• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of aacPermissionsJournals.ASM.orgJournalAAC ArticleJournal InfoAuthorsReviewers
Antimicrob Agents Chemother. Aug 1999; 43(8): 2077–2080.
PMCID: PMC89420
Note

A New Point Mutation (P157S) in the Reverse Transcriptase of Human Immunodeficiency Virus Type 1 Confers Low-Level Resistance to (−)-β-2′,3′-Dideoxy-3′-Thiacytidine

Abstract

A P157S mutation in the reverse transcriptase (RT) of human immunodeficiency virus type 1 conferred fivefold resistance to (−)-β-2′,3′-dideoxy-3′-thiacytidine in cell culture. Interestingly, the P157S mutation resulted in increased sensitivity (two- to threefold) to 3′-azido-3′-deoxythymidine (AZT) and to (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA). A similar increase in susceptibility to AZT and to PMPA was also conferred by the M184V mutation in RT.

The drugs 3TC [(−)-β-2′,3′-dideoxy-3′-thiacytidine, also known as lamivudine] and AZT (3′-azido-3′-deoxythymidine, also known as zidovudine) are nucleoside analogs commonly used in the treatment of patients infected with human immunodeficiency virus type 1 (HIV-1). The efficacy of these drugs in both monotherapy and combination therapy is limited by the emergence of drug-resistant variants (7, 17, 23, 32). Resistance to 3TC or AZT alone has been shown to result from specific mutations in the reverse transcriptase (RT)-encoding region of the pol gene (19, 33). However, the mechanism of resistance to the combination of 3TC plus AZT has remained somewhat elusive. Dual drug resistance in virus isolates derived from patients receiving 3TC plus AZT combination chemotherapy has recently been reported (23, 25). In one study, dual resistance was attributed to the combined presence of M184V (which alone confers >100-fold resistance to 3TC [2, 9, 20, 34, 42]), the mutations commonly associated with AZT resistance, and several additional mutations in the N-terminal portion of RT (25). Passage of virus in culture in the presence of 3TC and AZT has also provided HIV-1 isolates resistant to both inhibitors (14). In this case, dual resistance is attributed to the presence of a previously undocumented mutation at codon 333 in genomes containing other AZT and 3TC resistance mutations. In addition, virus isolates containing either the Q151M V75I F77L F116Y mutation series or a threonine-to-serine mutation followed by an insertion of two amino acids at codon 69 of RT are resistant to AZT and dideoxynucleosides and possess 5- to 40-fold-decreased susceptibility to 3TC in vitro (12, 46).

Our investigation of dual AZT-3TC resistance stems from previous work with the feline immunodeficiency virus (FIV). We recently reported the selection of 3TC-resistant mutants of FIV that contained a novel P156S mutation in RT (35). In addition to conferring 3TC resistance, the P156S mutation conferred low-level resistance to AZT alone and eightfold resistance to the combination of 3TC plus AZT (35). P156 is highly conserved in RTs from retroviruses and retroelements (8) and is located in a region which has 87% amino acid similarity with HIV-1 RT (35). The corresponding amino acid in HIV-1, P157, is predicted to reside in the “template grip” region of the enzyme and is proximal to M184, which is located in the active site of RT (10, 13, 15).

In the present study, we examined changes in drug susceptibility resulting from the P157S mutation in HIV-1 RT. Virus containing the M184V mutation, which is commonly found in 3TC-resistant HIV-1 (33), was also constructed and used as a reference strain in these experiments. Drug susceptibilities were examined in cell culture, and inhibition constants for drug triphosphates were determined in kinetic assays with purified recombinant RTs.

Infectivity of the P157S mutant.

To determine if HIV-1 containing the P157S mutation in RT is replication competent, molecular clones containing P157S, M184V, or wild-type RT were assayed for the ability to produce infectious virions in a single round of replication. Mutations were constructed in the R9ΔApa proviral clone (37) by using oligonucleotide-mediated mutagenesis (Muta-Gene phagemid mutagenesis kit; Bio-Rad) and the subcloning strategy of Iversen et al. (12). The presence of the desired mutations and the absence of additional changes were confirmed by automated DNA sequencing of the RT-encoding region of the pol gene. The R9ΔApa clone contains the gag, pol, and env genes from HIV-1NL4-3, with 5′ and 3′ long terminal repeats derived from HIV-1HXB2. Molecular clones were transfected into 293tsA1609neo (293T) cells for the production of virus (28). Genetic heterogeneity in the resulting stocks was minimal (<10−4 mutations per nucleotide [27]), as the 293T cultures do not express the CD4 receptor and therefore cannot be reinfected by progeny virions.

