Skip Navigation LinksHome > June 12, 2006 - Volume 20 - Issue 9 > HIV-1 subtype C viruses rapidly develop K65R resistance to t...
Text sizing:
A
A
A
AIDS:
doi: 10.1097/01.aids.0000232228.88511.0b
Fast Track

HIV-1 subtype C viruses rapidly develop K65R resistance to tenofovir in cell culture

Brenner, Bluma Ga; Oliveira, Maureena; Doualla-Bell, Florencea,b; Moisi, Daniela Da; Ntemgwa, Michela; Frankel, Fernandoa; Essex, Maxb; Wainberg, Mark Aa

Free Access
Article Outline
Collapse Box

Author Information

From the aMcGill University AIDS Centre, Jewish General Hospital, Montreal, Quebec, Canada

bBotswana-Harvard Laboratory, Gaborone, Botswana.

Received 31 January, 2006

Revised 9 March, 2006

Accepted 13 March, 2006

Correspondence to Mark A. Wainberg, McGill AIDS Centre, Jewish General Hospital, 3755 Cote Ste Catherine Road, Montreal, Quebec, Canada H3T 1E2. Tel: +1 514 340 8260; fax: +1 514 340 7537; e-mail: mark.wainberg@mcgill.ca

Collapse Box

Abstract

Background: Genotypic diversity among HIV-1 subtypes and circulating recombinant forms (CRF) may lead to distinct pathways to drug resistance. This study evaluated subtype-related differences in the development of resistance in culture to tenofovir.

Methods: Genotyping determined nucleotide diversity among subtypes. Representative subtype B, C, CRF1_AE, CRF2_AG, G, and HIV-2 isolates were selected for resistance to tenofovir, lamivudine and didanosine in cell culture. Phenotypic assays determined the effects of the K65R substitution in reverse transcriptase (RT) on drug susceptibility.

Results: Subtype C isolates show unique polymorphisms in RT codons 64 (AAG→AAA), 65 (AAA→AAG), and 66 (AAA→AAG), absent in other subtypes. The K65R mutation (AAG→AGG) arose with tenofovir by week 12 in four subtype C selections. In contrast, no tenofovir resistance arose in four subtype B (> 34–74 weeks), one each of CRF2_AG and G (> 30–33 weeks), and three HIV-2 (> 27–28 weeks) selections. K65R appeared after 55 and 73 weeks in two CRF1_AE selections with tenofovir. In contrast, times to the appearance of M184V with lamivudine pressure (weeks 8–14) did not vary among subtypes. Selective didanosine pressure resulted in the appearance of M184V and L74V after 38 weeks in two of four subtype C selections. The K65R transitions in subtype C and other subtypes (AGG and AGA) conferred similar 6.5–10-fold resistance to tenofovir and five to 25-fold crossresistance to each of abacavir, lamivudine, and didanosine, while not affecting zidovudine susceptibility.

Conclusion: Tenofovir -based regimens will need to be carefully monitored in subtype C infections for the possible selection of K65R.

Back to Top | Article Outline

Introduction

The emerging epidemics in Africa and Asia show increasing genetic diversification, with a shift towards non-B subtypes and circulating recombinant forms (CRF) [1–3]. Effective strategies must be developed to handle this growing wave of non-B infections with particular emphasis on subtypes C and A (including CRF1_AE and CRF2_AG), which presently account for over 50 and 30% of new infections worldwide, respectively [3,4].

Natural polymorphisms in non-B subtypes may influence drug susceptibility, therapy response and emerging pathways to drug resistance [5–10]. HIV-1 subtypes can vary by 10–15% in nucleotides and 5–10% in amino acids in the pol gene encoding reverse transcriptase (RT) and protease [11]. Our laboratory has described a subtype C signature mutation in which a valine polymorphism (GTG) codon at 106 facilitates a V106M transition (GTG→ATG) that confers resistance to non-nucleoside RT inhibitors [5].

Resistance to tenofovir is extremely difficult to select in culture [12], although the K65R mutation in RT is associated with such resistance in the clinic. In this study, we describe signature nucleotide polymorphisms in subtype C viruses at RT codons 64, 65, and 66, which may be implicated in emergent resistance to tenofovir. We evaluated the differential times to the development of resistance to tenofovir in cell culture comparing subtype C to other HIV subtypes.

Back to Top | Article Outline

Materials and methods

Viral isolates and selection of drug resistance

Subtype C viral isolates used in this study included BG-05 (AF492600), BG-15 (AF492601), and Mole 18 (AF492607) from Botswana and 4742 (AF492595) from Ethiopia [13,14]. Blood samples harbouring subtype A (n = 1), CRF1_AE (n = 2), CRF2_AG (n = 1), B (n = 4), G (n = 1) viruses were also obtained from treatment-naive patients in Montreal with ethics approval. Viruses were isolated by co-culture of peripheral blood mononuclear cells with cord blood mononuclear cells (CBMC) as previously described [14,15]. The GenBank accession numbers for the Quebec non-B isolates are as follows: 6050 (subtype A-DQ380550), 6343 (CRF1_AE-DQ380549), 6240 (CRF1_AE-DQ385889), 6383 (CRF2_AG-DQ380551), and 5880 (G-DQ380550).

The selection of drug-resistant subtype variants was performed by repeated serial passage of viruses in CBMC in the presence of increasing concentrations of drugs for up to 73 weeks for tenofovir, 30 weeks for lamivudine, and 40 weeks for didanosine. RT assays were performed weekly to assess viral replication [13]. Drug concentrations were escalated over time to maintain effective antiviral pressure, i.e. RT activities (> 10% and < 50%) compared with control cultures grown in the absence of drug. Genotyping was performed at select passages to evaluate time to the development of drug resistance.

