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Current HIV Research

Editor-in-Chief

ISSN (Print): 1570-162X
ISSN (Online): 1873-4251

Research Article

Coreceptor Tropism and Maraviroc Sensitivity of Clonally Derived Ethiopian HIV-1C Strains Using an in-house Phenotypic Assay and Commonly Used Genotypic Methods

Author(s): Amare Worku Kalu*, Nigus Fikrie Telele, Shambhu G Aralaguppe, Solomon Gebre-Selassie, Daniel Fekade, Gaetano Marrone and Anders Sonnerborg

Volume 16, Issue 2, 2018

Page: [113 - 120] Pages: 8

DOI: 10.2174/1570162X16666180515124836

Price: $65

Abstract

Objectives: Genotypic Tropism Testing (GTT) tools are generally developed based on HIV-1 subtype B (HIV-1B) and used for HIV-1C as well but with a large discordance of prediction between different methods. We used an established phenotypic assay for comparison with GTT methods and for the determination of in vitro maraviroc sensitivity of pure R5-tropic and dual-tropic HIV-1C.

Methods: Plasma was obtained from 58 HIV-1C infected Ethiopians. Envgp120 was cloned into a luciferase tagged NL4-3 plasmid. Phenotypic tropism was determined by in house method and the V3 sequences were analysed by five GTT methods. In vitro maraviroc sensitivity of R5-tropic and dual-tropic isolates were compared in the TZMbl cell-line.

Results: The phenotypes were classified as R5 in 92.4% and dual tropic (R5X4) in 7.6% of 79 clones. The concordance between phenotype and genotype ranged from 64.7% to 84.3% depending on the GTT method. Only 46.9% of the R5 phenotypes were predicted as R5 by all GTT tools while R5X4 phenotypes were predicted as X4 by four methods, but not by Raymond’s method. All six tested phenotypic R5 clones, as well as five of six of dual tropic clones, showed a dose response to maraviroc.

Conclusion: There is a high discordance between GTT methods, which underestimates the presence of R5 and overestimates X4 strains compared to a phenotypic assay. Currently available GTT algorithms should be further improved for tropism prediction in HIV-1C. Maraviroc has an in vitro activity against most HIV-1C viruses and could be considered as an alternative regimen in individuals infected with CCR5-tropic HIV-1C viruses.

Keywords: HIV, tropism, subtype C, maraviroc, Ethiopia, CCR5, CXCR4.

