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JAC Advance Access published online on August 20, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn335
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

HIV-2 integrase gene polymorphism and phenotypic susceptibility of HIV-2 clinical isolates to the integrase inhibitors raltegravir and elvitegravir in vitro

B. Roquebert1,2,3, F. Damond1,3, G. Collin1,3, S. Matheron2,4, G. Peytavin5, A. Bénard6, P. Campa7, G. Chêne6, F. Brun-Vézinet1,2,3, D. Descamps1,2,3,* on behalf of the French ANRS HIV-2 Cohort (ANRS CO 05 VIH-2)

1 AP-HP, Groupe hospitalier Bichat-Claude Bernard, Laboratoire de Virologie, Paris F-75018, France 2 Université Denis Diderot-Paris 7, Paris, France 3 INSERM U552, Paris, France 4 AP-HP, Groupe hospitalier Bichat-Claude Bernard, Service de Maladies Infectieuses et Tropicales, Paris F-75018, France 5 AP-HP, Groupe hospitalier Bichat-Claude Bernard, Pharmacie, Paris F-75018, France 6 INSERM U897, Bordeaux, France 7 AP-HP, Groupe hospitalier Saint Antoine, Service de Maladies Infectieuses et Tropicales, Paris F-75012, France

* Correspondence address. Laboratoire de Virologie, Hôpital Bichat Claude Bernard, 46 rue Henri Huchard, 75877 Paris Cedex 18, France. Tel: +33-1-40256150; Fax: +33-1-40256769; E-mail: diane.descamps{at}bch.aphp.fr

Received 3 June 2008; returned 14 July 2008; revised 18 July 2008; accepted 24 July 2008


   Abstract
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Objectives: We investigated the in vitro phenotypic susceptibility of HIV-2 isolates from integrase inhibitor (INI)-naive patients to INIs and its relation to HIV-2 integrase gene polymorphism.

Methods: We determined the phenotypic susceptibility to raltegravir and elvitegravir of co-cultured isolates obtained from the HIV-2 ROD reference strain and from 14 clinical isolates. IC50 values were compared with those for HIV-1 reference strains. HIV-2 integrase gene polymorphism was assessed in isolates from 52 INI-naive patients enrolled in the French HIV-2 cohort.

Results: Median raltegravir and elvitegravir IC50 values for the 14 clinical HIV-2 isolates were 2.4 and 0.7 nM, respectively, and were similar to those observed for HIV-2 ROD and HIV-1 reference strains. Overall, 38% of HIV-2 integrase amino acids were polymorphic. The catalytic triad DDE and the HHCC and RKK motifs were fully conserved, at the same genomic positions as described in HIV-1. In subtype B isolates, the total length of the integrase gene varied, owing to the presence of stop codons at positions 288, 294, 297 and 302. Fourteen of the positions associated with substitutions conferring INI resistance in HIV-1 were polymorphic in HIV-2.

Conclusions: Despite 40% heterogeneity between the HIV-1 and HIV-2 integrase genes, the phenotypic susceptibility of clinical HIV-2 isolates to INIs was similar to that of HIV-1. This new class of antiretroviral drugs thus represents a novel therapeutic possibility for HIV-2-infected patients who otherwise have few treatment options.

Key Words: HIV/AIDS , resistance , mutations , human immunodeficiency virus type 2


   Introduction
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Only few studies have been published concerning phenotypic susceptibility of human immunodeficiency virus type 2 (HIV-2) isolates to antiretroviral drugs. HIV-2 isolates appear to be sensitive to most nucleoside reverse transcriptase inhibitors (NRTIs) and to protease inhibitors, lopinavir and darunavir being the most active drugs.1,2 HIV-2 strains are naturally resistant to non-NRTIs and enfuvirtide.1,3 Integrase inhibitors (INIs) are a novel therapeutic option for HIV-1-infected patients.4,5 Raltegravir has been approved for clinical use in HIV-1 infection, and a second INI, elvitegravir, is undergoing advanced trials in HIV-1-infected patients.6,7 This new class of antiretroviral drugs might be a novel therapeutic option for HIV-2. However, the action of INIs on the integrase of HIV-2 has not been studied. HIV-2 is endemic in West Africa and has spread through Europe during the last two decades.8–11 In France, a cohort created in 1994 includes almost all HIV-2-infected patients living in France and monitored in hospital centres.12 The aim of this study was to determine the polymorphism of the HIV-2 integrase gene and the in vitro phenotypic susceptibility to INIs of HIV-2 isolates collected from INI-naive patients.


