Generic placeholder image

Current HIV Research

Author(s): Roca Tárcio Peixoto, Lima Felipe Souza Nogueira , Santos Alcione de Oliveira, Vieira Deusilene Souza and Botelho-Souza Luan Felipo *

DOI: 10.2174/1570162X17666191019114250

DownloadDownload PDF Flyer Cite As
Study of HIV Resistance Mutations Against Antiretrovirals using Bioinformatics Tools

Page: [343 - 349] Pages: 7

  • * (Excluding Mailing and Handling)

Abstract

Background: Antiretroviral drugs to HIV-1 (ARV) are divided into classes: Nucleotide Reverse Transcriptase Inhibitors (NRTIs); Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs); Protease Inhibitors (PIs); Integrase Inhibitors (INIs); fusion inhibitors and entry Inhibitors. The occurrence of mutations developing resistance to antiretroviral drugs used in HIV treatment take place in a considerable proportion and has accumulated over its long period of therapy.

Objective: This study aimed to identify resistance mutations to antiretrovirals used in the treatment of HIV-1 in strains isolated from Brazilian territory deposited at Genbank, as well as to relate to the clinical significance and mechanism of action.

Methods: Elucidation of these mutations was by comparative method of peptide sequence resulting from genes encoding therapeutic targets in HIV antiretroviral therapy (ART) of the strains with a reference sequence through bioinformatic genetic information manipulation techniques.

Results: Of the 399 sequences analyzed, 121 (30.3%) had some type of mutations associated with resistance to some class of antiretroviral drug. Resistance to NNRTIs was the most prevalent, detected in 77 (63.6%) of the 121 mutated sequences, compared to NRTIs and PIs, whose resistance was detected in 60 (49.6%) and 21 (17.3%), respectively, and to INIs, only 1 (0.8%) sample showed associated resistance mutation.

Conclusion: Resistance to HIV ARV was detected at a considerable rate of 30.3%, showing some concerns about the percentage of viral strains that escape the established therapeutic regimen and that circulate currently in Brazil. The non-use of NNRTIs in Brazil is justified by the emergence of resistance mutations. The low prevalence of mutations against INIs is because drugs in this class have a high genetic barrier.

Keywords: HIV, resistance, mutation, antiretrovirals, POL gene, GenBank.