Viral titers were quantitated by plating supernatants from 293T cultures onto P4 (HeLa-CD4-LTR-β-galactosidase) indicator cells and staining with 5-bromo-4-chloro-3-indolyl-β-d-galactopyranoside (X-Gal) to develop blue foci (4). Titers from the focal assay were normalized against the p24 concentration (DuPont HIV-1 p24 enzyme-linked immunosorbent assay) to determine the infectivity of the mutants relative to wild-type virus (Table (Table1).1). In this single-cycle assay, P157S did not substantially differ from M184V or wild-type clones with respect to p24 production and infectivity of the resulting particles. Studies of the M184V mutant in spreading infections show that replication fitness is cell type dependent. Thus, M184V virus exhibits reduced fitness relative to wild-type HIV-1 in peripheral blood mononuclear cells but not in a T-cell line (1). Our data indicate that both the M184V and P157S mutants replicate at near wild-type levels in CD4+ HeLa cells. However, subtle differences in replication capacity that are magnified over multiple rounds of replication in a spreading infection (5, 30) would not be detected in our single-cycle assay.

TABLE 1
Infectivity of M184V and P157S mutants relative to wild-type HIV-1 in CD4+ HeLa cellsa

Drug susceptibility in culture.

To examine the potential role of the P157S mutation in dual AZT-3TC resistance, we first determined the relative susceptibility of P157S virus to inhibition by 3TC (Fig. (Fig.1A).1A). Drug susceptibility was determined by measuring the dose-dependent reduction of focus formation in CD4+ HeLa indicator cell cultures. Concentrations of drug required to inhibit focus formation by 50% (50% effective concentrations [EC50s]) are summarized in Table Table2.2. P157S conferred fivefold resistance to 3TC, compared to the >100-fold resistance resulting from the M184V mutation. The low-level 3TC resistance conferred by P157S in HIV-1 is comparable to that observed in P156S mutants of FIV (eightfold) (35).

FIG. 1
Susceptibility of a wild-type strain (■) and M184V (○) and P157S ([open triangle]) mutants of HIV-1 to inhibition by 3TC (A) and AZT (B) in CD4+ HeLa cells. Foci were detected as described in the text. Data are plotted as the percentage ...
TABLE 2
Susceptibilities of wild-type, M184V, and P157S HIV-1 to antiviral compounds in CD4+ HeLa cells

We also determined the susceptibility of P157S, M184V, and wild-type virus to AZT (Fig. (Fig.1B).1B). Surprisingly, both P157S and M184V were slightly hypersensitive to AZT, with EC50s two- to threefold lower than that for wild-type virus (Table (Table2).2). Initial reports describe little or no change in AZT sensitivity for M184V relative to wild-type virus (2, 9, 20, 34, 42), with one exception: a virus isolate selected with (−)-β-2′,3′-dideoxy-5-fluoro-3′-thiacytidine and containing a mixture of M184I and M184V variants displayed a fivefold increase in susceptibility to AZT when assayed in MT-2 cells (34). In addition, recent studies demonstrate that two- to fivefold AZT hypersensitivity is conferred by M184V both in the HXB2D clonal background (44) and in recombinant constructs containing patient-derived RTs (22, 24, 41). Variability in reports of the AZT susceptibility of M184V HIV-1 may reflect differences in the genetic backgrounds used to select or construct the mutant or differences in the sensitivities of the particular assays used to quantitate drug susceptibility.

Cell culture assays with (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) revealed that the M184V and P157S mutations also confer a twofold increase in sensitivity to PMPA (Table (Table2).2). This result is consistent with recent reports that virus isolates containing the M184V mutation display increased susceptibility to PMPA (22, 44). Taken together, these data suggest that P157S and M184V mutants may be more effectively suppressed than wild-type virus by PMPA and AZT in vivo. AZT hypersensitivity may in part account for the observed delay in the appearance of AZT resistance mutations in viruses containing M184V (41).

A comparison of HIV-1 P157S and FIV P156S drug susceptibility reveals important similarities and differences between these two closely related lentiviruses. The resistance of both variants to 3TC demonstrates the utility of the FIV model for discovering candidate drug-resistant mutants of HIV-1 which otherwise may not have been identified. However, the P157S variant of HIV-1 does not share the AZT-resistant phenotype of the FIV mutant and is instead slightly hypersensitive to the drug. This result should be considered in future experiments when FIV is used for studying resistance to the combination of 3TC plus AZT.