   Patients and methods
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Integrase gene analysis

Integrase gene sequencing was performed on plasma specimens from 52 antiretroviral-naive HIV-2-infected patients, collected between 1994 and 2007 and stored at –80°C. All patients enrolled in the ANRS HIV-2 cohort gave written informed consent, and the study was approved by the Comité Consultatif de Traitement de l'Information dans la Recherche Scientifique et Médicale and the Commission Nationale Informatique et Libertés.

HIV-2 RNA was extracted automatically from 1 mL of plasma with the Magnapure method (Roche Diagnostics System, Meylan, France). Ten microlitres of viral RNA was used for amplification. The integrase gene was first amplified by RT–PCR according to the manufacturer's instructions (Titan One-Tube RT–PCR kit, Roche, Mannheim, Germany) by using the following primers: 1S: 5'-ATAGTAGACTCACARTATGTMATGGG-3' (nt 4334–4359) and 1AS: 5'-RGTTCCAATATSCYTGTAYCTCTAG-3' (nt 5538–5562). The RT step was carried out at 50°C for 30 min, followed by 2 min at 94°C. PCR cycling parameters were 40 repeat cycles (94°C for 30 s, 55°C for 30 s and 68°C for 90 s) and 68°C for 7 min. This was followed by second-round PCR using two different pairs of primers: 1S/2SA (5'-GTCATATCCCCTATTCCTC-3', nt 5094–5112) and 2RS (5'-TGCATGAATTTTAAAAGAAGGG-3', nt 5072-5093)/2R (5'-AATATTACYCTRCTGCAAGT-3', nt 5496–5515). Nested PCR reactions were performed with Taq polymerase (Applied Biosystems, Foster City, CA, USA) and 2.5 µL of internal primers (10 µM), following the manufacturer's instructions. The PCR conditions consisted of initial denaturation at 94°C for 5 min, followed by 30 repeated cycles (94°C for 30 s, 55°C for 30 s, 72°C for 60 s) and 72°C for 7 min. The HIV-2 integrase gene was sequenced with the four nested primers for complete double-strand coverage. Sequencing reactions were run with the ABI Prism Dye Terminator kit on an automated sequencer (Applied Biosystems). Sequence alignments were performed with Sequence Navigator software (Applied Biosystems). The sequences were compared with HIV-2 clade A and B consensus sequences (Los Alamos database: http://hiv.lanl.gov).13 Changes in amino acids were compared with those associated with resistance in HIV-1, identified from the International AIDS Society-USA (IAS-USA) panel expert list (www.iasusa.org) and from other published sources.14–17

HIV-2 subtype determination

HIV-2 subtypes were determined by analysing the protease (PR), RT and integrase genes. Nucleotide sequences were compared with reference sequences of known HIV-2 subtypes contained in GenBank (http://www.ncbi.nlm.nih.gov/retroviruses).