Back to Top | Article Outline
Genotypic and phenotypic resistance testing

The sequencing of extracted RNA or complementary DNA was performed by Bayer TruGene or by ABI technology to determine genotypic changes associated with drug resistance [5]. Drug susceptibility was measured in cell culture-based phenotypic assays, determining the extent to which antiretroviral drugs inhibit in-vitro HIV replication. Briefly, CBMC were infected with different subtype viral isolates and the 50% drug inhibitory concentrations (IC50) were ascertained for tenofovir and nucleoside analogues, including zidovudine, lamivudine, abacavir, and didanosine, both pre and post-selection with tenofovir [14,15].

Back to Top | Article Outline

Results

Nucleotide polymorphisms surrounding reverse transcriptase codon 65 in different subtypes

We examined non-B subtype sequences from the Quebec provincial genotyping program to identify natural nucleotide polymorphisms in the HIV-1 RT region that might be implicated in emergent drug resistance. Of note was the fact that subtype C viruses (n = 91/95) show a signature pattern of nucleotide polymorphisms compared with subtype B at RT codons 64 (AAG→AAA), 65 (AAA→AAG), and 66 (AAA→AAG), i.e. a KKK motif. This pattern is specific for subtype C. The codon 64 and codon 65 transitions are absent in subtype B (n = 0/49), A/CRF1_AE (0/35), and CRF2_AG (n = 1/35) infections. The codon 66 polymorphism was, however, observed in 22.4, 37 and 23% of subtype B, A/CRF1_AE and CRF2_AG isolates, respectively. The KKK amino acid motif was common at RT positions 64, 65 and 66 in all subtypes before selection for resistance.

Back to Top | Article Outline
Time to selection of tenofovir resistance in cell culture in different subtypes

To ascertain whether the nucleotide polymorphisms surrounding codon 65 may be implicated in resistance to tenofovir, four representative subtype B and C isolates were passaged in increasing dosages of tenofovir. As shown in Fig. 1, concentrations of tenofovir could be escalated more rapidly in subtype C selections. All four subtype C isolates developed K65R (AAG→AGG) within 12 weeks of serial passage in tenofovir, as rapidly as M184V was selected with lamivudine (Table 1). In contrast, none of the subtype B variants developed K65R in the last time of serial passage, i.e. weeks 34–74 (Table 1). Similarly, none of the subtype A, CRF1_AE, CRF2_AG or G isolates developed K65R at weeks 30–33 of serial passage in tenofovir, although the two CRF1_AE isolates were observed to develop K65R at weeks 55 and 73 (Table 1).

Fig. 1
Fig. 1
Image Tools
Table 1
Table 1
Image Tools
Back to Top | Article Outline
Facilitated development of tenofovir resistance in subtype C viruses

To ascertain whether the rapid development of K65R in subtype C viruses may be caused by virulence or replicative fitness, viral isolates were also selected for resistance to lamivudine and didanosine in parallel to tenofovir. No significant differences in times to the development of resistance to lamivudine were observed for all isolates tested, and M184I/V emerged by weeks 8–14 (Table 1). Of note is the fact that resistance to didanosine developed with two subtype C selections with the first emergence of M184V and L74V between weeks 22 and 25 (Table 1). No resistance-conferring mutations were detected by weeks 37–40 in the presence of didanosine with the remaining subtype B and C isolates (Table 1).

The levels of RT activity in amplified K65R viral stocks grown in the absence of drug were compared with matched wild-type controls. The replicative capacities (mean ± SEM) of the four K65R-containing subtype C isolates and the two K65R-containing subtype CRF1_AE isolates, compared with matched wild-type controls, were 62 ± 7 and 51 ± 3%, respectively, compared with 46 ± 5% for the K65R-containing recombinant B clone compared with wild type.

Back to Top | Article Outline
Drug susceptibility of K65R

Phenotypic drug susceptibility testing was performed to ascertain the drug sensitivity and resistance profiles of different viral subtypes. The baseline IC50 values for tenofovir sensitivity of the four subtype C isolates was 0.48 ± 0.18 μmol, within a similar range, 0.25 ± 0.15 μmol was observed for subtype B infections. Subtype C and CRF1_AE viruses harbouring K65R were assayed for their relative susceptibility to tenofovir and nucleoside analogues. As shown in Fig. 2, all variants harbouring K65R showed similar 6.5 to 10-fold resistance to tenofovir. These viruses also showed 8–22 ×, 10–23 ×, and 3–16 × levels of resistance to abacavir, lamivudine and didanosine, respectively. These viruses all remained susceptible to zidovudine.

Equation (Uncited)
Equation (Uncited)
Image Tools
Fig. 2
Fig. 2
Image Tools
Back to Top | Article Outline

Discussion

Tenofovir has been proposed as a drug of choice in antiviral drug strategies directed against the global pandemic [16], as a result of its favourable resistance profile, long intracellular half-life, and marginal adverse effects [17–20]. Current guidelines recommend tenofovir/emtricitavudine (Truvada) or zidovudine/lamivudine (Combivir) with efavirenz as two first-line treatments of choice for antiretroviral-naive patients [21]. Clinical trials to evaluate the efficiency of tenofovir in pre-exposure prophylaxis have been initiated in Africa, Asia, and the United States [22]. Among the reasons for choosing tenofovir over such drugs as lamivudine has been the reduced risk of developing resistance to tenofovir via the K65R mutation.

We have now demonstrated that tenofovir can rapidly select K65R in subtype C viruses in cell culture. The appearance of K65R with tenofovir is as rapid as that of M184V with lamivudine. These findings indicate that tenofovir-based regimens in subtype C infections will need to be carefully monitored. A recent report suggested that K65R is less prevalent in patients harbouring subtype A than in subtype B and C infections [8]. On the basis of our findings, the reduced prevalence of K65R in subtype A may partly be explained by a higher rate of selection in subtype C infections.