Inhibitor susceptibilities of purified RTs.

Changes in drug susceptibility resulting from the P157S mutation were further characterized in cell-free RT assays. P157S, M184V, and wild-type RTs were expressed in Escherichia coli and purified as p66-p51 heterodimers (36). The resulting enzyme preparations contained equal ratios of each subunit and were approximately 95% pure as judged by Coomassie-stained sodium dodecyl sulfate-polyacrylamide gels (data not shown). Sensitivities of the RTs to the 5′-triphosphate forms of 3TC (3TCTP) and AZT (AZTTP) were compared in kinetic assays (Table (Table3).3). Wild-type and mutant RTs exhibited similar apparent Km values for dCTP and dTTP, ranging from 13 to 25 μM. Based on Ki/Km ratios (45), the P157S and M184V RTs had 5- and 200-fold-increased resistance to 3TCTP, respectively. These results parallel the trend in 3TC sensitivity observed with cultured virus (wild-type > P157S [dbl greater-than sign] M184V) (Fig. (Fig.1A1A and Table Table2).2).

TABLE 3
Kinetic constants for wild-type, M184V, and P157S HIV-1 RTsa

Although the M184V and P157S viruses showed increased sensitivity to AZT in culture (Fig. (Fig.1B1B and Table Table2),2), the purified RTs containing these mutations both showed modest AZTTP resistance (two- and threefold, respectively) (Table (Table3).3). Similar discrepancies between virus susceptibility to AZT and inhibition of purified RTs by AZTTP have been noted in other studies (18, 31). The biochemical basis of this discordance is not fully understood, but it is clear that conventional assays used to measure AZTTP susceptibilities of purified RTs do not accurately reflect the susceptibilities of virus isolates to AZT.

Existence of low-level 3TC-resistant variants in vivo.

The P157S mutation described here was detected in a significant proportion of cloned RT sequences from a patient (C0034b) after 2 years of AZT-plus-3TC combination chemotherapy (25); M184V, five AZT resistance mutations (at amino acid positions 41, 67, 70, 215, and 219), and other mutations were also present in the sequences from this individual. A search of 912 viral sequences deposited in the Los Alamos HIV database also revealed the presence of the P157S mutation in the pol gene sequence from a German isolate of HIV-1 (clone NH51, accession no. LO7423) submitted in 1992 (16). Other point mutations conferring low-level resistance to 3TC (e.g., K70E, K65R, and V75T) are also occasionally observed in isolates from patients receiving nucleoside analog therapy (33). The clinical significance of these rare variants is not known. It is likely that such mutations exist in viral populations at low frequencies prior to and/or during the course of therapy (5) and may contribute to the development of high-level drug resistance in 3TC-treated individuals (5, 30).

Contribution of RT template grip to drug susceptibility.

Cocrystal structures of HIV-1 RT bound to template-primer show that P157 is located near the N terminus of helix αE, which contributes to the “template grip” functionality of the enzyme (10, 13). P157 interacts with the minor groove of the template strand, making van der Waals contacts with both the sugar and base moieties of the nucleotide located two residues from the catalytic active site. P157 does not directly interact with the incoming deoxynucleoside triphosphate. Thus, the altered drug susceptibility conferred by P157S must be due to an indirect effect on drug triphosphate recognition at the active site. This idea is supported by the observation that other mutations in the template grip region of RT resulted in resistance to phosphonoformic acid (a pyrophosphate analog) and altered susceptibility to a variety of nucleoside analogs (11, 21, 29, 3840, 43). Boyer et al. (3) propose that the template grip mutant E89G confers drug resistance by repositioning the template-primer at the active site, thereby perturbing the precise relative position of protein and nucleic acid required for normal substrate recognition. This mechanism might also explain the alterations in drug susceptibility resulting from P157S and other mutations in the template grip of RT. Additional biochemical, biophysical, and structural studies are required to directly test this model.

Acknowledgments

This work was supported by Public Health Service grants R01 AI34834, R01 AI38755, and P30 CA42014 to B.P., R01 AI28189 to T.N., and F32 AI10139 to R.A.S. from the National Institutes of Health and by the Department of Veterans Affairs and the Georgia Research Center on AIDS and HIV Infection (R.F.S.).

