The evolution of resistance is a universal challenge in antimicrobial chemotherapy. A key driver of resistance is that drug resistance mutations often persist even in the absence of drugs and despite the fact that resistance mutations are often associated with reduced pathogen replication (“fitness costs”). Such persistence may occur because fitness costs are low, especially if they are compensated by additional mutations in their “genetic background”. Here we assessed the role of fitness-cost and the genetic background for resistance in a real-world epidemiological setting by studying the persistence behavior of transmitted antiretroviral resistance mutations of HIV. This persistence behavior was associated with the predicted fitness cost of a given resistance mutation in the particular genetic background in which it occurred. We found that persistence behavior varied strongly across both mutation types and genetic backgrounds and that persistence was significantly associated with predicted fitness costs. In particular we found that even mutations of the same type tended to persist longer if they occurred in a genetic background where they caused weak fitness costs. Overall our results underline the variability of persistence behavior as well as the important role of fitness costs and the genetic background in the evolution of antimicrobial resistance.
Vyšlo v časopise: Persistence of Transmitted HIV-1 Drug Resistance Mutations Associated with Fitness Costs and Viral Genetic Backgrounds. PLoS Pathog 11(3): e32767. doi:10.1371/journal.ppat.1004722 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004722
1. Palella FJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. The new England journal of medicine 1998; 338 : 853–860. 9516219
2. von Wyl V, Yerly S, Bürgisser P, Klimkait T, Battegay M, Bernasconi E, et al. Long‐Term Trends of HIV Type 1 Drug Resistance Prevalence among Antiretroviral Treatment–Experienced Patients in Switzerland. Clin Infect Dis 2009; 48 : 979–987. doi: 10.1086/597352 19228107
3. Vercauteren J, Wensing AM, van de Vijver DA, Albert J, Balotta C, Hamouda O, et al. Transmission of Drug‐Resistant HIV‐1 Is Stabilizing in Europe. J Infect Dis 2009; 200 : 1503–1508. doi: 10.1086/644505 19835478
4. Yerly S, Vora S, Rizzardi P, Chave JP, Vernazza PL, Flepp M, et al. Acute HIV infection: impact on the spread of HIV and transmission of drug resistance. AIDS 2001; 15 : 2287–2292. 11698702
5. Yerly S, von Wyl V, Ledergerber B, Böni J, Schüpbach J, Bürgisser P, et al. Transmission of HIV-1 drug resistance in Switzerland: a 10-year molecular epidemiology survey. AIDS 2007; 21 : 2223–2229. 18090050
6. Little SJ. Transmission and prevalence of HIV resistance among treatment-naive subjects. Antiviral Therapy 2000;
7. Jakobsen MR, Tolstrup M, Søgaard OS, Jørgensen LB, Gorry PR, Laursen A, et al. Transmission of HIV-1 drug-resistant variants: prevalence and effect on treatment outcome. Clin Infect Dis 2010; 50 : 566–573. doi: 10.1086/650001 20085464
8. Wensing AMJ, van de Vijver DA, Angarano G, Asjö B, Balotta C, Boeri E, et al. Prevalence of drug-resistant HIV-1 variants in untreated individuals in Europe: implications for clinical management. J Infect Dis 2005; 192 : 958–966. 16107947
9. Manasa J, Katzenstein D, Cassol S, Newell M-L, de Oliveira T. Southern Africa Treatment And Resistance Network (SATuRN). Primary drug resistance in South Africa: data from 10 years of surveys. AIDS Res Hum Retroviruses 2012; 28 : 558–565. doi: 10.1089/AID.2011.0284 22251009
10. Aghokeng AF, Kouanfack C, Laurent C, Ebong E, Atem-Tambe A, Butel C, et al. Scale-up of antiretroviral treatment in sub-Saharan Africa is accompanied by increasing HIV-1 drug resistance mutations in drug-naive patients. AIDS 2011; 25 : 2183–2188. doi: 10.1097/QAD.0b013e32834bbbe9 21860346
11. Bennett DE, Camacho RJ, Otelea D, Kuritzkes DR, Fleury H, Kiuchi M, et al. Drug resistance mutations for surveillance of transmitted HIV-1 drug-resistance: 2009 update. PLoS ONE. 2009; 4:e4724. doi: 10.1371/journal.pone.0004724 19266092
12. von Wyl V, Yerly S, Böni J, Bürgisser P, Klimkait T, Battegay M, et al. Emergence of HIV-1 drug resistance in previously untreated patients initiating combination antiretroviral treatment: a comparison of different regimen types. Arch. Intern. Med. 2007; 167 : 1782–1790. 17846398
13. Little SJ, Frost SD, Wong JK, Smith DM, Pond SL, Ignacio CC, et al. Persistence of Transmitted Drug Resistance among Subjects with Primary Human Immunodeficiency Virus Infection. Journal of Virology 2008; 82 : 5510–5518. doi: 10.1128/JVI.02579-07 18353964