The mechanisms involved in the more rapid selection of K65R among subtype C viruses may relate to the sequences that naturally encode a wild-type KKK motif at codons 64, 65 and 66. Only a single point mutation is required for the emergence of K65R in each of the viral subtypes evaluated. Conceivably, the nucleotide environment of the position 65 codon plays a role in governing the frequency of K65R substitutions, allowing for the more rapid amplification of K65R viruses under conditions of drug pressure. It does not appear that K65R subtype C variants are less impacted in terms of replication capacity, compared with wild-type, than subtype B viruses containing this same substitution [23].

There are potential limitations in extrapolating in-vitro selection data to the in-vivo situation. Site-directed mutagenesis studies in which the AAA codon 65 of a subtype B clone is replaced by AAG and in which the AAG at codon 65 in subtype C viruses is replaced by AAA are ongoing. Previous work showing that a V106M substitution in subtype C viruses is selected by efavirenz provides proof of concept that in-vitro findings may be reflected in the clinical setting [5]. Several recent studies have shown non-responsiveness to tenofovir/lamivudine/abacavir regimens, leading to the rapid appearance of K65R in 48–68% of patients [24,25]. In contrast, the 934 study showed clinical benefit of a tenofovir/emtricitabine/efavirenz regimen with no appearance of K65R [26]. Such studies demonstrated that drug potency, low genetic barrier to tenofovir resistance, and physiological factors may all contribute to differential responsiveness to tenofovir [27]. Our study highlights the need for careful evaluation of tenofovir-based regimens in subtype C infections.

Although the K65R mutation remains relatively uncommon, an increase in its prevalence in western countries has been observed over the past 4 years, as a result of the increased clinical use of tenofovir [26,28–30]. The K65R mutation may also be associated with the Q151M resistance pathway [29]. Our group has shown with others that three out of eight treated patients in Botswana developed K65R with didanosine-containing regimens [31]. Of note is the fact that the the four subtype C isolates selected with didanosine in this study did not develop K65R, although M184V and L74V were observed in two selections.

It is still unknown whether K65R will become increasingly prevalent in subtype C infections after the usage of tenofovir. Our findings indicate the need for vigilance in adapting antiretroviral regimens and prophylactic schedules for use in developing countries, and that subtype differences in regard to the development of drug resistance need to be carefully monitored whenever antiretroviral drugs are introduced.

Sponsorship: This work was sponsored by the Canadian Institutes for Health Research (CIHR), the Canadian Foundation for AIDS research (CANFAR), and Fonds de la Recherche en Santé du Québec-SIDA (FRSQ-SIDA).

Back to Top | Article Outline

References

1. Spira S, Wainberg MA, Loemba H, Turner D, Brenner BG. The impact of clade diversity on HIV-1 virulence, antiretroviral drug sensitivity and drug resistance. J Antimicrob Chemother 2003; 51:229–240.

2. Essex M, Mboup S. Regional variations in the African epidemics. In: Essex M, Mboup S, Kanki PJ, Marlink RG, Tlou SD, editors. AIDS in Africa. New York: Kluwer/Plenum Publishers; 2002.

3. Kantor R, Katzenstein DA, Efron B, Carvalho AP, Wynhoven B, Cane P, et al. Impact of HIV-1 subtype and antiretroviral therapy on protease and reverse transcriptase genotype: results of a global collaboration. PLOS Med 2005; 2:325–337.

4. Osmanov S, Pattou C, Walker N, Schwardlander B, Esparza J. WHO–UNAIDS Network for HIV Isolation and Characterization. Estimated global distribution and regional spread of HIV-1 genetic subtypes in the year 2000. J Acquir Immune Defic Syndr 2002; 29:184–190.

5. Brenner B, Turner D, Oliveira M, Moisi D, Detorio M, Carobene M, et al. A V106M mutation in HIV-1 clade C viruses exposed to efavirenz confers cross-resistance to non-nucleoside reverse transcriptase inhibitors. AIDS 2003; 17:F1–F5.

6. Abecasis AB, Deforche K, Snoeck J, Bacheler L, McKenna P, Carvalho AP, et al. Protease mutation M89I/V is linked to therapy failure in patients infected with the HIV-1 non-B subtypes C. F or G AIDS 2005; 19:1799–1806.

7. Eshleman S, Guay LA, Wang J, Mwatha A, Brown ER, Musoke P, et al. Distinct Patterns of emergence and fading of K103N and Y181C in women with subtype A vs. D after single-dose nevirapine: HIVNET 012. J Acquir Immune Defic Syndr 2005; 40:24–29.

8. Gupta RK, Chrystie IL, O'Shea S, Mullen JE, Kulasegaram R, Tong CYW. K65R and Y181C are less prevalent in HAART-experienced HIV-1 subtype A patients. AIDS 2005; 19:1916–1919.

9. Grossman Z, Istomin V, Averbach D, Lorber M, Risenberg K, Levi I, et al. Genetic variation at NNRTI resistance-associated positions in patients infected with HIV-1 subtype C. AIDS 2004; 18:909–915.

10. Grossman Z, Paxinos EE, Averback D, Maayan S, Parkin NT, Engelhard D, et al. Mutation D30N is not preferentially selected by human immunodeficiency virus type 1 subtype C in the development of resistance to nelfinavir. Antimicrob Agents Chemother 2004; 48:2159–2165.

11. Turner D, Brenner B, Moisi D, Detorio M, Cesaire R, Kurimuri T, et al. Nucleotide and amino acid polymorphisms at drug resistance sites in non-B subtype HIV-1 variants. Antimicrob Agents Chemother 2004; 48:2993–2998.

12. Wainberg MA, Miller MD, Quan Y, Salomon H, Mulato AS, Lamy PD, et al. In vitro selection and characterization of HIV-1 with reduced susceptibility to PMPA. Antiviral Ther 1999; 4:87–94.