REFERENCES

1. Back N K, Nijhuis M, Keulen W, Boucher C A, Oude Essink B O, van Kuilenburg A B, van Gennip A H, Berkhout B. Reduced replication of 3TC-resistant HIV-1 variants in primary cells due to a processivity defect of the reverse transcriptase enzyme. EMBO J. 1996;15:4040–4049. [PMC free article] [PubMed]
2. Boucher C A B, Cammack N, Schipper P, Schuurman R, Rouse P, Wainberg M A, Cameron J M. 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;37:2231–2234. [PMC free article] [PubMed]
3. Boyer P L, Tantillo C, Jacobo-Molina A, Nanni R G, Ding J, Arnold E, Hughes S H. Sensitivity of wild type human immunodeficiency virus type 1 reverse transcriptase to dideoxynucleotides depends on template length; the sensitivity of drug resistant mutants does not. Proc Natl Acad Sci USA. 1994;91:4882–4886. [PMC free article] [PubMed]
4. Charneau P, Mirambeau G, Roux P, Paulous S, Buc H, Clavel F. HIV 1 reverse transcription. A termination step at the center of the genome. J Mol Biol. 1994;241:651–662. [PubMed]
5. Coffin J M. HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science. 1995;267:483–489. [PubMed]
6. Cronn R C, Remington K M, Preston B D, North T W. Inhibition of reverse transcriptase from feline immunodeficiency virus by analogs of 2′-deoxyadenosine-5′-triphosphate. Biochem Pharmacol. 1992;44:1375–1381. [PubMed]
7. D’Aquila R T, Johnson V A, Welles S L, Japour A J, Kuritzkes D R, DeGruttola V, Reichelderfer P S, Coombs R W, Crumpacker C S, Kahn J O, Richman D D. Zidovudine resistance and HIV-1 disease progression during antiretroviral therapy. AIDS Clinical Trials Group Protocol 116B/117 Team and the Virology Committee Resistance Working Group. Ann Intern Med. 1995;122:401–408. [PubMed]
8. Doolittle R F, Feng D F, Johnson M S, McClure M A. Origins and evolutionary relationships of retroviruses. Q Rev Biol. 1989;64:1–30. [PubMed]
9. Gao Q, Gu Z, Parniak M A, Cameron J, Cammack N, Boucher C, Wainberg M A. The same mutation that encodes low-level human immunodeficiency virus type 1 resistance to 2′,3′-dideoxyinosine and 2′,3′-dideoxycytidine confers high-level resistance to the (−) enantiomer of 2′,3′-dideoxy-3′-thiacytidine. Antimicrob Agents Chemother. 1993;37:1390–1392. [PMC free article] [PubMed]
10. Huang H, Chopra R, Verdine G L, Harrison S C. Structure of a covalently trapped catalytic complex of HIV 1 reverse transcriptase: implications for drug resistance. Science. 1998;282:1669–1675. [PubMed]
11. Im G J, Tramontano E, Gonzalez C J, Cheng Y C. Identification of the amino acid in the human immunodeficiency virus type 1 reverse transcriptase involved in the pyrophosphate binding of antiviral nucleoside triphosphate analogs and phosphonoformate. Implications for multiple drug resistance. Biochem Pharmacol. 1993;46:2307–2313. [PubMed]
12. Iversen A K N, Shafer R W, Wehrly K, Winters M A, Mullins J I, Chesebro B, Merigan T C. Multidrug-resistant human immunodeficiency virus type 1 strains resulting from combination antiretroviral therapy. J Virol. 1996;70:1086–1090. [PMC free article] [PubMed]
13. Jacobo-Molina A, Ding J, Nanni R G, Clark A D, Jr, Lu X, Tantillo C, Williams R L, Kamer G, Ferris A L, Clark P, Hizi A, Hughes S H, Arnold E. Crystal structure of human immunodeficiency virus type 1 reverse transcriptase complexed with double-stranded DNA at 3.0 Å resolution shows bent DNA. Proc Natl Acad Sci USA. 1993;90:6320–6324. [PMC free article] [PubMed]
14. Kemp S D, Shi C, Bloor S, Harrigan P R, Mellors J W, Larder B A. A novel polymorphism at codon 333 of human immunodeficiency virus type 1 reverse transcriptase can facilitate dual resistance to zidovudine and l-2′,3′-dideoxy-3′-thiacytidine. J Virol. 1998;72:5093–5098. [PMC free article] [PubMed]
