1 In Vitro Phenotypic Susceptibility of Human Immunodeficiency Virus Type 2 Clinical Isolates to Protease Inhibitors. Delphine Desbois, Bénédicte Roquebert, Gilles Peytavin, Florence Damond, Gilles Collin, Antoine Bénard, Pauline Campa, Sophie Matheron, Geneviève Chêne, Françoise Brun-Vézinet, et al. To cite this version: Delphine Desbois, Bénédicte Roquebert, Gilles Peytavin, Florence Damond, Gilles Collin, et al.. In Vitro Phenotypic Susceptibility of Human Immunodeficiency Virus Type 2 Clinical Isolates to Protease Inhibitors.. Antimicrobial Agents and Chemotherapy, American Society for Microbiology, 2008, 52 (4), pp < /AAC >. <inserm > HAL Id: inserm Submitted on 12 Mar 2008
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3 AAC Accepts, published online ahead of print on 28 January 2008 Antimicrob. Agents Chemother. doi: /aac Copyright 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved. HAL author manuscript 1 Antimicrobial Agents and Chemotherapy 2008;:epub 2008;52(4): ahead of print In vitro Phenotypic Susceptibility of HIV-2 Clinical Isolates to Protease Inhibitors Running title: Phenotypic susceptibility of HIV-2 to protease inhibitors Delphine Desbois 1, Bénédicte Roquebert 1, Gilles Peytavin 2, Florence Damond 1, Gilles Collin 1, Antoine Bénard 5, Pauline Campa 4, Sophie Matheron 3, Geneviève Chêne 5, Françoise Brun-Vézinet 1 and Diane Descamps 1 * for the French ANRS HIV-2 Cohort (ANRS CO 05 VIH-2). 1-Laboratoire de Virologie, Service de Microbiologie, Hôpital Bichat-Claude Bernard, Paris, France 2-Laboratoire de Toxicologie, Service de Pharmacie, Hôpital Bichat-Claude Bernard, Paris, France 15 3-Service de Maladies Infectieuses et Tropicales, Hôpital Bichat-Claude Bernard, Paris, 16 France 17 4-Service de Maladies Infectieuses et Tropicales, Hôpital Saint-Antoine, Paris, France 18 5-ISPED Université Victor Segalen Bordeaux 2 INSERM U593, Bordeaux, France *Corresponding author:
4 21 Dr Diane Descamps 22 Laboratoire de Virologie Hôpital Bichat Claude Bernard 46 rue Henri Huchard Paris, France Tel: ; Fax: ;
5 30 31 Abstract We determine phenotypic susceptibility of HIV-2 isolates to amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, saquinavir and tipranavir. Saquinavir, lopinavir and darunavir are potent on wild-type HIV-2 isolates and should be preferred as first-line options for HIV-2- infected patients. Other protease inhibitors are less active on HIV-2 than on HIV-1. Key words: HIV-2, phenotypic susceptibility, protease inhibitors, phenotypic resistance, resistance mutations
6 40 41 Few data are available on HIV-2 susceptibility to antiretroviral agents. In France, as recommended by the national expert group on the treatment of HIV infection, HIV-2-infected patients receive highly active antiretroviral therapy (HAART) regimens as HIV-1-infected individuals except non nucleoside reverse transcriptase inhibitors or fusion inhibitors classes (17) (12). However, a recent study showed that CD4 cell recovery was poor in antiretroviral- naive HIV-2 infected patients starting treatment with HAART (8). Thus it appears crucial to determine HIV-2 susceptibility to the current PIs available, in order to define the optimal regimen to be recommended. We selected nine PI-naive HIV-2-infected patients from the French HIV-2 ANRS cohort. Six of these patients subsequently received HAART regimens including a PI (indinavir, nelfinavir, saquinavir and/or ritonavir) for a median of 13 months (range 2-36), and had plasma viruses harboring mutations in the protease gene. PBMC co-culture isolates were available for these patients before (T0, n=6) and during (T1 (n=6), T2 (n=2)) PI exposure. Protease gene sequences of plasma and PBMC isolates were determined as previously described (3). Amino acid changes were compared with those associated with drug resistance in HIV-1 (International AIDS Society-USA (IAS-USA). We determine the in vitro phenotypic susceptibility of clinical HIV-2 isolates and HIV-2 ROD and HIV-1 BRU reference strains to amprenavir, atazanavir, darunavir, 58 indinavir, lopinavir, nelfinavir, saquinavir and tipranavir using the ANRS PBMC assay (4). 