13. Loemba H, Brenner B, Parniak MA, Ma'ayan S, Spira B, Moisi D, et al. Polymorphisms of cytotoxic T-lymphocyte (CTL) and T-helper epitopes within reverse transcriptase (RT) of HIV-1 subtype C from Ethiopia and Botswana following selection of antiretroviral drug resistance. Antiviral Res 2002; 56:129–142.

14. Loemba H, Brenner B, Parniak MA, Ma'ayan S, Spira B, Moisi D, et al. Genetic divergence of HIV-1 Ethiopian clade C reverse transcriptase (RT) and rapid development of resistance against non-nucleoside inhibitors of RT. Antimicrob Agents Chemother 2002; 46:2087–2094.

15. Salomon H, Belmonte A, Nguyen K, Gu Z, Gelfand M, Wainberg MA. Comparison of cord blood and peripheral blood mononuclear cells as targets for viral isolation and drug sensitivity studies involving human immunodeficiency virus type 1. J Clin Microbiol 1994; 32:2000–2002.

16. Wainberg MA. Generic HIV drugs-enlightened policy for global health. N Engl J Med 2005; 352:747–750.

17. De Clercq E, Holy A. Acyclic nucleoside phosphonates: a key class of antiviral drugs. Nat Rev 2005; 4:928–940.

18. Gallant JE, Deresinski S. Tenofovir disproxyl fumarate. Clin Infect Dis 2003; 37:849–859.

19. Gallant JE, Staszewski S, Pozniak AL, DeJesus E, Sulieman JM, Miller MD, et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients. A 3-year randomized trial. JAMA 2004; 292:191–201.

20. Barditch-Crovo P, Deeks SG, Collier A, Safrin S, Coakley DF, Miller M, et al. Phase i/ii trial of the pharmacokinetics, safety, and antiretroviral activity of tenofovir disoproxil fumarate in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother 2001; 45:2733–2739.

21. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Available at: http://AIDSinfo.nih.gov. Accessed: 6 October 2005.

22. Grant RM, Buchbinder S, Cates W Jr, Clarke E, Coates T, Cohen MS, et al. Promote HIV chemoprophylaxis research, don't prevent it. Science 2005; 309:2170–2171.

23. White KL, Margot NA, Wrin T, Petropoulos CJ, Miller MD, Naeger LK. Molecular mechanisms of resistance to human immunodeficiency virus type 1 with reverse transcriptase mutations K65R and K65R+M184V and their effects on enzyme function and viral replication capacity. Antimicrob Agents Chemother 2002; 46:3437–3446.

24. Gallant JE, Rodriguez AE, Weinberg WG, Young B, Berger DS, Lim ML, et al. Early virologic nonresponse to tenofovir, abacavir, and lamivudine in HIV-infected antiretroviral-naive subjects. J Infect Dis 2005; 192:1921–1930.

25. Delauney C, Brun-Vezinet F, Landman R, Collin G, Peytavin G, Trylesinski A, et al. 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; 79:9572–9578.

26. Gallant JE, DeJesus E, Arribas JR, Pozniak AL, Gazzard B, Campo RE, et al. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med 2006; 354:251–260.

27. Kuritkes DR. Less than the sum of its parts: failure of a tenofovir-abacavir-lamivudine triple-nucleoside regimen. J Infect Dis 2005; 192:1867–1868.

28. Winston A, Pozniak A, Mandalia S, Gazzard B, Pillay D, Nelson M. Which nucleoside and nucleotide backbone combinations select for the K65R mutation in HIV-1 reverse transcriptase. AIDS 2004; 18:949–951.

29. Valer L, Martin-Carbonero L, de Mendoza C, Corral A, Soriano V. Predictors of selection of K65R: tenofovir use and lack of thymidine analogue mutations. AIDS 2004; 18:2094–2096.

30. Gianotti N, Seminari E, Fusetti G, Salpietro S, Boeri E, Galli A, et al. Impact of a treatment including tenofovir plus didanosine on the selection of the 65R mutation in highly drug-experienced HIV-infected patients. AIDS 2004; 18:2205–2208.

31. Doualla-Bell F, Gaseitsiwe S, Ndung'u T, Modukanele M, Peter T, Novitsky V, et al. Mutations and polymorphisms associated with antiretroviral drugs in HIV-1C-infected African patients. Antivir Chem Chemother 2004; 15:189–200.

Cited By:

This article has been cited 64 time(s).