Graphical Abstract
[1]
Berger EA, Doms RW, Fenyo EM, et al. A new classification for HIV-1. Nature 1998; 391(6664): 240.
[2]
Alkhatib G, Combadiere C, Broder CC, et al. CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1. Sci 1996; 272(5270): 1955-8.
[3]
Feng Y, Broder CC, Kennedy PE, Berger EA. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science 1996; 272(5263): 872-7.
[4]
Surdo M, Balestra E, Saccomandi P, et al. Inhibition of dual/mixed tropic HIV-1 isolates by CCR5-inhibitors in primary lymphocytes and macrophages. PLoS One 2013; 8(7): e68076.
[5]
Xiang SH, Pacheco B, Bowder D, Yuan W, Sodroski J. Characterization of a dual-tropic human immunodeficiency virus (HIV-1) strain derived from the prototypical X4 isolate HXBc2. Virology 2013; 438(1): 5-13.
[6]
Naif HM. Pathogenesis of HIV Infection. Infect Dis Rep 2013; 5(Suppl. 1): e6.
[7]
Wilen CB, Tilton JC, Doms RW. HIV: Cell binding and entry. Cold Spring Harb Perspect Med 2012; 2(8): a006866.
[8]
de Roda Husman AM, Schuitemaker H. Chemokine receptors and the clinical course of HIV-1 infection. Trends Microbiol 1998; 6(6): 244-9.
[9]
Ross TM, Bieniasz PD, Cullen BR. Role of chemokine receptors in HIV-1 infection and pathogenesis. Adv Virus Res 1999; 52: 233-67.
[10]
Kristiansen TB, Knudsen TB, Eugen-Olsen J. Chemokine receptors and their crucial role in human immunodeficiency virus infection: major breakthroughs in HIV research. Scand J Immunol 1998; 48(4): 339-46.
[11]
Martin-Garcia J, Kolson DL, Gonzalez-Scarano F. Chemokine receptors in the brain: their role in HIV infection and pathogenesis. AIDS 2002; 16(13): 1709-30.
[12]
Suresh P, Wanchu A. Chemokines and chemokine receptors in HIV infection: role in pathogenesis and therapeutics. J Postgrad Med 2006; 52(3): 210-7.
[13]
Gorry PR, Sterjovski J, Churchill M, et al. The role of viral coreceptors and enhanced macrophage tropism in human immunodeficiency virus type 1 disease progression. Sex Health 2004; 1(1): 23-34.
[14]
Burger H, Hoover D. HIV-1 tropism, disease progression, and clinical management. J Infect Dis 2008; 198(8): 1095-7.
[15]
Weiser B, Philpott S, Klimkait T, et al. HIV-1 coreceptor usage and CXCR4-specific viral load predict clinical disease progression during combination antiretroviral therapy. AIDS 2008; 22(4): 469-79.
[16]
Gijsbers EF, van Sighem A, Harskamp AM, et al. The presence of CXCR4-using HIV-1 prior to start of antiretroviral therapy is an independent predictor of delayed viral suppression. PLoS One 2013; 8(10): e76255.
[17]
Brumme ZL, Dong WW, Yip B, et al. Clinical and immunological impact of HIV envelope V3 sequence variation after starting initial triple antiretroviral therapy. AIDS 2004; 18(4): F1-9.
[18]
Seclen E, Soriano V, Gonzalez MM, et al. Impact of baseline HIV-1 tropism on viral response and CD4 cell count gains in HIV-infected patients receiving first-line antiretroviral therapy. J Infect Dis 2011; 204(1): 139-44.
[19]
Waters L, Mandalia S, Randell P, Wildfire A, Gazzard B, Moyle G. The impact of HIV tropism on decreases in CD4 cell count, clinical progression, and subsequent response to a first antiretroviral therapy regimen. Clin Infect Dis 2008; 46(10): 1617-23.
[20]
Lanca AM, Collares JK, Ferreira JL, et al. HIV-1 tropism and CD4 T lymphocyte recovery in a prospective cohort of patients initiating HAART in Ribeirao Preto, Brazil. Mem Inst Oswaldo Cruz 2012; 107(1): 96-101.
[21]
Perry CM. Maraviroc: A review of its use in the management of CCR5-tropic HIV-1 infection. Drugs 2010; 70(9): 1189-213.
[22]
Vandekerckhove LP, Wensing AM, Kaiser R, et al. European guidelines on the clinical management of HIV-1 tropism testing. Lancet Infect Dis 2011; 11(5): 394-407.
[23]
Perez-Olmeda M, Alcami J. Determination of HIV tropism and its use in the clinical practice. Expert Rev Anti Infect Ther 2013; 11(12): 1291-302.
[24]
Poveda E, Alcami J, Paredes R, et al. Genotypic determination of HIV tropism - clinical and methodological recommendations to guide the therapeutic use of CCR5 antagonists. AIDS Rev 2010; 12(3): 135-48.
[25]