Phenotypic susceptibility studies

In vitro phenotypic susceptibility to raltegravir and elvitegravir was determined for 14 HIV-2 clinical isolates collected from INI-naive patients by using the ANRS PBMC assay.18 Among these 14 HIV-2 isolates, two were obtained from RT inhibitors-experienced patients with viruses harbouring the Q151M mutation in the RT gene. The phenotypic susceptibility of HIV-1 (BRU) and HIV-2 (ROD) reference strains was also determined. Briefly, after HIV-2 isolation from peripheral blood mononuclear cells (PBMC), the cell-free HIV-2 positive supernatant was serially diluted (100–10–2) and incubated with fresh normal phytohaemagglutinin-stimulated PBMC. After being washed, the cells were placed in 96-well plates containing six serial dilutions of the antiretroviral drugs. Each dilution was tested in quadruplicate. On day 3, the supernatant was collected and the 50% tissue culture-infective dose (TCID50) was assessed by measuring the number of RNA HIV-2 copies in the supernatant with a real-time quantitative RT–PCR assay.19 Drug concentrations inhibiting the replication of 100 TCID50 by 50% and 90% were calculated (IC50 and IC90). Raltegravir and elvitegravir were kindly provided by Merck Sharp & Dohme-Chibret (West Point, PA, USA) and Gilead Sciences (Foster City, CA, USA), respectively. Genotypic analyses of all the HIV-2 supernatants were performed at day 0 and day 3 in order to ensure that there was no change in the integrase gene sequences during the phenotypic susceptibility assay.


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Polymorphism of the integrase gene

Thirty-two of the 52 patients were infected by HIV-2 subtype A, 19 by subtype B and 1 by subtype H. A total of 52 HIV-2 integrase gene sequences were determined to analyse natural polymorphism. Amino acids mutated with a prevalence of <1% were not considered to be variable. The length of the HIV-2 integrase gene differed between HIV-2 subtype A (total genomic length 293 codons) and subtype B (total genomic length between 287 and 301 codons). The overall frequency of amino acid polymorphism was 38%. When compared with HIV-2 clade A (ROD) and B (EHO) consensus sequences, the polymorphism of subtypes A and B was 30% (85/293) and 27% (80/296), respectively. The catalytic triad DDE and the HHCC and RKK motifs were fully conserved in HIV-2 at positions 64, 116 and 152 (DDE), 12, 16, 40 and 43 (HHCC), and 231, 258 and 264 (RKK), respectively. Most of the differences (>20%) were located at 31 positions in subtype A strains and at 29 positions in subtype B strains. Total polymorphism was observed at two positions in subtype A (codons 180 and 222) and at three positions in subtype B (codons 34, 146 and 240) (Figure 1). Among the 32 positions known to be associated with INI resistance in HIV-1, 17 were non-polymorphic and 5 were polymorphic (Y143C and V249I in subtype A and V72I, T97A and H156 N in subtype B). Atypical residues of unknown significance were found at several other positions. As shown in Table 1, the presence of amino acids known to be associated with INI resistance in HIV-1 was observed for the HIV-2 reference strains ROD (clade A) and EHO (clade B). This natural polymorphism involved five positions in HIV-2 clade A (72, 74, 153, 165 and 201) and three positions in clade B (74, 153 and 165).


Figure 1
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  		Figure 1. Whole integrase amino acid variation of HIV-2 isolates from INI-naive patients. Amino acid residues are represented as the subtypes A (ROD) and B (EHO) consensus. Degrees of conservation are colour-coded. Positions thought to be critical for integrase activity are shown in bold.

 


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  		Table 1. Frequency of integrase amino acid polymorphisms in INI-naive HIV-2-infected patients at positions known to be associated with in vitro or in vivo resistance to INI compounds in HIV-1 isolates

 
Phenotypic susceptibility

Phenotypic susceptibility to raltegravir and elvitegravir for the 14 isolates is presented in Table 2. No changes were observed in the integrase genes for all of the HIV-2 clinical isolates between day 0 and day 3 of the ANRS phenotypic susceptibility assay. Median raltegravir and elvitegravir IC50 values for the 14 tested HIV-2 isolates were 2.4 nM (1.3–5.0) and 0.7 nM (0.3–0.9), respectively. The integrase sequences of these HIV-2 supernatant isolates contained substitutions at positions 72I (n = 11/14), 97A (n = 1/14), 165I (n = 15/14) and 201I (n = 10/14). The presence of the Q151M mutation in the RT gene of two isolates had no impact on their phenotypic susceptibility to raltegravir and elvitegravir.