Graphical Abstract

[1]
HIV/AIDS-Fact Sheets 2018. Available form: https://www.who.int/en/news-room/fact-sheets/detail/hiv-aids [Accessed on April 16, 2019]
[2]
Brazil Epidemiological Bulletin AIDS Ministry of Health, National Secretariat of Special Health Programs, Division of Sexually Transmitted Diseases and AIDS / AIDS; 2018.
[3]
PCDT - Clinical protocol and therapeutic guidelines for managing HIV infection in adults 2018.
[4]
Hymes KB, Cheung T, Greene JB, et al. Kaposi’s sarcoma in homosexual men-a report of eight cases. Lancet 1981; 2(8247): 598-600.
[http://dx.doi.org/10.1016/S0140-6736(81)92740-9] [PMID: 6116083]
[5]
Grotto RM, Pardini MIMC. Molecular biology of the HIV-1 and genetics of human resistance to AIDS. Arq Ciênc Saúde 2006; p. 13.
[6]
Updating Current Trends: Acquired Immunodeficiency Syndrome. MMWR Morb Mortal Wkly 1986; 35: 757-60.: 765-60.
[7]
Berger EA, Murphy PM, Farber JM. Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease. Annu Rev Immunol 1999; 17: 657-700.
[http://dx.doi.org/10.1146/annurev.immunol.17.1.657] [PMID: 10358771]
[8]
Li G, De Clercq E. HIV Genome-Wide Protein Associations: a Review of 30 Years of Research. Microbiol Mol Biol Rev 2016; 80(3): 679-731.
[http://dx.doi.org/10.1128/MMBR.00065-15] [PMID: 27357278]
[9]
Connor RI, Ho DD. Etiology of AIDS: Biology of human retroviruses: vol. 203, 1992.
[10]
Malim MH, Emerman M. HIV-1 accessory proteins-ensuring viral survival in a hostile environment. Cell Host Microbe 2008; 3: 388-98.
[http://dx.doi.org/10.1016/j.chom.2008.04.008]
[11]
Marlink R, Kanki P, Thior I, et al. Reduced rate of disease development after HIV-2 infection as compared to HIV-1. Science 1994; 265(5178): 1587-90.
[http://dx.doi.org/10.1126/science.7915856]
[12]
Lever AML. HIV: the virus. Medicine (Baltimore) 2005; 33: 1-3.
[http://dx.doi.org/10.1383/medc.33.6.1.65999]
[13]
FDA. HIV/AIDS Treatment - Antiretroviral drugs used in the treatment of HIV infection 2018. Available from: https://www.fda.gov/ForPatients/Illness/HIVAIDS/Treatment/ucm118915.htm [Accessed on April 17, 2019].
[14]
Clutter DS, Jordan MR, Bertagnolio S, Shafer RW. HIV-1 drug resistance and resistance testing. Infect Genet Evol 2016; 46: 292-307.
[http://dx.doi.org/10.1016/j.meegid.2016.08.031] [PMID: 27587334]
[15]
90-90-90: An ambitious treatment target to help end the AIDS epidemic 2014.
[16]
Global HIV & AIDS statistics - 2019 fact sheet, UNAIDS 2019. Available from: https://www.unaids.org/en/resources/fact-sheet [Accessed on July 22, 2019].
[17]
Van den Eede P, Van Wesenbeeck L, Verlinden Y, et al. HIV-1 genotyping of the protease-reverse transcriptase and integrase genes to detect mutations that confer antiretroviral resistance. Methods Mol Biol 2013; 1030: 37-55.
[http://dx.doi.org/10.1007/978-1-62703-484-5_5] [PMID: 23821259]
[18]
Dudley DM, Bailey AL, Mehta SH, et al. Cross-clade simultaneous HIV drug resistance genotyping for reverse transcriptase, protease, and integrase inhibitor mutations by Illumina MiSeq. Retrovirology 2014; 11: 122.
[http://dx.doi.org/10.1186/s12977-014-0122-8] [PMID: 25533166]
[19]
Roberts JD, Bebenek K, Kunkel TA. The accuracy of reverse transcriptase from HIV-1. Science 1988; 242: 1171-3.
[http://dx.doi.org/10.1126/science.2460925]
[20]
Weber IT, Harrison RW. Decoding HIV resistance: from genotype to therapy. Future Med Chem 2017; 9(13): 1529-38.