Poveda E, Paredes R, Moreno S, et al. Update on clinical and methodological recommendations for genotypic determination of HIV tropism to guide the usage of CCR5 antagonists. AIDS Rev 2012; 14(3): 208-17.
[26]
Parra J, Portilla J, Pulido F, et al. Clinical utility of maraviroc. Clin Drug Investig 2011; 31(8): 527-42.
[27]
Ratcliff AN, Shi W, Arts EJ. HIV-1 resistance to maraviroc conferred by a CD4 binding site mutation in the envelope glycoprotein gp120. J Virol 2013; 87(2): 923-34.
[28]
Surdo M, Alteri C, Puertas MC, et al. Effect of maraviroc on non- R5 tropic HIV-1: refined analysis of subjects from the phase IIb study A4001029. Clin Microbiol Infect 2015; 21(1): 103 e1-6.
[29]
Svicher V, Balestra E, Cento V, et al. HIV-1 dual/mixed tropic isolates show different genetic and phenotypic characteristics and response to maraviroc in vitro. Antiviral Res 2011; 90(1): 42-53.
[30]
Ray N, Doms RW. HIV-1 coreceptors and their inhibitors. Curr Top Microbiol Immunol 2006; 303: 97-120.
[31]
Kagan RM, Johnson EP, Siaw M, et al. A genotypic test for HIV-1 tropism combining Sanger sequencing with ultradeep sequencing predicts virologic response in treatment-experienced patients. PLoS One 2012; 7(9): e46334.
[32]
Cardozo T, Kimura T, Philpott S, Weiser B, Burger H, Zolla-Pazner S. Structural basis for coreceptor selectivity by the HIV type 1 V3 loop. AIDS Res Hum Retroviruses 2007; 23(3): 415-26.
[33]
McGovern RA, Thielen A, Portsmouth S, et al. Population-based sequencing of the V3-loop can predict the virological response to maraviroc in treatment-naive patients of the MERIT trial. J Acquir Immune Defic Syndr (1999). 2012; 61(3): 279-86.
[34]
Swenson LC, Mo T, Dong WW, et al. Deep V3 sequencing for HIV type 1 tropism in treatment-naive patients: a reanalysis of the MERIT trial of maraviroc. Clin Infect Dis 2011; 53(7): 732-42.
[35]
Swenson LC, Mo T, Dong WW, et al. Deep sequencing to infer HIV-1 co-receptor usage: application to three clinical trials of maraviroc in treatment-experienced patients. J Infect Dis 2011; 203(2): 237-45.
[36]
Thompson MA, Aberg JA, Hoy JF, et al. Antiretroviral treatment of adult HIV infection: 2012 recommendations of the International Antiviral Society-USA panel. JAMA 2012; 308(4): 387-402.
[37]
Brown J, Burger H, Weiser B, et al. A genotypic HIV-1 proviral DNA coreceptor tropism assay: characterization in viremic subjects. AIDS Res Ther 2014; 11(1): 14.
[38]
Parisi SG, Andreis S, Mengoli C, et al. Baseline cellular HIV DNA load predicts HIV DNA decline and residual HIV plasma levels during effective antiretroviral therapy. J of Clin Microbiol 2012; 50(2): 258-63.
[39]
Soulie C, Fourati S, Lambert-Niclot S, et al. Factors associated with proviral DNA HIV-1 tropism in antiretroviral therapy-treated patients with fully suppressed plasma HIV viral load: implications for the clinical use of CCR5 antagonists. J Antimicrob Chemother 2010; 65(4): 749-51.
[40]
Jensen MA, Coetzer M, van ’t Wout AB, Morris L, Mullins JI. A reliable phenotype predictor for human immunodeficiency virus type 1 subtype C based on envelope V3 sequences. J Virol 2006; 80(10): 4698-704.
[41]
Lengauer T, Sander O, Sierra S, Thielen A, Kaiser R. Bioinformatics prediction of HIV coreceptor usage. Nat Biotechnol 2007; 25(12): 1407-10.
[42]
Zhang H, Tully DC, Zhang T, Moriyama H, Thompson J, Wood C. Molecular determinants of HIV-1 subtype C coreceptor transition from R5 to R5X4. Virology 2010; 407(1): 68-79.
[43]
Groenink M, Andeweg AC, Fouchier RA, et al. Phenotype-associated env gene variation among eight related human immunodeficiency virus type 1 clones: evidence for in vivo recombination and determinants of cytotropism outside the V3 domain. J Virol 1992; 66(10): 6175-80.
[44]
Monno L, Saracino A, Scudeller L, et al. Impact of mutations outside the V3 region on coreceptor tropism phenotypically assessed in patients infected with HIV-1 subtype B. Antimicrob Agents Chemother 2011; 55(11): 5078-84.
[45]
Zhang J, Gao X, Martin J, et al. Evolution of coreceptor utilization to escape CCR5 antagonist therapy. Virol 2016; 494: 198-214.
[46]