15. Kohlstaedt L A, Wang J, Friedman J M, Rice P A, Steitz T A. Crystal structure at 3.5 Å resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science. 1992;256:1783–1790. [PubMed]
16. Korber, B., B. Hahn, B. Foley, J. W. Mellors, T. Leitner, G. Myers, F. McCutchan, and F. Kuiken (ed.). December 1998, revision date. Human retroviruses and AIDS 1998: a compilation and analysis of nucleic acid and amino acid sequences. [Online.] Theoretical Biology and Biophysics Group, Los Alamos, N. Mex. http://hiv-web.lanl.gov. [11 March 1999, last date accessed.].
17. Kuritzkes D R, Quinn J B, Benoit S L, Shugarts D L, Griffin A, Bakhtiari M, Poticha D, Eron J J, Fallon M A, 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;10:975–981. [PubMed]
18. Lacey S F, Reardon J E, Furfine E S, Kunkel T A, Bebenek K, Eckert K A, Kemp S D, Larder B A. Biochemical studies on the reverse transcriptase and RNase H activities from human immunodeficiency virus strains resistant to 3′-azido-3′-deoxythymidine. J Biol Chem. 1992;267:15789–15794. [PubMed]
19. Larder B A. Interactions between drug resistance mutations in human immunodeficiency virus type 1 reverse transcriptase. J Gen Virol. 1994;75:951–957. [PubMed]
20. Larder B A, Kemp S D, Harrigan P R. Potential mechanism for sustained antiretroviral efficacy of AZT-3TC combination therapy. Science. 1995;269:696–699. [PubMed]
21. Mellors J W, Bazmi H Z, Schinazi R F, Roy B M, Hsiou Y, Arnold E, Weir J, Mayers D L. Novel mutations in reverse transcriptase of human immunodeficiency virus type 1 reduce susceptibility to foscarnet in laboratory and clinical isolates. Antimicrob Agents Chemother. 1995;39:1087–1092. [PMC free article] [PubMed]
22. Miller M D, Anton K E, Mulato A S, Lamy P D, Cherrington J M. Human immunodeficiency virus type 1 expressing the lamivudine associated M184V mutation in reverse transcriptase shows increased susceptibility to adefovir and decreased replication capability in vitro. J Infect Dis. 1999;179:92–100. [PubMed]
23. Miller V, Phillips A, Rottmann C, Staszewski S, Pauwels R, Hertogs K, de Bethune M P, Kemp S D, Bloor S, Harrigan P R, Larder B A. Dual resistance to zidovudine and lamivudine in patients treated with zidovudine-lamivudine combination therapy: association with therapy failure. J Infect Dis. 1998;177:1521–1532. [PubMed]
24. Miller V, Sturmer M, Staszewski S, Groschel B, Hertogs K, de Bethune M P, Pauwels R, Harrigan P R, Bloor S, Kemp S D, Larder B A. 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;12:705–712. [PubMed]
25. Nijhuis M, Schuurman R, de Jong D, van Leeuwen R, Lange J, Danner S, Keulen W, de Groot T, Boucher C A. 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;176:398–405. [PubMed]
26. North T W, Cronn R C, Remington K M, Tandberg R T. Direct comparisons of inhibitor sensitivities of reverse transcriptases from feline and human immunodeficiency viruses. Antimicrob Agents Chemother. 1990;34:1505–1507. [PMC free article] [PubMed]
27. O’Neil, P. K., G. Sun, H. Yu, J. P. Dougherty, and B. D. Preston.Unpublished results.
28. Pear W S, Nolan G P, Scott M L, Baltimore D. Production of high titer helper free retroviruses by transient transfection. Proc Natl Acad Sci USA. 1993;90:8392–8396. [PMC free article] [PubMed]
29. Prasad V R, Lowy I, de los Santos T, Chiang L, Goff S P. Isolation and characterization of a dideoxyguanosine triphosphate resistant mutant of human immunodeficiency virus reverse transcriptase. Proc Natl Acad Sci USA. 1991;88:11363–11367. [PMC free article] [PubMed]
30. Preston B D. Reverse transcriptase fidelity and HIV 1 variation. Science. 1997;275:228–229. [PubMed]
31. Remington K M, Zhu Y-Q, Phillips T R, North T W. Rapid phenotypic reversion of zidovudine-resistant feline immunodeficiency virus without loss of drug-resistant reverse transcriptase. J Virol. 1994;68:632–637. [PMC free article] [PubMed]