AIDS Research and Human Retroviruses
HIV-1 Subtype Distribution Trends and Evidence of Transmission Clusters Among Incident Cases in a Rural Clinical Cohort in Southwest Uganda, 2004-2010
Kapaata, A; Lyagoba, F; Ssemwanga, D; Magambo, B; Nanyonjo, M; Levin, J; Mayanja, BN; Mugasa, C; Parry, CM; Kaleebu, P
AIDS Research and Human Retroviruses, 29(3): 520-527.
10.1089/aid.2012.0170
CrossRef
Cold Spring Harbor Perspectives in Medicine
The HIV-1 Epidemic: Low- to Middle-Income Countries
Shao, YM; Williamson, C
Cold Spring Harbor Perspectives in Medicine, 2(3): -.
ARTN a007187
CrossRef
Virology
Connection subdomain mutations in HIV-1 subtype-C treatment-experienced patients enhance NRTI and NNRTI drug resistance
Delviks-Frankenberry, KA; Lengruber, RB; Santos, AF; Silveira, JM; Soares, MA; Kearney, MF; Maldarelli, F; Pathak, VK
Virology, 435(2): 433-441.
10.1016/j.viro1.2012.09.021
CrossRef
Plos One
Monitoring HIV Viral Load in Resource Limited Settings: Still a Matter of Debate?
Arnedo, M; Alonso, E; Eisenberg, N; Ibanez, L; Ferreyra, C; Jaen, A; Flevaud, L; Khamadi, S; Roddy, P; Gatell, JM; Dalmau, D
Plos One, 7(): -.
ARTN e47391
CrossRef
Journal of the International AIDS Society
Virological outcome and patterns of HIV-1 drug resistance in patients with 36 months' antiretroviral therapy experience in Cameroon
Aghokeng, AF; Kouanfack, C; Eymard-Duvernay, S; Butel, C; Edoul, GE; Laurent, C; Koulla-Shiro, S; Delaporte, E; Mpoudi-Ngole, E; Peeters, M
Journal of the International AIDS Society, 16(): -.
ARTN 18004
CrossRef
Plos One
Potential Impact of Antiretroviral Chemoprophylaxis on HIV-1 Transmission in Resource-Limited Settings
Abbas, UL; Anderson, RM; Mellors, JW
Plos One, 2(9): -.
ARTN e875
CrossRef
Journal of Antimicrobial Chemotherapy
Once-daily dosing of nevirapine in HAART
Clotet, B
Journal of Antimicrobial Chemotherapy, 61(1): 13-16.
10.1093/jac/dkm432
CrossRef
AIDS Reviews
Characterization and Structural Analysis of HIV-1 Integrase Conservation
Ceccherini-Silberstein, F; Malet, I; D'Arrigo, R; Antinori, A; Marcelin, AG; Perno, CF
AIDS Reviews, 11(1): 17-29.

Retrovirology
Comparative biochemical analysis of HIV-1 subtype B and C integrase enzymes
Bar-Magen, T; Sloan, RD; Faltenbacher, VH; Donahue, DA; Kuhl, BD; Oliveira, M; Xu, HT; Wainberg, MA
Retrovirology, 6(): -.
ARTN 103
CrossRef
Plos Medicine
Criteria for drugs used in pre-exposure prophylaxis trials against HIV infection
Derdelinckx, I; Wainberg, MA; Lange, JMA; Hill, A; Halima, Y; Boucher, CAB
Plos Medicine, 3(): 1999-2004.
ARTN e454
CrossRef
Antiviral Therapy
Effects of HIV type-1 immune selection on susceptability to integrase inhibitor resistance
Tschochner, M; Chopra, A; Maiden, TM; Ahmad, IF; James, I; Furrer, H; Gunthard, HF; Mallal, S; Rauch, A; John, M
Antiviral Therapy, 14(7): 953-964.
10.3851/IMP1419
CrossRef
Journal of Infectious Diseases
Slow Accumulation of HIV Resistance Mutations: Implications for Resource-Limited Settings?
Stevens, WS
Journal of Infectious Diseases, 200(5): 670-672.
10.1086/604732
CrossRef
Retrovirology
New pandemics: HIV and AIDS, HCV and chronic hepatitis, influenza virus and flu
Gatignol, A; Dubuisson, J; Wainberg, MA; Cohen, EA; Darlix, JL
Retrovirology, 4(): -.
ARTN 8
CrossRef
AIDS Research and Human Retroviruses
Drug resistance in plasma and breast milk after single-dose nevirapine in subtype C HIV type 1: Population and clonal sequence analysis
Kassaye, S; Lee, E; Kantor, R; Johnston, E; Winters, M; Zijenah, L; Mateta, P; Katzenstein, D
AIDS Research and Human Retroviruses, 23(8): 1055-1061.
10.1089/aid.2007.0045
CrossRef
New England Journal of Medicine
Medical progress: The challenge of HIV-1 subtype diversity
Taylor, BS; Sobieszczyk, ME; McCutchan, FE; Hammer, SM
New England Journal of Medicine, 358(): 1590-1602.

Journal of Antimicrobial Chemotherapy
High rate of early virological failure with the once-daily tenofovir/lamivudine/nevirapine combination in naive HIV-1-infected patients
Rey, D; Hoen, B; Chavanet, P; Schmitt, MP; Hoizey, G; Meyer, P; Peytavin, G; Spire, B; Allavena, C; Diemer, M; May, T; Schmit, JL; Duong, M; Calvez, V; Lang, JM
Journal of Antimicrobial Chemotherapy, 63(2): 380-388.
10.1093/jac/dkn471
CrossRef
Antimicrobial Agents and Chemotherapy
High prevalence of the K65R mutation in human immunodeficiency virus type 1 subtype C isolates from infected patients in Botswana treated with didanosine-based regimens
Doualla-Bell, F; Avalos, A; Brenner, B; Gaolathe, T; Mine, M; Gaseitsiwe, S; Oliveira, M; Moisi, D; Ndwapi, N; Moffat, H; Essex, M; Wainberg, MA
Antimicrobial Agents and Chemotherapy, 50(): 4182-4185.
10.1128/AAC.00714-06
CrossRef
Journal of Virology
Candidate microbicide PPCM blocks human immunodeficiency virus type 1 infection in cell and tissue cultures and prevents genital herpes in a murine model
Mesquita, PMM; Wilson, SS; Manlow, P; Fischetti, L; Keller, MJ; Herold, BC; Shattock, RJ
Journal of Virology, 82(): 6576-6584.
10.1128/JVI.00335-08
CrossRef
Antiviral Therapy
The status of HIV-1 resistance to antiretroviral drugs in sub-Saharan Africa
Hamers, RL; Derdelinckx, I; van Vugt, M; Stevens, W; de Wit, TFR; Schuurman, R
Antiviral Therapy, 13(5): 625-639.