14. Metzner KJ, Scherrer AU, Preiswerk B, Joos B, von Wyl V, Leemann C, et al. Origin of Minority Drug-Resistant HIV-1 Variants in Primary HIV-1 Infection. J Infect Dis 2013; 208 : 1102–1112. doi: 10.1093/infdis/jit310 23847055
15. Jain V, Sucupira MC, Bacchetti P, Hartogensis W, Diaz RS, Kallas EG, et al. Differential Persistence of Transmitted HIV-1 Drug Resistance Mutation Classes. J Infect Dis 2011; 203 : 1174–1181. doi: 10.1093/infdis/jiq167 21451005
16. Metzner KJ, Leemann C, Di Giallonardo F, Grube C, Scherrer AU, Braun D, et al. Reappearance of Minority K103N HIV-1 Variants after Interruption of ART Initiated during Primary HIV-1 Infection. PLoS ONE 2011;
17. Barbour JD, Hecht FM, Wrin T, Liegler TJ, Ramstead CA, Busch MP, et al. Persistence of primary drug resistance among recently HIV-1 infected adults. AIDS 2004; 18 : 1683–1689. 15280779
18. Martinez-Picado J, Martínez MA. HIV-1 reverse transcriptase inhibitor resistance mutations and fitness: A view from the clinic and ex vivo. 2008; 134 : 104–123. doi: 10.1016/j.virusres.2007.12.021 18289713
19. Wittkop L, Günthard HF, de Wolf F, Dunn D, Cozzi-Lepri A, de Luca A, et al. Effect of transmitted drug resistance on virological and immunological response to initial combination antiretroviral therapy for HIV (EuroCoord-CHAIN joint project): a European multicohort study. The Lancet Infectious Diseases 2011; 11 : 363–371. doi: 10.1016/S1473-3099(11)70032-9 21354861
20. Grant RM, Hecht FM, Warmerdam M, Liu L, Liegler T, Petropoulos CJ, et al. Time Trends in Primary HIV-1 Drug Resistance Among Recently Infected Persons. JAMA 2002; 288 : 181–188. 12095382
21. Cong M-E, Heneine W, García-Lerma JG. The fitness cost of mutations associated with human immunodeficiency virus type 1 drug resistance is modulated by mutational interactions. Journal of Virology 2007; 81 : 3037–3041. 17192300
22. Little SJ, Holte S, Routy J-P, Daar E, Markowitz M, Collier A, et al. Antiretroviral-drug resistance among patients recently infected with HIV. The New England Journal of mMedicine 2002; 347 : 385–394. 12167680
23. Hirsch MS, Günthard HF, Schapiro JM, Vezinet F-B, Clotet B, Hammer S, et al. Antiretroviral drug resistance testing in adult HIV-1 infection: 2008 recommendations of an International AIDS Society-USA panel. Clin Infect Dis. 2008; 47 : 266–285. doi: 10.1086/589297 18549313
24. Swiss HIV Cohort Study. Cohort profile: the Swiss HIV Cohort study. Int J Epidemiol 2010; 39 : 1179–1189. doi: 10.1093/ije/dyp321 19948780
25. Ledergerber B, Egger M, Opravil M, Telenti A, Hirschel B, Battegay M, et al. Clinical progression and virological failure on highly active antiretroviral therapy in HIV-1 patients: a prospective cohort study. Swiss HIV Cohort Study. Lancet 1999; 353 : 863–868. 10093977
26. Gunthard HF, Wong JK, Ignacio CC, Havlir DV, Richman DD. Comparative performance of high-density oligonucleotide sequencing and dideoxynucleotide sequencing of HIV type 1 pol from clinical samples. AIDS Res Hum Retroviruses 1998; 14 : 869–876. 9671215
27. Hinkley T, Martins J, Chappey C, Haddad M, Stawiski E, Whitcomb JM, et al. A systems analysis of mutational effects in HIV-1 protease and reverse transcriptase. Nature Genetics 2011; 43 : 487–489. doi: 10.1038/ng.795 21441930
28. Kouyos RD, von Wyl V, Hinkley T, Petropoulos CJ, Haddad M, Whitcomb JM, et al. Assessing predicted HIV-1 replicative capacity in a clinical setting. PLoS Pathog. 2011; 7:e1002321. doi: 10.1371/journal.ppat.1002321 22072960
29. Castro H, Pillay D, Cane P, Asboe D, Cambiano V, Phillips A, et al. Persistence of HIV-1 transmitted drug resistance mutations. J Infect Dis 2013; 208 : 1459–1463. doi: 10.1093/infdis/jit345 23904291
30. Yerly S, Rakik A, De Loes SK, Hirschel B, Descamps D, Brun-Vézinet F, et al. 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. Journal of Virology 1998; 72 : 3520–3523. 9557630
31. Garcia-Lerma JG, Nidtha S, Blumoff K, Weinstock H, 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; 98 : 13907–13912. 11698656
32. Wiesch zur PA, Kouyos RD, Engelstädter J, Regoes RR, Bonhoeffer S. Population biological principles of drug-resistance evolution in infectious diseases. The Lancet Infectious Diseases 2011; 11 : 236–247. doi: 10.1016/S1473-3099(10)70264-4 21371657
33. Andersson DI, Hughes D. Antibiotic resistance and its cost: is it possible to reverse resistance? Nat. Rev. Microbiol. 2010; 8 : 260–271. doi: 10.1038/nrmicro2319 20208551
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