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  		Table 2. Phenotypic susceptibilities to raltegravir and elvitegravir for the 14 HIV-2 subtypes A, B and H clinical isolates and HIV-1 and HIV-2 reference isolates

 

   Discussion
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Integrase gene polymorphism has been described for HIV-1 groups M and O, but this is the first such study of a large number of HIV-2 clinical isolates, and the first analysis of HIV-2 in vitro phenotypic susceptibility to INIs.15,16

The overall rate of amino acid heterogeneity was 43% relative to the HIV-1 HXB2 consensus sequence and the HIV-2 ROD reference strain. We studied HIV-2 integrase sequences from 52 INI-naive patients. Whereas the HIV-1 integrase gene always encodes 288 amino acids, the length of the HIV-2 integrase gene was found to depend on the position of the carboxy terminal stop codon. The carboxy terminal domain, starting at codon 213, has strong DNA binding activity and is thought to play a role in binding to viral and host DNA.20 The impact of this feature on enzyme activity needs to be investigated in biochemical studies.

We found 38% of amino acid variation, a value similar to that reported by Hackett et al.15 for HIV-1 non-B subtypes (39%) but lower than that reported by Lataillade et al.,16 who found a rate of 64% in 243 HIV-1 clade B integrase genes. Positions 72, 201 and 206, which are extremely variable in HIV-1 (18–51%, 13–87%, and 12–32% respectively), were also variable in HIV-2. In contrast, in the carboxy terminal domain, the residue at position 280, which is a cysteine in HIV-1, was highly variable in HIV-2, with shifts from glycine to serine and/or vice versa ranging from 32% for subtype B and 44% for subtype A.

Positions involved in the zinc-binding domain (HHCC motif), the DDE catalytic domain and the RKK motif, present at the same genomic positions as in HIV-1, were 100% conserved in HIV-2.15,16,21,22 Integrase residues at positions crucial for DNA binding (Q148), integration and replication (Q62, H67, N120, N144, Q148 and N155) in HIV-1 were also conserved in HIV-2. The fact that these highly conserved integrase positions are shared by the two viruses supports their crucial importance for enzymatic activity.23

Three percent of HIV-2 subtype A strains harboured a cysteine at residue 143. Resistance studies from BENCHMRK phase III trials of raltegravir compared with reference antiretroviral regimens point to the existence of another possible pathway of raltegravir resistance involving the Y143R/C mutation.7,24 This mutation is linked to raltegravir and elvitegravir resistance in the Stanford (http://hivdb.stanford.edu) and ANRS version 17 (http://hivfrenchresistance.org) genotypic interpretation algorithms.

We found that HIV-1 and HIV-2 had similar phenotypic susceptibility to raltegravir and elvitegravir. Even extensive polymorphism at some residues or at positions involved in HIV-1 resistance seemed to have no impact on HIV-2 phenotypic susceptibility to the two INIs.25,26 For example, the presence of an isoleucine at positions 72, 165 and/or 201, known to confer in vitro phenotypic resistance to several other INIs than raltegravir and elvitegravir in HIV-1,27,28 had no impact on HIV-2 phenotypic susceptibility to raltegravir and elvitegravir.27,28 In HIV-1, alanine at position 97 has been described in vivo as part of the raltegravir ‘N155H resistance pathway’ and was not associated with raltegravir resistance when present alone. In our study we did not observe any impact in vitro on raltegravir phenotypic susceptibility of the T97A substitution that was present in one HIV-2 isolate.29 The re-verification of integrase mutations showing no change in the integrase sequences in viruses at day 3 of the phenotypic assay might ensure that a clonal virus of wild-type viruses was not responsible for the natural drug susceptibility.

The HIV RT and integrase enzymes interact physically, and their functional interaction might play an important role in viral replication. Furthermore, it has been postulated that INI activity on HIV-1 might be compromised by mutations in the RT gene.30 In our study, the presence of the Q151M mutation in the RT gene, known to be associated with resistance to multiple nucleoside RT inhibitors, had no impact on HIV-2 susceptibility to raltegravir and elvitegravir.