AIDS Research and Human Retroviruses
HIV Type 1 Antiretroviral Resistance Mutations in Subtypes B, C, and F in the City of Sao Paulo, Brazil
Munerato, P; Sucupira, MC; Oliveros, MPR; Janini, LM; de Souza, DF; Pereira, AA; Inocencio, LA; Diaz, RS
AIDS Research and Human Retroviruses, 26(3): 265-273.
10.1089/aid.2009.0288
CrossRef
Retrovirology
Effects of the K65R and K65R/M184V reverse transcriptase mutations in subtype C HIV on enzyme function and drug resistance
Xu, HT; Martinez-Cajas, JL; Ntemgwa, ML; Coutsinos, D; Frankel, FA; Brenner, BG; Wainberg, MA
Retrovirology, 6(): -.
ARTN 14
CrossRef
Antimicrobial Agents and Chemotherapy
Reverse Transcriptase Inhibitors as Potential Colorectal Microbicides
Herrera, C; Cranage, M; McGowan, I; Anton, P; Shattock, RJ
Antimicrobial Agents and Chemotherapy, 53(5): 1797-1807.
10.1128/AAC.01096-08
CrossRef
Journal of Virology
Template Usage Is Responsible for the Preferential Acquisition of the K65R Reverse Transcriptase Mutation in Subtype C Variants of Human Immunodeficiency Virus Type 1
Coutsinos, D; Invernizzi, CF; Xu, HT; Moisi, D; Oliveira, M; Brenner, BG; Wainberg, MA
Journal of Virology, 83(4): 2029-2033.
10.1128/JVI.01349-08
CrossRef
Antiviral Research
Genotypic analysis of the protease and reverse transcriptase of non-B HIV type 1 clinical isolates from naive and treated subjects
Monno, L; Scudeller, L; Brindicci, G; Saracino, A; Punzi, G; Chirianni, A; Lagioia, A; Ladisa, N; Lo Caputo, S; Angarano, G
Antiviral Research, 83(2): 118-126.
10.1016/j.antiviral.2009.04.001
CrossRef
Journal of Medical Virology
Prevalence of the K65R Resistance Reverse Transcriptase Mutation in Different HIV-1 Subtypes in Israel
Turner, D; Shahar, E; Katchman, E; Kedem, E; Matus, N; Katzir, M; Hassoun, G; Pollack, S; Kessner, R; Wainberg, MA; Avidor, B
Journal of Medical Virology, 81(9): 1509-1512.
10.1002/jmv.21567
CrossRef
Plos Medicine
Antiretroviral therapy for prevention of HIV infection: New clues from an animal model
Cohen, MS; Kashuba, ADM
Plos Medicine, 5(2): 190-192.
ARTN e30
CrossRef
Lancet Infectious Diseases
Virological follow-up of adult patients in antiretroviral treatment programmes in sub-Saharan Africa: a systematic review
Barth, RE; van der Loeff, MFS; Schuurman, R; Hoepelmon, AIM; Wensing, AMJ
Lancet Infectious Diseases, 10(3): 155-166.

AIDS Research and Human Retroviruses
HIV Type 1 Subtype C Drug Resistance among Pediatric and Adult South African Patients Failing Antiretroviral Therapy
Pillay, V; Pillay, C; Kantor, R; Venter, F; Levin, L; Morris, L
AIDS Research and Human Retroviruses, 24(): 1449-1454.
10.1089/aid.2008.0180
CrossRef
Journal of Virology
Replicative Capacity Differences of Thymidine Analog Resistance Mutations in Subtype B and C Human Immunodeficiency Virus Type 1
Armstrong, KL; Lee, TH; Essex, M
Journal of Virology, 83(9): 4051-4059.
10.1128/JVI.02645-08
CrossRef
AIDS Research and Human Retroviruses
Single-stranded DNA aptamer RT1t49 inhibits RT polymerase and RNase H functions of HIV type 1, HIV type 2, and SIVCPZ RTs
Kissel, JD; Held, DM; Hardy, RW; Burke, DH
AIDS Research and Human Retroviruses, 23(5): 699-708.
10.1089/aid.2006.0262
CrossRef
Plos Pathogens
Theme and variations in the evolutionary pathways to virulence of an RNA plant virus species
Pinel-Galzi, A; Rakotomalala, M; Sangu, E; Sorho, F; Kanyeka, Z; Traore, O; Sereme, D; Poulicard, N; Rabenantoandro, Y; Sere, Y; Konate, G; Ghesquiere, A; Hebrard, E; Fargette, D
Plos Pathogens, 3(): 1761-1770.
ARTN e180
CrossRef
Antiviral Therapy
Clinical implications of resistance to antiretrovirals: new resistance technologies and interpretations
Mascolini, M; Richman, D; Larder, B; Mellors, J; Boucher, CAB
Antiviral Therapy, 13(2): 319-334.

American Journal of Reproductive Immunology
Impact of microbicides and sexually transmitted infections on mucosal immunity in the female genital tract
Keller, MJ; Herold, BC
American Journal of Reproductive Immunology, 56(): 356-363.
10.1111/j.1600-0897.2006.00436.x
CrossRef
AIDS Reviews
HIV-1 drug resistance mutations: an updated framework for the second decade of HAART
Shafer, RW; Schapiro, JM
AIDS Reviews, 10(2): 67-84.

Antiviral Research
Perspectives on antiviral drug development
Wainberg, MA
Antiviral Research, 81(1): 1-5.
10.1016/j.antiviral.2008.09.003
CrossRef
Journal of Infectious Diseases
Chemoprophylaxis of HIV infection: Moving forward with caution
Grant, RM; Wainberg, MA
Journal of Infectious Diseases, 194(7): 874-876.

Antiviral Therapy
Virological response to salvage therapy in HIV-infected persons carrying the reverse transcriptase K65R mutation
Antinori, A; Trotta, MP; Lorenzini, P; Torti, C; Gianotti, N; Maggiolo, F; Ceccherini-Silberstein, F; Nasta, P; Castogna, A; De Luca, A; Mussini, C; Andreoni, M; Perno, CF
Antiviral Therapy, 12(8): 1175-1183.