59 Phenotypic inhibitory quotients (PIQs) were calculated for each clinical HIV-2 isolate, as the 60 ratio between the trough plasma PI concentration and the IC50. The PIQs were not adjusted for 61 protein binding. The Table shows the phenotypic results and protease gene sequences of the 62 HIV-2 clinical isolates, and the HIV-2 and HIV-1 reference isolates. 63 The protease sequences of wild-type HIV-2 strains, when compared to HIV-1 clade B consensus 64 sequence, contained several amino acids associated with HIV-1 PI resistance, such as 10I/V 65 16E, 20V, 32I, 33V, 35G, 36I, 43T, 46I, 47V, 58E, 62V, 69K, 71V, 73A, 82I and 93L. Other
7 66 differences were observed at positions involved in but not associated with HIV-1 resistance, 67 such as 13A, 34A, 60K, 63E, 76M, 77T, 85F and 89I. Relative to HIV-1 reference strain, the 68 median IC50 values of the HIV-2 wild-type isolates were 31-fold higher for amprenavir, 8-fold higher for atazanavir, 7-fold higher for tipranavir, and 3-fold higher for indinavir and nelfinavir. Darunavir, lopinavir and saquinavir IC50 and IC90 values were similar for HIV-1 and the wild- type HIV-2 isolates (table). Viruses isolated from the six PI experienced patients at T1 and T2 harboured the I82F, I84V and L90M substitutions, alone or in combination with minor HIV-1 PI mutations such as V10I, V33I, I54M, I64V, V71I and I89V. Compared to the corresponding wild-type isolates, the eight mutants showed 4 to >10-fold increases in the IC50 and/or IC90 values of all tested PIs, at both T1 and T2. The PIQs values of amprenavir, atazanavir, indinavir, nelfinavir and tipranavir were respectively 33-fold, 8-fold, 3-fold, 3-fold and 7-fold lower for HIV-2 wild-type strains than for HIV-1. Darunavir, lopinavir and saquinavir PIQ values were similar. PIs are designed to fit the active site of the HIV-1 protease and are sensitive to structural changes in the viral protein. It has been reported that the therapeutic outcome of HIV-2-infected patients might be influenced by the choice of PIs (1) (15). For amprenavir our data are in keeping with those reported elsewhere, showing significantly lesser activity against HIV-2 wildtype strains than against HIV-1 (9) (14) (16). These phenotypic results could be explained by the natural presence in HIV-2 protease of amino acids associated with resistance to HIV-1, 85 which might influence the binding affinity of the PIs for HIV-2 protease (2) (3) (9) (10) (11). In 86 our study, all the HIV-2 wild-type strains protease sequences naturally presented the amino 87 acids 32I and 47V associated with resistance in HIV-1 infection to amprenavir according to IAS 88 USA list and to different genotypic resistance interpretation algorithms 89 (www.hivfrenchresistance.org,www.hivdb.stanford.edu,www.kuleuven.be/rega/cev/links/rega_a 90 lgorithm). We found that clinical HIV-2 isolates and HIV-1 reference strains had similar 91 phenotypic susceptibility to saquinavir, lopinavir and darunavir. As amprenavir and darunavir 92 are structurally close, we expected darunavir to be relatively ineffective in HIV-2.