Despite almost 40% of genotypic heterogeneity between the HIV-1 and HIV-2 integrase genes, we found that HIV-2 phenotypic susceptibility to INIs was similar to that of HIV-1. As fewer antiretroviral drugs are active on HIV-2 than on HIV-1, this new class of drugs represents a novel therapeutic option for HIV-2-infected patients and for HIV-1/HIV-2 co-infected patients. Our in vitro results are in keeping with two recent reports of short-term immunological and virological efficacy of INI-containing regimens in two heavily pretreated HIV-2-infected patients.31,32 Due to the few number of active antiretroviral drugs available for the treatment of HIV-2-infected patients, this new class of antiretroviral drugs might represent a new therapeutic option for HIV-2-infected patients, which remains to be evaluated through multicentre trials.


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This work was supported by ANRS (Agence nationale de Recherche sur le SIDA et les Hépatites virales).


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The authors report no conflicts of interest. All authors have contributed to, seen and approved the final, submitted version of this manuscript.


   Acknowledgements
 
This work was presented at the Fifteenth Conference on Retroviruses and Opportunistic Infection, Boston, USA, 2008 (Abstract 886).

French HIV-2 Cohort Study Group (ANRS CO 05 VIH-2)

Clinical investigators. J. P. Viard, O. Lortholary, C. Boitard, A. Maignan (Necker, Paris); M. C. Meyohas, P. M. Girard, D. Bollens, J. L. Meynard, L. Fonquernie, P. Campa, C. Boudraa (St Antoine, Paris); O. Picard, B. Cabanne, P. Tangre, J. Tredup, N. Desplanque (St Antoine, Paris); A. Brunet, L. Guillevin, O. Launay (Cochin, Paris); A. Compagnucci, M. Boudjioudi J. B. Dubuisson, L. Finkielsztejn (Cochin, Paris); J. B. Guiard-Schmid, G. Pialloux, A. Coridian, B. Cardon, P. Mariot, F. Bani Sadr, T. Nguyen, L. Slama, J. P. Vincensini, V. Jousselin (Tenon, Paris); J. Gilquin, A. Cros (St Joseph, Paris); S. Matheron, P. Yéni, A. Lepretre, S. Mas, G. Morau, R. Landman, C. Voyer, I. Fournier, A. Kissila, S. Lariven, G. Pahlavan, S. Fegueux, P. Klutse, P. Longuet (Bichat Cl Bernard, Paris); R. Tubiana, F. Bricaire, V. Zeller, M. Pauchard, D. Danis (Pitié Salpétrière, Paris); F. Meier, M. Bloch (L Mourier, Colombes); M. A. Khuong, D. Méchali, T. Labergere, B. Taverne, Dr Khélil (Delafontaine, St Denis); M. Bentata, A. Krivitzky, F. Rouges, P. Honore (Avicenne, Bobigny); E. Teicher, D. Vittecoq (Paul Brousse, Villejuif); F. J. Timsit, P. Morel, E. Splinder (St Louis, Paris); S. Dos Santos, V. Jeantils, S. Tassi (J. Verdier, Bondy); C. Semaille, O. Patey, J. Bantsimba, L. Richier (Villeneuve St Georges); Y. Quertainmont, J. F. Delfraissy, M. T. Rannou, C. Goujard (Bicêtre, Le Kremlin Bicêtre); E. Oksenhendler, L. Gérard, M. Martinie (St Louis, Paris); G. Cessot, M. Beumont-Mauviel (institut A Fournier, Paris); A. M. Simon-Poli, P. Vinceneux, E. Lafon, F. Zeng (L Mourier, Colombes); E. Froguel, F. David-Ouaknine, P. Lagarde, B. Gourdel (Lagny sur Marne); Y. Welker (St Germain en Laye); K. Chemlal, M. Ruel (M Fourestier, Nanterrre); P. Genet, L. Sutton, F. Lionnet, T. Touhari (V Dupouy, Argenteuil); A. Leprêtre, P. Polomeni (S Veil, Montmorency); D. Zucman, O. Bletry, C. Majerholc (Foch, Suresnes); G. Force, D. Champetier de Ribes (Notre Dame du Perpétuel Secours, Levallois Perret); A. Coutellier, S. Herson, N. Amirate, Mme Brançon (Pitié Salpétrière, Paris); N. Dupin (Cochin, Paris); C. Picketty, L. Weiss, N. Bengrait, M. Karmochkine, D. Derouineau, D. Batisse, D. Tisne-Dessus (G Pompidou, Paris); V. Garrait, M Chousterman, L. Richier (Créteil); H. Masson Colin, D. Hillion, F. Cordonnier (Poissy); L. Blum, O. Danne, M. Eouzan (R Dubos, Pontoise); P. Lesprit, A. Sobel, Y. Lévy, F. Bourdillon, C. Jung, M. L. Dubreuil-Lemaire (H Mondor, Créteil); H. Bideault, P. Chardon (Bligny, Briis sous Forge); V. Perrone, F. Granier, V. Leclerc (F Quesnay, Mantes la jolie); C. Winter, M. Janowski (A Grégoire, Montreuil); F. Bournerias (St Cloud); J. M. Zini, G. Tobelem (Lariboisière, Paris); C. Lascoux-Combe, D. Séréni, C. Pintado (St Louis, Paris); D. Ponscarme, J. M. Molina, Y. Quertainmont, N. Colin de Verdière, M. Lafaurie (St Louis, Paris); P. Brunet (Arpajon); A. Schaeffer, B. Godeau (H Mondor, Créteil); P. Chevojon, G. Charpentier, C. Petitdidier, P. Kousignian, I. Turpault, B. Mourgeon (G de Corbeil, Corbeil Essones); S. Daum-Morelon, E. Rouveix, C. Dupond, H. Berthe (A Paré, Boulogne Billancourt); S. Kernbaum, R. SteinMetzer (Hôpital Américain de Paris, Neuilly sur Seine); B. Gachot (Institut Pasteur, Paris); J. L. Delassus, D. Malbec (R Balanger, Aulnay sous Bois); L. Bodard, M. Gayraud, L. Rafenne, A. Meudec (Institut Montsouris, Paris); D. Israel-Biet, H. Sors (G Pompidou, Paris); P. Imbert, T. Debord (Bégin, Saint Mandé); P. Galanaud, D. Emilie, F. Boué, R. Fior, D. Bornarel (A Béclère, Clamart); A. Uludag, B. Fantin (Beaujon, Clichy); S. Abgrall, O. Bouchaud, S. Thuyet Huynh Thi (Avicenne, Bobigny); A. Compagnucci, G. Huchon, C. Pintado (Hotel Dieu, Paris); K. Asselah, M. Bary, A. Boulkhemair (Moulin Joly, H. Dunand, Paris); I. La Torre (Montargis); C. Beck, G. Beck-Wirth, M. Benomar (Mulhouse); E. Billau, J. Barrier, F. Raffi, H. Hue, M. Sicot, D. Brosseau (Hôtel-Dieu, Nantes); J. F. Stalder (Hôtel Dieu, Nantes); C. Drobacheff, R. Laurent, A. Foltzer (St Jacques, Besançon); M. Lapine (Niort); L. Cotte, C. Trépo, N. Benmakhlouf, C. Brochier, V. Thoirain (Hôtel-Dieu, Lyon); T. Allègre, A. P. Blanc (C H du pays d'Aix, Aix en Provence); M. P. Drogoul, J. A. Gastaut (Fabre, Marseille); S. Le Moal, E. Duhamel, A. Hascouet, S. Daniel- Sebbar (Saint Brieuc); D. Merrien, P. Veyssier (Compiègne); P. Granier (Fleyriat, Bourg en Bresse); P. Nau, P. Choutet, J. M. Besnier (Bretonneau, Tours); F. Borsa Lebas, F. Caron, Y. Debab, S. El Koubi (C Nicolle, Rouen); P. Leclercq, C. Brambilla, M. C. Gailland (Michalon, Grenoble); G. Adam, M Mornet (J Cœur, Bourges); J. Moreau, J. P. Delmont, P. Brouqui, E. Vandergheynst, A. M. Tourba (Nord, Marseille); F. Andrieux, T. Cartier, C. Bouvier, C. Arvieux, C. Poncelle (Pontchaillou, Rennes); B. Héry, M. H. Delangle (Saint Nazaire); J. P. Breux, B. Becq-Giraudon (J Bernard, Poitiers); P. Arsac (Orléans); A. Lafeuillade, P. Jolly (Chalucet, Toulon); J. M. Ragnaud (Pellegrin, Bordeaux); S. Durupt, M. J. Chantereau (W Morey, Chalon-sur-Saône); P. Perré, I. Suault (La Roche sur Yon); H. Dutronc, M. Dupon, I. Raymond (Pellegrin, Bordeaux); P. Mercié, J. L. Pellegrin (Haut—Lévêque, Bordeaux Pessac); B. Vialatte, P. Simonet, N. Montagne, Y. Bianco (Cannes); L. Boyer, T. May, S. Wassoumbou (CHU de Nancy Brabois, Vandoeuvre les Nancy); B. Manoury (St Quentin); J. Reynes, F. Janbon, H. Mansaray, C. Tramoni (Montpellier); A. Smail, J. L. Schmit (Nord, Amiens); Y. Poinsignon, H. Jardel, D. Le Pichon (P Chubert, Vannes); C. Jacomet, J. Beytout, F. Gourdon (Hôtel Dieu, Clermont Ferrand); M. Buisson, H. Portier, C. Braconnier (Bocage, Dijon); J. G. Fuzibet (Archet, Nice); V. Baclet, Y. Mouton, G. Dos Santos, S. Pavel, M. C. Marien (G Dron, Tourcoing); A. Riché, M. Bonnefoy (Angoulême); M. Bensalem, J. P. Bru, J. Gaillat (Annecy); D. Rey, J. M. Lang, P. Fischer, G. Hess (Strasbourg); J. F. Abino (Ajaccio); P. Foullon (Draguignan); L. Rezzouk (CH Hauts Clos, Troyes); P. Gourbin, R. Verdon (Caen); J. M. Livrozet, F. Jeanblanc (E Herriot, Lyon); G. Le Moal (Poitiers); S. C. Germain, S. Farbos (CH Côte Basque, Bayonne); F. Lucas, F. Prevoteau du Clary (La Grave, Toulouse); K. Cochonnat (Lens); P. Chennebault (Angers); D. Liné (Soissons); A. Arnaud (Caremeau, Nimes); N. Randrianasolo (Chaumont); C. Merle, C. Lebrun (CHI haute Saône, Vesoul); P. Granet (Digne les bains); L. Caunègre (Dax).