[http://dx.doi.org/10.4155/fmc-2017-0048] [PMID: 28791894]
[21]
Cortez KJ, Maldarelli F. Clinical management of HIV drug resistance. Viruses 2011; 3(4): 347-78.
[http://dx.doi.org/10.3390/v3040347] [PMID: 21994737]
[22]
Iyidogan P, Anderson KS. Current perspectives on HIV-1 antiretroviral drug resistance. Viruses 2014; 6(10): 4095-139.
[http://dx.doi.org/10.3390/v6104095] [PMID: 25341668]
[23]
Kumar S, Stecher G, Tamura K. MEGA7: Molecular Evolutionary Genetics Analysis Version 7.0 for Bigger Datasets. Mol Biol Evol 2016; 33(7): 1870-4.
[http://dx.doi.org/10.1093/molbev/msw054] [PMID: 27004904]
[24]
Edgar RC. MUSCLE: a multiple sequence alignment method with reduced time and space complexity. BMC Bioinformatics 2004; 5: 113.
[http://dx.doi.org/10.1186/1471-2105-5-113] [PMID: 15318951]
[25]
Edgar RC. MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res 2004; 32(5): 1792-7.
[http://dx.doi.org/10.1093/nar/gkh340] [PMID: 15034147]
[26]
HIV Drug Resistance Database. Available from: https://hivdb.stanford.edu/ [Accessed on July 29, 2019]
[27]
Gupta RK, Hill A, Sawyer AW, et al. Virological monitoring and resistance to first-line highly active antiretroviral therapy in adults infected with HIV-1 treated under WHO guidelines: a systematic review and meta-analysis. Lancet Infect Dis 2009; 9(7): 409-17.
[http://dx.doi.org/10.1016/S1473-3099(09)70136-7] [PMID: 19555900]
[28]
Gupta RK, Gregson J, Parkin N, et al. HIV-1 drug resistance before initiation or re-initiation of first-line antiretroviral therapy in low-income and middle-income countries: a systematic review and meta-regression analysis. Lancet Infect Dis 2018; 18(3): 346-55.
[http://dx.doi.org/10.1016/S1473-3099(17)30702-8] [PMID: 29198909]
[29]
Hogg RS, Bangsberg DR, Lima VD, et al. Emergence of drug resistance is associated with an increased risk of death among patients first starting HAART. PLoS Med 2006; 3(9)e356
[http://dx.doi.org/10.1371/journal.pmed.0030356] [PMID: 16984218]
[30]
Akanbi MO, Scarsi KK, Taiwo B, Murphy RL, Murphy RL. Combination nucleoside/nucleotide reverse transcriptase inhibitors for treatment of HIV infection. Expert Opin Pharmacother 2012; 13(1): 65-79.
[http://dx.doi.org/10.1517/14656566.2012.642865] [PMID: 22149368]
[31]
Das K, Arnold E. HIV-1 reverse transcriptase and antiviral drug resistance. Part 1. Curr Opin Virol 2013; 3(2): 111-8.
[http://dx.doi.org/10.1016/j.coviro.2013.03.012] [PMID: 23602471]
[32]
Sarafianos SG, Das K, Clark AD Jr, et al. Lamivudine (3TC) resistance in HIV-1 reverse transcriptase involves steric hindrance with beta-branched amino acids. Proc Natl Acad Sci USA 1999; 96(18): 10027-32.
[http://dx.doi.org/10.1073/pnas.96.18.10027] [PMID: 10468556]
[33]
Götte M. Mechanisms of resistance associated with excision of incorporated nucleotide analogue inhibitors of HIV-1 reverse transcriptase. Curr Opin HIV AIDS 2007; 2(2): 103-7.
[http://dx.doi.org/10.1097/COH.0b013e3280287a60] [PMID: 19372874]
[34]
Das K, Arnold E. HIV-1 reverse transcriptase and antiviral drug resistance. Part 2. Curr Opin Virol 2013; 3(2): 119-28.
[http://dx.doi.org/10.1016/j.coviro.2013.03.014] [PMID: 23602470]
[35]
Johnson VA, Calvez V, Gunthard HF, et al. Update of the drug resistance mutations in HIV-1: March 2013. Top Antivir Med 2013; 21(1): 6-14.
[PMID: 23596273]
[36]
