistance to multiple nucleoside inhibitors. J Clin Invest 1998.
- ^ Larder BA, Bloor S, Kemp SD, Hertogs K, Desmet RL, Miller V, Sturmer M, Staszewski S, Ren J, Stammers DK, Stuart DI and Pauwels R. A family of insertion mutations between codons 67 and 70 of human immunodeficiency virus type 1 reverse transcriptase confer multinucleoside analog resistance. Antimicrob Agents Chemother 1999.
- ^ Masquelier B, Race E, Tamalet C, Descamps D, Izopet J, Buffet-Janvresse C, Ruffault A, Mohammed AS, Cottalorda J, Schmuck A, Calvez V, Dam E, Fleury H and Brun-Vezinet F. Genotypic and phenotypic resistance patterns of human immunodeficiency virus type 1 variants with insertions or deletions in the reverse transcriptase (RT): multicenter study of patients treated with RT inhibitors. Antimicrob Agents Chemother 2001.
- ^ White KL, Chen JM, Margot NA, Wrin T, Petropoulos CJ, Naeger LK, Swaminathan S and Miller MD. Molecular mechanisms of tenofovir resistance conferred by human immunodeficiency virus type 1 reverse transcriptase containing a diserine insertion after residue 69 and multiple thymidine analog-associated mutations. Antimicrob Agents Chemother 2004.
- ^ Winters MA, Coolley KL, Cheng P, Girard YA, Hamdan H, Kovari LC and Merigan TC. Genotypic, phenotypic, and modeling studies of a deletion in the beta3-beta4 region of the human immunodeficiency virus type 1 reverse transcriptase gene that is associated with resistance to nucleoside reverse transcriptase inhibitors. J Virol 2000.
- 160.0 160.1 Imamichi T, Murphy MA, Imamichi H and Lane HC. Amino acid deletion at codon 67 and Thr-to-Gly change at codon 69 of human immunodeficiency virus type 1 reverse transcriptase confer novel drug resistance profiles. J Virol 2001.
- 161.0 161.1 Kisic M, Matamoros T, Nevot M, Mendieta J, Martinez-Picado J, Martinez MA and Menendez-Arias L. Thymidine analogue excision and discrimination modulated by mutational complexes including single amino acid deletions of Asp-67 or Thr-69 in HIV-1 reverse transcriptase. J Biol Chem 2011.
- ^ Villena C, Prado JG, Puertas MC, Martinez MA, Clotet B, Ruiz L, Parkin NT, Menendez-Arias L and Martinez-Picado J. Relative fitness and replication capacity of a multinucleoside analogue-resistant clinical human immunodeficiency virus type 1 isolate with a deletion of codon 69 in the reverse transcriptase coding region. J Virol 2007.
- ^ Derache A, Wallis CL, Vardhanabhuti S, Bartlett J, Kumarasamy N and Katzenstein D. Phenotype, Genotype, and Drug Resistance in Subtype C HIV-1 Infection. J Infect Dis 2016.
- ^ Schinazi RF, Massud I, Rapp KL, Cristiano M, Detorio MA, Stanton RA, Bennett MA, Kierlin-Duncan M, Lennerstrand J and Nettles JH. Selection and characterization of HIV-1 with a novel S68 deletion in reverse transcriptase. Antimicrob Agents Chemother 2011.
- ^ Fitzgibbon JE, Howell RM, Haberzettl CA, Sperber SJ, Gocke DJ and Dubin DT. Human immunodeficiency virus type 1 pol gene mutations which cause decreased susceptibility to 2',3'-dideoxycytidine. Antimicrob Agents Chemother 1992.
- ^ Naugler WE, Yong FH, Carey VJ, Dragavon JA, Coombs RW and Frenkel LM. T69D/N pol mutation, human immunodeficiency virus type 1 RNA levels, and syncytium-inducing phenotype are associated with CD4 cell depletion during didanosine therapy. J Infect Dis 2002.
- ^ Marcelin AG, Flandre P, Pavie J, Schmidely N, Wirden M, Lada O, Chiche D, Molina JM and Calvez V. Clinically relevant genotype interpretation of resistance to didanosine. Antimicrob Agents Chemother 2005.
- ^ Assoumou L, Cozzi-Lepri A, Brun-Vezinet F, Degruttola V, Kuritzkes DR, Phillips A, Zolopa A, Miller V, Flandre P and Costagliola D. Development of a didanosine genotypic resistance interpretation system based on large derivation and validation datasets. AIDS 2010.
- ^ Winters MA and Merigan TC. Variants other than aspartic acid at codon 69 of the human immunodeficiency virus type 1 reverse transcriptase gene affect susceptibility to nuleoside analogs. Antimicrob Agents Chemother 2001.
- ^ Lacey SF and Larder BA. Novel mutation (V75T) in human immunodeficiency virus type 1 reverse transcriptase confers resistance to 2',3'-didehydro-2',3'-dideoxythymidine in cell culture. Antimicrob Agents Chemother 1994.
- ^ Ariyoshi K, Matsuda M, Miura H, Tateishi S, Yamada K and Sugiura W. Patterns of point mutations associated with antiretroviral drug treatment failure in CRF01_AE (subtype E) infection differ from subtype B infection. J Acquir Immune Defic Syndr 2003.
- 172.0 172.1 172.2 Yap SH, Sheen CW, Fahey J, Zanin M, Tyssen D, Lima VD, Wynhoven B, Kuiper M, Sluis-Cremer N, Harrigan PR and Tachedjian G. N348I in the Connection Domain of HIV-1 Reverse Transcriptase Confers Zidovudine and Nevirapine Resistance. PLoS Med 2007.
- 173.0 173.1 Hachiya A, Kodama EN, Sarafianos SG, Schuckmann MM, Sakagami Y, Matsuoka M, Takiguchi M, Gatanaga H and Oka S. Amino acid mutation N348I in the connection subdomain of human immunodeficiency virus type 1 reverse transcriptase confers multiclass resistance to nucleoside and nonnucleoside reverse transcriptase inhibitors. J Virol 2008.
- ^ Waters JM, O'Neal W, White KL, Wakeford C, Lansdon EB, Harris J, Svarovskaia ES, Miller MD and Borroto-Esoda K. Mutations in the thumb-connection and RNase H domain of HIV type-1 reverse transcriptase of antiretroviral treatment-experienced patients. Antivir Ther 2009.
- ^ Gupta S, Fransen S, Paxinos EE, Stawiski E, Huang W and Petropoulos CJ. Combinations of mutations in the connection domain of human immunodeficiency virus type 1 reverse transcriptase: assessing the impact on nucleoside and nonnucleoside reverse transcriptase inhibitor resistance. Antimicrob Agents Chemother 2010.
- ^ Gupta S, Vingerhoets J, Fransen S, Tambuyzer L, Azijn H, Frantzell A, Paredes R, Coakley E, Nijs S, Clotet B, Petropoulos CJ, Schapiro J, Huang W and Picchio G. Connection domain mutations in HIV-1 reverse transcriptase do not impact etravirine susceptibility and virologic responses to etravirine-containing regimens. Antimicrob Agents Chemother 2011.