32. Richman D D. Resistance, drug failure, and disease progression. AIDS Res Hum Retroviruses. 1994;10:901–905. [PubMed]
33. Schinazi R F, Larder B A, Mellors J W. Resistance table: mutations in retroviral genes associated with drug resistance. 1999–2000 update. Int Antivir News. 1999;7:46–69.
34. Schinazi R F, Lloyd R M, Jr, Nguyen M-H, Cannon D L, McMillan A, Ilksoy N, Chu C K, Liotta D C, Bazmi H Z, Mellors J W. Characterization of human immunodeficiency viruses resistant to oxathiolane-cytosine nucleosides. Antimicrob Agents Chemother. 1993;37:875–881. [PMC free article] [PubMed]
35. Smith R A, Remington K M, Preston B D, Schinazi R F, North T W. A novel point mutation at position 156 of reverse transcriptase from feline immunodeficiency virus confers resistance to the combination of (−)-β-2′,3′-dideoxy-3′-thiacytidine and 3′-azido-3′-deoxythymidine. J Virol. 1998;72:2335–2340. [PMC free article] [PubMed]
36. Stahlhut M W, Olsen D B. Expression and purification of retroviral HIV 1 reverse transcriptase. Methods Enzymol. 1996;275:122–133. [PubMed]
37. Swingler S, Gallay P, Camaur D, Song J, Abo A, Trono D. The Nef protein of human immunodeficiency virus type 1 enhances serine phosphorylation of the viral matrix. J Virol. 1997;71:4372–4377. [PMC free article] [PubMed]
38. Tachedjian G, Hooker D J, Gurusinghe A D, Bazmi H, Deacon N J, Mellors J, Birch C, Mills J. Characterisation of foscarnet resistant strains of human immunodeficiency virus type 1. Virology. 1995;212:58–68. [PubMed]
39. Tachedjian G, Mellors J, Bazmi H, Birch C, Mills J. Zidovudine resistance is suppressed by mutations conferring resistance of human immunodeficiency virus type 1 to foscarnet. J Virol. 1996;70:7171–7181. [PMC free article] [PubMed]
40. Tachedjian G, Mellors J W, Bazmi H, Mills J. Impaired fitness of foscarnet resistant strains of human immunodeficiency virus type 1. AIDS Res Hum Retroviruses. 1998;14:1059–1064. [PubMed]
41. Tian H, Whitcomb J, Limoli K, Wrin T, Winslow G, Parkin N, Smith D, Lie Y, Bakthiari M, Shugarts D, Schooley R, Kuritzkes D, Petropoulos C. Programme and abstracts of the 2nd International Workshop on HIV Drug Resistance and Treatment Strategies. London, United Kingdom: International Medical Press; 1998. Zidovudine/lamivudine co-resistance is preceded by a transient period of zidovudine hypersensitivity, abstr. 30; pp. 22–23.
42. Tisdale M, Kemp S D, Parry N R, Larder B A. 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 USA. 1993;90:5653–5656. [PMC free article] [PubMed]
43. Tramontano E, Piras G, Mellors J W, Putzolu M, Bazmi H Z, La Colla P. Biochemical characterization of HIV 1 reverse transcriptases encoding mutations at amino acid residues 161 and 208 involved in resistance to phosphonoformate. Biochem Pharmacol. 1998;56:1583–1589. [PubMed]
44. Wainberg, M. A., M. D. Miller, Y. Quan, H. Solomon, A. S. Mulato, P. D. Lamy, N. A. Margot, K. E. Anton, and J. M. Cherrington.In vitro selection and characterization of HIV-1 with reduced susceptibility to PMPA. Antivir. Ther., in press. [PubMed]
45. Wilson J E, Aulabaugh A, Caligan B, McPherson S, Wakefield J K, Jablonski S, Morrow C D, Reardon J E, Furman P A. Human immunodeficiency virus type-1 reverse transcriptase. Contribution of Met-184 to binding of nucleoside 5′-triphosphate. J Biol Chem. 1996;271:13656–13662. [PubMed]
46. Winters M A, Coolley K L, Girard Y A, Levee D J, Hamdan H, Shafer R W, Katzenstein D A, Merigan T C. A 6-basepair insert in the reverse transcriptase gene of human immunodeficiency virus type 1 confers resistance to multiple nucleoside inhibitors. J Clin Investig. 1998;102:1769–1775. [PMC free article] [PubMed]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...