8 93 Crystallographic studies with HIV-1 showed that darunavir interacts directly with the main 94 chains of aspartic acid residues (Asp-29 and Asp-30), whereas other PIs interact with side 95 chains in the S2 subsite of the HIV-1 enzyme (6) (7). Moreover, it has been reported in HIV that the binding affinity of darunavir for wild-type protease was > 100-fold higher than other PIs due to a slower dissociation rate of this molecule from the protease active site (5). In the same way, crystallography structure studies of the HIV-2 protease and binding affinity experiments might help us to understand the difference observed in the natural susceptibility of HIV-2 strains for these two drugs as well as phenotypic resistance in HIV-2 mutated strains. The IC50 and IC90 values of atazanavir, indinavir, nelfinavir and tipranavir for the HIV-2 isolates were higher than those observed for HIV-1 raising the hypothesis of a lower activity of these PIs against HIV-2. However these values were lower than their respective trough plasma concentrations. This might be explained by the fact that HIV-2 wild-type isolates harbored several amino acids associated with PI resistance in HIV-1. PI treatment-associated amino acid changes in the HIV-2 protease gene occurred at positions known to confer PI resistance in HIV-1 and were not associated with the use of a particular PI without any order of accumulation. They altered the phenotypic susceptibility of the isolates to all the PIs tested here. These results are in keeping with data published elsewhere (2) (3) (9) (11) (13) (15). Mutagenesis experiments coupled with phenotypic susceptibility testing might help to determine the impact of each substitutions in PI resistance. Saquinavir, lopinavir and 112 darunavir appear to be the best choices for first-line therapy of HIV-2 infection, while 113 amprenavir should not be used. Atazanavir and tipranavir might be used with care (17). Our 114 results suggest that treatment guidelines for HIV-1-infected patients should not be directly 115 extrapolated to HIV-2-infected patients. Virological efficacy data in vivo might help us to 116 evaluate the place of PIs in HIV-2 antiretroviral strategy.
9 117 Acknowledgements 118 This work was supported by Agence nationale de Recherche sur le SIDA et les Hépatites 119 virales (ANRS). 120 We thank Laetitia Stephant for her technical skills This work was presented at the 14th Conference on Retroviruses and Opportunistic Infection, February 25-28, 2007, Los Angeles, CA, USA. Drugs and sources Amprenavir was provided by GlaxoSmithKline (Marly-le-Roi, France), atazanavir by Bristol-Myers Squibb (Rueil-Malmaison, France), darunavir by Tibotec (Mechelen, Belgium), indinavir by Merck Sharp & Dohme-Chibret (West Point, PA, USA), lopinavir by Abbott (Rungis, France), nelfinavir and saquinavir by Roche (Neuilly sur Seine, France) and tipranavir by Boehringer-Ingelheim (Ridgefield, CT, USA). 130
10 131 References Adje-Toure, C. A., R. Cheingsong, J. G. Garcia-Lerma, S. Eholie, M. Borget, J. Bouchez, R. A. Otten, C. Maurice, M. Sassan-Morokro, R. E. Ekpini, M. Nolan, T. Chorba, W. Heneine, and J. N. Nkengasong Antiretroviral therapy in HIV-2- infected patients: Changes in plasma viral load, CD4+ cells counts and drug resistance profiles of patients treated in Abidjan, Cote d'ivoire. AIDS 17:S49-S Colson, P., M. Henry, M. Tivoli, H. Gallais, J. A. Gastaut, J. Moreau, and C. Tamalet Presented at the XII International HIV drug resistance workshop: Basic principles and Clinical Implications, Los Cabos, Mexico. 