Whitcomb JM, Parkin NT, Chappey C, Hellmann NS, Petropoulos CJ. Broad nucleoside reverse-transcriptase inhibitor cross-resistance in human immunodeficiency virus type 1 clinical isolates. J Infect Dis 2003; 188(7): 992-1000.
[http://dx.doi.org/10.1086/378281] [PMID: 14513419]
[37]
Melikian GL, Rhee S-Y, Taylor J, et al. Standardized comparison of the relative impacts of HIV-1 reverse transcriptase (RT) mutations on nucleoside RT inhibitor susceptibility. Antimicrob Agents Chemother 2012; 56(5): 2305-13.
[http://dx.doi.org/10.1128/AAC.05487-11] [PMID: 22330916]
[38]
Boyer PL, Sarafianos SG, Arnold E, 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; 76(7): 3248-56.
[http://dx.doi.org/10.1128/JVI.76.7.3248-3256.2002] [PMID: 11884549]
[39]
Larder B, Kemp S, Harrigan P. Potential mechanism for sustained antiretroviral efficacy of AZT-3TC combination therapy. Science 1995; 269: 696-9.
[http://dx.doi.org/10.1126/science.7542804]
[40]
St Clair M, Martin J, Tudor-Williams G, et al. Resistance to ddI and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase. Science 1991; 253: 1557-9.
[http://dx.doi.org/10.1126/science.1716788]
[41]
Miranda LR, Götte M, Liang F, 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; 49(7): 2648-56.
[http://dx.doi.org/10.1128/AAC.49.7.2648-2656.2005] [PMID: 15980332]
[42]
Menéndez-Arias L. Mechanisms of resistance to nucleoside analogue inhibitors of HIV-1 reverse transcriptase. Virus Res 2008; 134(1-2): 124-46.
[http://dx.doi.org/10.1016/j.virusres.2007.12.015] [PMID: 18272247]
[43]
Larder B, Kemp S. Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to zidovudine (AZT). Science 1989; 246: 1155-8.
[http://dx.doi.org/10.1126/science.2479983]
[44]
Arion D, Sluis-Cremer N, 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; 275(13): 9251-5.
[http://dx.doi.org/10.1074/jbc.275.13.9251] [PMID: 10734063]
[45]
Girouard M, Diallo K, Marchand B, McCormick S, Götte 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; 278(36): 34403-10.
[http://dx.doi.org/10.1074/jbc.M303528200] [PMID: 12819190]
[46]
Delaugerre C, Mouroux M, Yvon-Groussin A, et al. 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; 45(3): 946-8.
[http://dx.doi.org/10.1128/AAC.45.3.946-948.2001] [PMID: 11181387]
[47]
Montes B, 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; 66(3): 299-303.
[http://dx.doi.org/10.1002/jmv.2145] [PMID: 11793380]
[48]
Ren J, Nichols CE, Stamp A, et al. Structural insights into mechanisms of non-nucleoside drug resistance for HIV-1 reverse transcriptases mutated at codons 101 or 138. FEBS J 2006; 273(16): 3850-60.
[http://dx.doi.org/10.1111/j.1742-4658.2006.05392.x] [PMID: 16911530]
[49]
Parkin NT, Schapiro JM. Antiretroviral drug resistance in non-subtype B HIV-1, HIV-2 and SIV. Antivir Ther (Lond) 2004; 9(1): 3-12.
[PMID: 15040531]
[50]
Schauer G, Leuba S, Sluis-Cremer N. Biophysical Insights into the Inhibitory Mechanism of Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors. Biomolecules 2013; 3(4): 889-904.
[http://dx.doi.org/10.3390/biom3040889] [PMID: 24970195]
[51]
Rimsky L, Vingerhoets J, Van Eygen V, et al. Genotypic and phenotypic characterization of HIV-1 isolates obtained from patients on rilpivirine therapy experiencing virologic failure in the phase 3 ECHO and THRIVE studies: 48-week analysis. J Acquir Immune Defic Syndr 2012; 59(1): 39-46.