Virological investigators. F. Brun-Vézinet, F. Damond, D. Descamps (Bichat, Paris); F. Simon, P. Palmer (St Louis, Paris); L. Morand-Joubert (St Antoine, Paris); D. Cottalorda (F. de médecine, Nice); M. P. Schmitt (F. de médecine, Strasbourg); P. Billaudel, V. Ferre (Institut de biologie, Nantes); P. Lab, A. Bassignot (Besançon); P. Barin (Bretonneau, Tours); P. Boulanger, D. Tardy (Université, Lyon); D. Raoult, C. Tamalet (La Timone, Marseille); P. Avril, M Kerriguy (Pontchaillou, Rennes); J. Puel, A. Jaafar (Purpan, Toulouse); P Buffet-Janvresse (C. Nicolle, Rouen); P. Seigneurin, D. Morand (Grenoble); P. Agius, M. Bourgoin (J. Bourgoin, Poitiers); P. Fleury, B. Masquelier (Pellegrin-Tripode, Bordeaux); D. Duverlie, M Roussel (Amiens); H. La Feuille, D. Henquell (F. de médecine, Clermond-Ferrand); A. Chiacha (St Michel, Angoulême); D. Trevoux, D. Delarbre (Mulhouse); C. Brehant, M. Marty (La Rochelle); P. Watry, D. Bocket (Lille); B. Montes (St Eloi, Montpellier).


   References
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Funding
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M. L. Ntemgwa, T. d. Toni, B. G. Brenner, R. J. Camacho, and M. A. Wainberg
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