Proceedings of the National Academy of Sciences of the United States of America
The paradoxical effects of using antiretroviral-based microbicides to control HIV epidemics
Wilson, DP; Coplan, PM; Wainberg, MA; Blower, SM
Proceedings of the National Academy of Sciences of the United States of America, 105(): 9835-9840.
10.1073/pnas.0711813105
CrossRef
Journal of Clinical Virology
Evolution of genotypic resistance to enfuvirtide in HIV-1 isolates from different group M subtypes
Covens, K; Kabeya, K; Schrooten, Y; Dekeersmaeker, N; Van Wijngaerden, E; Vandamme, AM; De Wit, S; Van Laethem, K
Journal of Clinical Virology, 44(4): 325-328.
10.1016/j.jcv.2009.01.012
CrossRef
Plos One
The HIV-1 Subtype C Epidemic in South America Is Linked to the United Kingdom
de Oliveira, T; Pillay, D; Gifford, RJ
Plos One, 5(2): -.
ARTN e9311
CrossRef
Antiviral Therapy
HIV type-1 clade C resistance genotypes in treatment-naive patients and after first virological failure in a large community antiretroviral therapy programme
Orrell, C; Walensky, RP; Losina, E; Pitt, J; Freedberg, KA; Wood, R
Antiviral Therapy, 14(4): 523-531.

AIDS Research and Human Retroviruses
Changes in Drug Resistance Patterns following the Introduction of HIV Type 1 Non-B Subtypes in Spain
De Mendoza, C; Garrido, C; Poveda, E; Corral, A; Zahonero, N; Trevino, A; Anta, L; Soriano, V
AIDS Research and Human Retroviruses, 25(): 967-972.
10.1089/aid.2008.0166
CrossRef
Antiviral Therapy
Progress in basic and clinical research on HIV resistance: report on the XVIII International HIV Drug Resistance Workshop
Mascolini, M; Boucher, CAB; Mellors, JW; Larder, BA; Richman, DD
Antiviral Therapy, 14(7): 1015-1037.
10.3851/IMP1423
CrossRef
Plos One
Nucleic Acid Template and the Risk of a PCR-Induced HIV-1 Drug Resistance Mutation
Varghese, V; Wang, E; Babrzadeh, F; Bachmann, MH; Shahriar, R; Liu, T; Mappala, SJM; Gharizadeh, B; Fessel, WJ; Katzenstein, D; Kassaye, S; Shafer, RW
Plos One, 5(6): -.
ARTN e10992
CrossRef
Clinical Infectious Diseases
Antiretroviral drug resistance testing in adult HIV-1 infection: 2008 recommendations of an International AIDS Society-USA panel
Hirsch, MS; Gunthard, HF; Schapiro, JM; Brun-Vezinet, F; Clotet, B; Hammer, SM; Johnson, VA; Kuritzkes, DR; Mellors, JW; Pillay, D; Yeni, PG; Jacobsen, DM; Richman, DD
Clinical Infectious Diseases, 47(2): 266-285.
10.1086/589297
CrossRef
Future Virology
Antiviral drug development: progress and pitfalls
Coutsinos, D; Sloan, R; Wainberg, MA
Future Virology, 3(6): 529-532.
10.2217/17460794.3.6.529
CrossRef
AIDS Reviews
Role of Genetic Diversity amongst HIV-1 Non-B Subtypes in Drug Resistance: A Systematic Review of Virologic and Biochemical Evidence
Martinez-Cajas, JL; Pant-Pai, N; Klein, MB; Wainberg, MA
AIDS Reviews, 10(4): 212-223.