[http://dx.doi.org/10.1097/QAI.0b013e31823df4da] [PMID: 22067667]
[52]
Vingerhoets J, Tambuyzer L, Azijn H, et al. Resistance profile of etravirine: combined analysis of baseline genotypic and phenotypic data from the randomized, controlled Phase III clinical studies. AIDS 2010; 24(4): 503-14.
[http://dx.doi.org/10.1097/QAD.0b013e32833677ac] [PMID: 20051805]
[53]
Rhee S-Y, Liu T, Ravela J, Gonzales MJ, 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; 48(8): 3122-6.
[http://dx.doi.org/10.1128/AAC.48.8.3122-3126.2004] [PMID: 15273130]
[54]
Clotet B. Efavirenz: resistance and cross-resistance. Int J Clin Pract Suppl 1999; 103: 21-5.
[PMID: 10622039]
[55]
Hsiou Y, Ding J, Das K, et al. The Lys103Asn mutation of HIV-1 RT: a novel mechanism of drug resistance. J Mol Biol 2001; 309(2): 437-45.
[http://dx.doi.org/10.1006/jmbi.2001.4648] [PMID: 11371163]
[56]
Ferreira ACG, Coelho LE, Grinsztejn E, et al. Transmitted drug resistance in patients with acute/recent HIV infection in Brazil. Braz J Infect Dis 2017; 21(4): 396-401.
[http://dx.doi.org/10.1016/j.bjid.2017.03.013] [PMID: 28539254]
[57]
Tambuyzer L, Azijn H, Rimsky LT, et al. Compilation and prevalence of mutations associated with resistance to non-nucleoside reverse transcriptase inhibitors. Antivir Ther (Lond) 2009; 14(1): 103-9.
[PMID: 19320243]
[58]
Melikian GL, Rhee S-Y, Varghese V, et al. Non-nucleoside reverse transcriptase inhibitor (NNRTI) cross-resistance: implications for preclinical evaluation of novel NNRTIs and clinical genotypic resistance testing. J Antimicrob Chemother 2014; 69(1): 12-20.
[http://dx.doi.org/10.1093/jac/dkt316] [PMID: 23934770]
[59]
Vingerhoets J, Azijn H, Fransen E, et al. TMC125 displays a high genetic barrier to the development of resistance: evidence from in vitro selection experiments. J Virol 2005; 79(20): 12773-82.
[http://dx.doi.org/10.1128/JVI.79.20.12773-12782.2005] [PMID: 16188980]
[60]
Huang W, Gamarnik A, Limoli K, Petropoulos CJ, Whitcomb JM. Amino acid substitutions at position 190 of human immunodeficiency virus type 1 reverse transcriptase increase susceptibility to delavirdine and impair virus replication. J Virol 2003; 77(2): 1512-23.
[http://dx.doi.org/10.1128/JVI.77.2.1512-1523.2003] [PMID: 12502865]
[61]
Martins NH. HIV-1 protease enzymatic assays of Brazilian subtypes. Dissertation (Master in Applied Physics) - São Carlos Institute of Physics, University of São Paulo, São Carlos 2007.
[62]
Rhee S-Y, Gonzales MJ, Kantor R, Betts BJ, Ravela J, Shafer RW. Human immunodeficiency virus reverse transcriptase and protease sequence database. Nucleic Acids Res 2003; 31(1): 298-303.
[http://dx.doi.org/10.1093/nar/gkg100] [PMID: 12520007]
[63]
Zhengtong LV, Chu Y, Wang Y. HIV protease inhibitors: A review of molecular selectivity and toxicity. HIV/AIDS - Res. Palliat Care 2015; 7: 95-104.
[http://dx.doi.org/10.2147/HIV.S79956]
[64]
Santos JR, Llibre JM, Imaz A, et al. Mutations in the protease gene associated with virological failure to lopinavir/ritonavir-containing regimens. J Antimicrob Chemother 2012; 67(6): 1462-9.
[http://dx.doi.org/10.1093/jac/dks080] [PMID: 22431669]
[65]
Sterrantino G, Zaccarelli M, Colao G, et al. Genotypic resistance profiles associated with virological failure to darunavir-containing regimens: a cross-sectional analysis. Infection 2012; 40(3): 311-8.