3. Damond, F., F. Brun-Vezinet, S. Matheron, G. Peytavin, P. Campa, S. Pueyo, F. Mammano, S. Lastere, I. Farfara, F. Simon, G. Chene, and D. Descamps Polymorphism of the human immunodeficiency virus type 2 (HIV-2) protease gene and selection of drug resistance mutations in HIV-2-infected patients treated with protease inhibitors. J Clin Microbiol 43: Damond, F., G. Collin, S. Matheron, G. Peytavin, P. Campa, S. Delarue, A. Taieb, A. Benard, G. Chene, F. Brun-Vezinet, and D. Descamps Letter. In vitro phenotypic susceptibility to nucleoside reverse transcriptase inhibitors of HIV-2 isolates with the Q151M mutation in the reverse transcriptase gene. Antivir Ther 10: De Wit, M., I. Keuleers, E. Gustin, I. Dierynck, S. Hallenberger, and K. Hertogs Presented at the XIV Conference on Retroviruses and Opportunistic Infections., Los 151 Angeles,CA, US, February 25-28, Koh, Y., H. Nakata, K. Maeda, H. Ogata, G. Bilcer, T. Devasamudram, J. F. Kincaid, P. 153 Boross, Y. F. Wang, Y. Tie, P. Volarath, L. Gaddis, R. W. Harrison, I. T. Weber, A. K. 154 Ghosh, and H. Mitsuya Novel bis-tetrahydrofuranylurethane-containing nonpeptidic 155 protease inhibitor (PI) UIC (TMC114) with potent activity against multi-pi-resistant 156 human immunodeficiency virus in vitro. Antimicrob Agents Chemother 47:
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13 Legend of the table Table Title : Phenotypic susceptibilities to PIs and protease mutations compared to HIV-2 subtypes A and B consensus sequences of the 9 wild-type isolates
14 ISOLATES IC50 IC90 IC50 IC90 IC50 IC90 IC50 IC90 IC50 IC90 IC50 IC90 IC50 IC90 IC50 IC90 BRU (HIV-1 reference isolate) HIV-2 Isolates ROD (HIV-2 reference isolate) Patient 1 (subtype H) T0: 10I-40P-41Y-60H-63N-70T-73G-89L-92E T1: 10I-34E*-40P-41Y-60H-63N-70T-73G-82F*-89L-92E Fold increase in IC50 between T1/T Patient 2 (subtype A) T0: 14H-17D-43T-68N/D <0.01 < <0.006 < T1: 5L/F*-14Y/H*-17G/D*-43T-54I/M*-62V/A*-70R/K*-71I* >12.5 > Fold increase in IC50 between T1/T / / / / Patient 3 (subtype A) T0: 14H-60K/N-65E T1: 54M*-65E-71I*-74N*-90M* >12.5 > Fold increase in IC50 between T1/T / / 15 5 Patient 4 (subtype A) T0: 10I-17D-40D-43I-46V-66V/A-70R/K T1: 10I-17D-40D-43I-45K/R*-46V-54M*-64I/V*-69K/R*-71V/I*-90M* Fold increase in IC50 between T1/T Patient 5 (subtype A) T0: 14H-40D-70K-72R/K-91T/S T1: 10I*-40D-43I*-70K-82F*-84V*-85L*-89V*-90M*-91T/L*-98N/K* >17.6 > T2: 10V/I*-40D-43I*-56V*-70K-82F*-84V*-89V*-90M* Fold increase in IC50 between T1/T / / Fold increase in IC50 between T2/T Patient 6 (subtype B) T0: 14Y-61N-99L T1: 14Y-19P*-33I*-61N-71I*-75M*-84V*-90M* T2: 14Y-19P*-61N-64V*-71I*-90M*-95I* >17.6 > Fold increase in IC50 between T1/T Fold increase in IC50 between T2/T / / Patient 7 (subtype B) T0: 12T-14Y-19P-40N-41D-61N-62I-96S-99L Phenotypic susceptibilities to PIs and protease mutations compared to HIV-2 subtypes A and B consensus sequences before (T0) and after (T1. T2) PIs initiating treatment of the 9 HIV-2 isolates. Amprenavir Atazanavir Darunavir Indinavir Lopinavir Nelfinavir Saquinavir Tipranavir Patient 8 (subtype B) T0: 12Q-14R-17G/D-19P-61N-62I-92A Patient 9 (subtype A) T0: 41D Median IC 50 and IC 90 value at T0 (+/- SD) 0.60 (+/- 0.20) 3.30 (+/- 1.50) 0.06 (+/- 0.05) 0.30 (+/- 0.08) (+/- 0.04) 0.03 (+/- 0.16) 0.02 (+/- 0.10) 0.40 (+/- 0.80) 0.03 (+/- 0.01) 0.14 (+/- 0.10) 0.06 (+/- 0.08) 0.40 (+/- 0.60) (+/- 4.60) 0.05 (+/- 27.0) 0.30 (+/- 0.05) 2.50 (+/- 1.10) *Substitutions selected between T0 and T1/T2. IC50 and IC90 values are measured in µm
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