Antimicrobial Agents and Chemotherapy
Nucleoside and Nucleotide Analogs Select in Culture for Different Patterns of Drug Resistance in Human Immunodeficiency Virus Types 1 and 2
Ntemgwa, ML; Toni, TD; Brenner, BG; Oliveira, M; Asahchop, EL; Moisi, D; Wainberg, MA
Antimicrobial Agents and Chemotherapy, 53(2): 708-715.
10.1128/AAC.01109-08
CrossRef
Journal of Infectious Diseases
Signature Nucleotide Polymorphisms at Positions 64 and 65 in Reverse Transcriptase Favor the Selection of the K65R Resistance Mutation in HIV-1 Subtype C
Invernizzi, CF; Coutsinos, D; Oliveira, M; Moisi, D; Brenner, BG; Wainberg, MA
Journal of Infectious Diseases, 200(8): 1202-1206.
10.1086/605894
CrossRef
AIDS Research and Human Retroviruses
Discrepancies in assignment of subtype/recombinant forms by genotyping programs for HIV type 1 drug resistance testing may falsely predict superinfection
Ntemgwa, M; Gill, MJ; Brenner, BG; Moisi, D; Wainberg, MA
AIDS Research and Human Retroviruses, 24(7): 995-1002.
10.1089/aid.2008.0064
CrossRef
Virology
The increasing prevalence of HIV-1 subtype C in Southern Brazil and its dispersion through the continent
Graf, T; Pinto, AR
Virology, 435(1): 170-178.
10.1016/j.virol.2012.08.048
CrossRef
Journal of Infectious Diseases
Nucleoside Reverse Transcriptase Inhibitor Resistance Mutations Associated with First-Line Stavudine-Containing Antiretroviral Therapy: Programmatic Implications for Countries Phasing Out Stavudine
Tang, MW; Rhee, SY; Bertagnolio, S; Ford, N; Holmes, S; Sigaloff, KC; Hamers, RL; de Wit, TFR; 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; Shafer, RW
Journal of Infectious Diseases, 207(): S70-S77.
10.1093/infdis/jit114
CrossRef
AIDS
K65R development among subtype C HIV-1-infected patients in tenofovir DF clinical trials
Miller, MD; Margot, N; McColl, D; Cheng, AK
AIDS, 21(2): 265-266.
10.1097/QAD.0b013e32801199ee
PDF (232) | CrossRef
AIDS
Tolerance and viral resistance after single-dose nevirapine with tenofovir and emtricitabine to prevent vertical transmission of HIV-1
The TEmAA ANRS 12109 Study group,
AIDS, 23(7): 825-833.
10.1097/QAD.0b013e32832949d5
PDF (129) | CrossRef
AIDS
The public health approach to identify antiretroviral therapy failure: high-level nucleoside reverse transcriptase inhibitor resistance among Malawians failing first-line antiretroviral therapy
Fiscus, SA; Nelson, JA; Eron, JJ; Kumwenda, J; Hosseinipour, MC; van Oosterhout, JJ; Weigel, R; Phiri, S; Kamwendo, D; Parkin, N
AIDS, 23(9): 1127-1134.
10.1097/QAD.0b013e32832ac34e
PDF (170) | CrossRef
AIDS
Rational use of antiretroviral therapy in low-income and middle-income countries: optimizing regimen sequencing and switching
Elliott, JH; Lynen, L; Calmy, A; De Luca, A; Shafer, RW; Zolfo, M; Clotet, B; Huffam, S; Boucher, CA; Cooper, DA; Schapiro, JM
AIDS, 22(16): 2053-2067.
10.1097/QAD.0b013e328309520d
PDF (330) | CrossRef
AIDS
Silent mutations are selected in HIV-1 reverse transcriptase and affect enzymatic efficiency
Harrigan, PR; Sheen, C; Gill, VS; Wynhoven, B; Hudson, E; Lima, VD; Lecocq, P; Aguirre, R; Poon, AF; Sluis-Cremer, N
AIDS, 22(18): 2501-2508.
10.1097/QAD.0b013e328318f16c
PDF (410) | CrossRef
Current Opinion in Infectious Diseases
Impact of HIV-1 pol diversity on drug resistance and its clinical implications
Kantor, R
Current Opinion in Infectious Diseases, 19(6): 594-606.
10.1097/QCO.0b013e3280109122
PDF (215) | CrossRef
JAIDS Journal of Acquired Immune Deficiency Syndromes
Varied Patterns of HIV-1 Drug Resistance on Failing First-Line Antiretroviral Therapy in South Africa
Wallis, CL; Mellors, JW; Venter, WD; Sanne, I; Stevens, W
JAIDS Journal of Acquired Immune Deficiency Syndromes, 53(4): 480-484.
10.1097/QAI.0b013e3181bc478b
PDF (353) | CrossRef
JAIDS Journal of Acquired Immune Deficiency Syndromes
Lack of Minority K65R-Resistant Viral Populations Detected After Repeated Treatment Interruptions of Tenofovir/Zidovudine and Lamivudine in a Resource-Limited Setting
McCormick, AL; Goodall, RL; Joyce, A; Ndembi, N; Chirara, M; Katundu, P; Walker, S; Yirrell, D; Gilks, CF; Pillay, D; on behalf of the DART Virology Group Trial Team,
JAIDS Journal of Acquired Immune Deficiency Syndromes, 54(2): 215-216.
10.1097/QAI.0b013e3181cc1058
PDF (317) | CrossRef
JAIDS Journal of Acquired Immune Deficiency Syndromes
Development of HIV-1 Drug Resistance Through 144 Weeks in Antiretroviral-Naïve Subjects on Emtricitabine, Tenofovir Disoproxil Fumarate, and Efavirenz Compared With Lamivudine/Zidovudine and Efavirenz in Study GS-01-934
and the Study 934 Team, ; Margot, NA; Enejosa, J; Cheng, AK; Miller, MD; McColl, DJ
JAIDS Journal of Acquired Immune Deficiency Syndromes, 52(2): 209-221.
10.1097/QAI.0b013e3181b05f7c
PDF (244) | CrossRef
JAIDS Journal of Acquired Immune Deficiency Syndromes
Clinical and Genotypic Findings in HIV-Infected Patients With the K65R Mutation Failing First-Line Antiretroviral Therapy in Nigeria
and APIN Plus/Harvard PEPFAR Team, ; Hawkins, CA; Chaplin, B; Idoko, J; Ekong, E; Adewole, I; Gashau, W; Murphy, RL; Kanki, P
JAIDS Journal of Acquired Immune Deficiency Syndromes, 52(2): 228-234.
10.1097/QAI.0b013e3181b06125
PDF (111) | CrossRef
The Pediatric Infectious Disease Journal
Diminished Selection for Thymidine-Analog Mutations Associated With the Presence of M184V in Ethiopian Children Infected With HIV Subtype C Receiving Lamivudine-Containing Therapy
Averbuch, D; Schapiro, JM; Lanier, ER; Gradstein, S; Gottesman, G; Kedem, E; Einhorn, M; Grisaru-Soen, G; Ofir, M; Engelhard, D; Grossman, Z
The Pediatric Infectious Disease Journal, 25(11): 1049-1056.
10.1097/01.inf.0000243211.36690.d5
PDF (301) | CrossRef
Sexually Transmitted Diseases
Understanding Basic Mechanisms and Optimizing Assays to Evaluate the Efficacy of Vaginal Microbicides
Keller, MJ; Herold, BC
Sexually Transmitted Diseases, 36(3): S92-S95.
10.1097/OLQ.0b013e318199417d
PDF (147) | CrossRef
Back to Top | Article Outline
Keywords:

HIV-1 subtype diversity; K65R; subtype C; tenofovir

© 2006 Lippincott Williams & Wilkins, Inc.

Login

Search for Similar Articles
You may search for similar articles that contain these same keywords or you may modify the keyword list to augment your search.