[http://dx.doi.org/10.1007/s15010-011-0237-y] [PMID: 22237471]
[66]
Karmochkine M, Si Mohamed A, Piketty C, et al. The cumulative occurrence of resistance mutations in the HIV-1 protease gene is associated with failure of salvage therapy with ritonavir and saquinavir in protease inhibitor-experienced patients. Antiviral Res 2000; 47(3): 179-88.
[http://dx.doi.org/10.1016/S0166-3542(00)00110-8] [PMID: 10974370]
[67]
Naeger LK, Struble KA. Food and Drug Administration analysis of tipranavir clinical resistance in HIV-1-infected treatment-experienced patients. AIDS 2007; 21(2): 179-85.
[http://dx.doi.org/10.1097/QAD.0b013e3280119213] [PMID: 17197808]
[68]
Koh Y, Amano M, Towata T, et al. In vitro selection of highly darunavir-resistant and replication-competent HIV-1 variants by using a mixture of clinical HIV-1 isolates resistant to multiple conventional protease inhibitors. J Virol 2010; 84(22): 11961-9.
[http://dx.doi.org/10.1128/JVI.00967-10] [PMID: 20810732]
[69]
Koh Y, Aoki M, Danish ML, et al. Loss of protease dimerization inhibition activity of darunavir is associated with the acquisition of resistance to darunavir by HIV-1. J Virol 2011; 85(19): 10079-89.
[http://dx.doi.org/10.1128/JVI.05121-11] [PMID: 21813613]
[70]
Molla A, Korneyeva M, Gao Q, et al. Ordered accumulation of mutations in HIV protease confers resistance to ritonavir. Nat Med 1996; 2(7): 760-6.
[http://dx.doi.org/10.1038/nm0796-760] [PMID: 8673921]
[71]
Grossman Z, Paxinos EE, Averbuch 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(6): 2159-65.
[http://dx.doi.org/10.1128/AAC.48.6.2159-2165.2004] [PMID: 15155216]
[72]
Zolopa AR, Shafer RW, Warford A, et al. HIV-1 genotypic resistance patterns predict response to saquinavir-ritonavir therapy in patients in whom previous protease inhibitor therapy had failed. Ann Intern Med 1999; 131(11): 813-21.
[http://dx.doi.org/10.7326/0003-4819-131-11-199912070-00003] [PMID: 10610625]
[73]
Rhee S-Y, Taylor J, Fessel WJ, et al. HIV-1 protease mutations and protease inhibitor cross-resistance. Antimicrob Agents Chemother 2010; 54(10): 4253-61.
[http://dx.doi.org/10.1128/AAC.00574-10] [PMID: 20660676]
[74]
Oliveiros MPR. Evolution of protease inhibitor resistance mutations in patients infected with HIV-1 subtype F Thesis (Doctorate in Sciences) - School of Medicine, University of São Paulo, São Paulo 2009.
[75]
Anstett K, Brenner B, Mesplede T, Wainberg MA. HIV drug resistance against strand transfer integrase inhibitors. Retrovirology 2017; 14(1): 36.
[http://dx.doi.org/10.1186/s12977-017-0360-7] [PMID: 28583191]
[76]
Mesplède T, Osman N, Wares M, et al. Addition of E138K to R263K in HIV integrase increases resistance to dolutegravir, but fails to restore activity of the HIV integrase enzyme and viral replication capacity. J Antimicrob Chemother 2014; 69(10): 2733-40.
[http://dx.doi.org/10.1093/jac/dku199] [PMID: 24917583]
[77]
Quashie PK, Oliviera M, Veres T, et al. Differential effects of the G118R, H51Y, and E138K resistance substitutions in different subtypes of HIV integrase. J Virol 2015; 89(6): 3163-75.
[http://dx.doi.org/10.1128/JVI.03353-14] [PMID: 25552724]
[78]
Unger NR, Worley MV, Kisgen JJ, Sherman EM, Childs-Kean LM. Elvitegravir for the treatment of HIV. Expert Opin Pharmacother 2016; 17(17): 2359-70.
[http://dx.doi.org/10.1080/14656566.2016.1250885] [PMID: 27767362]