Ceresola ER, Nozza S, Sampaolo M, et al. Performance of commonly used genotypic assays and comparison with phenotypic assays of HIV-1 coreceptor tropism in acutely HIV-1-infected patients. J Antimicrob Chemother 2015; 70(5): 1391-5.
[47]
Raymond S, Delobel P, Mavigner M, et al. Development and performance of a new recombinant virus phenotypic entry assay to determine HIV-1 coreceptor usage. J Clin Virol 2010; 47(2): 126-30.
[48]
Low AJ, Swenson LC, Harrigan PR. HIV coreceptor phenotyping in the clinical setting. AIDS Rev 2008; 10(3): 143-51.
[49]
Braun P, Wiesmann F. Phenotypic assays for the determination of coreceptor tropism in HIV-1 infected individuals. Eur J Med Res 2007; 12(9): 463-72.
[50]
Kalu AW, Telele NF, Gebreselasie S, et al. Prediction of coreceptor usage by five bioinformatics tools in a large Ethiopian HIV-1 subtype C cohort. PLoS One 2017; 12(8): e0182384.
[51]
Siddik AB, Haas A, Rahman MS, et al. Phenotypic co-receptor tropism and Maraviroc sensitivity in HIV-1 subtype C from East Africa. Sci Rep 2018; 8(1): 2363.
[52]
Gupta S, Neogi U, Srinivasa H, Banerjea AC, Shet A. HIV-1 coreceptor tropism in India: increasing proportion of X4-tropism in subtype C strains over two decades. J Acquir Immune Defic Syndr 2014; 65(4): 397-404.
[53]
Ashokkumar M, Aralaguppe SG, Tripathy SP, Hanna LE, Neogi U. Unique Phenotypic Characteristics of Recently Transmitted HIV-1 Subtype C Envelope Glycoprotein gp120: Use of CXCR6 Coreceptor by Transmitted Founder Viruses. J Virol 2018; 92(9): e00063-18.
[54]
Edwards S, Stucki H, Bader J, et al. A diagnostic HIV-1 tropism system based on sequence relatedness. J of Clin Microbiol 2015; 53(2): 597-610.
[55]
Sarzotti-Kelsoe M, Bailer RT, Turk E, et al. Optimization and validation of the TZM-bl assay for standardized assessments of neutralizing antibodies against HIV-1. J Immunol Methods 2014; 409: 131-46.
[56]
Pankaj K. Methods for Rapid Virus Identification and Quantification. Mater Methods 2013; 3: 207.
[57]
Wulff NH, Tzatzaris M, Young PJ. Monte Carlo simulation of the Spearman-Kaerber TCID50. J Clin Bioinforma 2012; 2(1): 5.
[58]
Cashin K, Gray LR, Harvey KL, et al. Reliable genotypic tropism tests for the major HIV-1 subtypes. Sci Rep 2015; 5: 8543.
[59]
Raymond S, Delobel P, Mavigner M, et al. Correlation between genotypic predictions based on V3 sequences and phenotypic determination of HIV-1 tropism. AIDS 2008; 22(14): F11-6.
[60]
Mulinge M, Lemaire M, Servais JY, et al. HIV-1 tropism determination using a phenotypic Env recombinant viral assay highlights overestimation of CXCR4-usage by genotypic prediction algorithms for CRF01_AE and CRF02_AG. PLoS One 2013; 8(5): e60566. [corrected].
[61]
Gupta S, Neogi U, Srinivasa H, Shet A. Performance of genotypic tools for prediction of tropism in HIV-1 subtype C V3 loop sequences. Intervirology 2015; 58(1): 1-5.
[62]
Tremblay C, Hardy I, Lalonde R, et al. HIV-1 tropism testing and clinical management of CCR5 antagonists: Quebec review and recommendations. Can J Infect Dis Med Microbiol 2013; 24(4): 202-8.
[63]
Delgado E, Fernandez-Garcia A, Vega Y, et al. Evaluation of genotypic tropism prediction tests compared with in vitro co-receptor usage in HIV-1 primary isolates of diverse subtypes. J Antimicrob Chemother 2012; 67(1): 25-31.
[64]
Abebe A, Demissie D, Goudsmit J, et al. HIV-1 subtype C syncytium- and non-syncytium-inducing phenotypes and coreceptor usage among Ethiopian patients with AIDS. AIDS 1999; 13(11): 1305-11.
[65]
Bjorndal A, Sonnerborg A, Tscherning C, Albert J, Fenyo EM. Phenotypic characteristics of human immunodeficiency virus type 1 subtype C isolates of Ethiopian AIDS patients. AIDS Res Hum Retroviruses 1999; 15(7): 647-53.
[66]
Kalu AW, Telele NF, Gebreselasie S, et al. Monophylogenetic HIV-1C epidemic in Ethiopia is dominated by CCR5-tropic viruses-an analysis of a prospective country-wide cohort. BMC Infect Dis 2017; 17(1): 37.
[67]
Symons J, van Lelyveld SF, Hoepelman AI, et al. Maraviroc is able to inhibit dual-R5 viruses in a dual/mixed HIV-1-infected patient. J Antimicrob Chemother 2011; 66(4): 890-5.

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