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Olga Kalinina, Olga Znoiko Saint-Petersburg Pasteur Institute Moscow State University of Dentistry and Medicine CLINICAL AND EPIDEMIOLOGICAL FEATURES OF.

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Presentation on theme: "Olga Kalinina, Olga Znoiko Saint-Petersburg Pasteur Institute Moscow State University of Dentistry and Medicine CLINICAL AND EPIDEMIOLOGICAL FEATURES OF."— Presentation transcript:

1 Olga Kalinina, Olga Znoiko Saint-Petersburg Pasteur Institute Moscow State University of Dentistry and Medicine CLINICAL AND EPIDEMIOLOGICAL FEATURES OF THE NATURAL HEPATITIS C VIRUS RECOMBINANT RF1_2k/1b RF1_2k/1b

2 Genome organization of Hepatitis C Virion Lindenbach and Rice, 2005 IRES

3 Genetic diversity of Hepatitis C Virus based on a high mutation rate a high mutation rate Quasispecies Genotypes/ Clades Genotypes/ Clades from 1 to % Subtypes Subtypes varying numbers from a to …20-25% Isolates10%

4 Geographic Distribution of HCV Clades/Genotypes India Europa North America Latin America Egypt 1b 1b 1a, 2a, 2b, 2c, 3a 1a, 1b 1a, 1b 2a, 2b, 3a 4 5a South Africa 1b, 3a 1b, 6, 3a, 2a Australia China, Cambodia, Vietnam Japan Russia 1b, 3a 1b, 3a 1a, 2a, 2b, 2c, 2k 1b Cameroon 4, 1

5 Genetic diversity of Hepatitis C Virion based on recombination PJ6CF USA PH77CV Chimera HC-J6 Japan 778 St.Petersburg 686 St.Petersburg 300 St.Petersbur g BEBE1 Japan HCJK081 Jakarta HCJK139 Thailand 611 R St.Petersburg 203 R St.Petersburg 747 R St.Petersburg 796 R St.Petersburg 674 R St.Petersburg 687 R St.Petersburg VAT-96 Moldova 464 St.Petersburg HCJK025 Jakarta HCJK109 Jakarta Md2b-1 VN004 Vietnam VN405 Vietnam VN235 Vietnam HCJK046 Jakarta 2 6 5a b e k f c a CORE HC16362 Korea HCV-JS Japan MD8-2 Japan HCV-L2 Korea HC-C2 China HPVHCVN Japan HCV-HB China MD4-1 Japan 309 St.Petersburg 576 St.Petersburg 204 St.Petersburg HCJTa Japan HCJTb Japan 643 St.Petersburg 788 St.Petersburg 779 St.Petersburg 704 St.Petersburg 615 St.Petersburg HD-1 Germany 747 R St.Petersburg 674 R St.Petersburg 796 R St.Petersburg 687 R St.Petersburg 611 R St.Petersburg 203 R St.Petersburg 761 St.Petersburg 185 St.Petersburg 783 St.Petersburg 735 St.Petersburg 589 St.Petersburg 789 St.Petersburg 728 St.Petersburg 700 St.Petersburg 732 St.Petersburg MD1-1 Japan MD1-2 Japan MD5-1 Japan HPCPP Japan HCV-H USA PH77CV Chimera HC-J1 USA 785 St.Petersburg EUH1480 South Africa 1 5a a b NS5B Flaviviridae  Flavivirus Dengue virus (Holmes et al, 1999; Tolou et al, 2001)  Pestivirus Bovine viral diarrehea virus virus (Ridpath et al, 2000)  Hepacivirus Hepatitis C virus (Kalinina et al. 2002) SimPlot – Query: 687 R 2k/1b Saint-Petersburg K1-S2 1b VAT-96 2k

6 CJTA... CJTB HCV N Estonia MD HPCGENOM HPCRNA... HPVHCVN HCD HC MD HCU Estonia MD Estonia Estonia... CJ HC J Estonia Estonia Estonia Estonia Estonia... GQ cirrhosis Indonesia Estonia K1 R CON AF bSweden... MD MD MD HPCPP GQ indonesia Estonia... JF USA pat D DQ Madagascar HM Irlend 2011 non recom 1... EU australia Рекомбинант RF_2k/1b J K1 S3... K1 R2... K1 S2... HD DQ Tunisia hemodialysis Estonia... K1 S Estonia HCV AD HCVPOLYP Estonia Estonia Estonia EF Tailand HPCP1... субтип 1а

7 Recently revelead inter-genotype HCV Recombinants 2i/6p recombination point within the NS2/NS3 region from blood donor, Ho Chi Minh City Vietnam /5 recombination point within the NS2/NS3 region, France b/1b recombination point within the NS2/NS3 region Metro Manila Philippines 2006 RF1_2k/1b Russia, Siberia, Estonia, Uzbekistan, Sweden, Ireland, Holland, France, Azerbaijan, Cyprus 2b/1a recombination point within the NS2/NS3 region, USA b/6w recombination point beginning the NS3 region Taiwan 2010

8 Recently revelead intra-genotype HCV Recombinants 1b/1a recombination point within the NS5B Peru a/1c two recombination points within the E1-E2 regions Japan a/1c five recombination points within the core- NS3 regions India b/1a recombination point within the core Uruguay 2009

9 CONCLUSIONS I  Currently, more than 40 recombinant RF1_2k/1b strains circulating in the human population are known; most of them from the former Soviet Union Countries where recombinant has likely emerged  At present, six natural inter-genotyping and four intra-genotyping recombinant HCV forms were identified in the world Recombination plays a significant role in the HCV evolution by creating genetic variants with new properties that has to be studied  Recombination plays a significant role in the HCV evolution by creating genetic variants with new properties that has to be studied

10 Genome organization of HCV Recombinant RF1_2k/1b Predicted amino acid sequences for HCV Recombinant number of the amino acid residues genome region genotype2 (HC-J6) RF1-2k/1b (N687 StP) subtype1b (HC-J4) subtype 1b (N589 StP) ORF Core 191 E1 192 E p7 63 NS2 217 NS3 631 NS4a 54 NS4b 261 NS5a NS5b 591 ISDR region within NS5A APSLKATCTTHHDSPDADLIEANLLWRQEMGGNITRVESENK HC-J4 1b R R k1-s2 1b R A b....R......GKAY.V.MVD...F DV..I...S. HCJ6 2a....R....A.AKNYAVEMVD..FF----..SDV..I...T. Vat96 2k Q..RPH...E.VN S T. CB 3a Q..RPH...E.VD S T. NZL1 3a RDRSELSPLLLSTTEWQTLPC HC-J4 1b I... k1-s2 1b I b....Q.....H.....AI R.... Q.....H.....AI R....Q.....H.....AI R....Q.....H.....AI R....Q.....H.....AI... Vat96 2k....Q.....H.....AI... HCJ6 2a.....QH...H....LAI... CB 3a.....QH...H....LAI... NZL1 3a PePHD region within E2

11 Serine at position 2300 is associated with resistance to interferon + ribaverin therapy (Bouzgarrou et al., 2009) ILDSFDPLRAEEDEREVSVAAEILRKSKKFPPALPIWARPDYNPPL HC-J4 1b V......I.P P R...R.M RF Q P R...R.I M21 RF.....E LP R.....M k1-s2 1b.....E I..P R b V...L..MVE.RSDL.P.IPS.YMLPK.R......A HC-J6 2a....L..SVE......P..PS.Y.LPK....Q...V V VAT-96 2k.....E.....T.DA.L.....CFK.PP.Y CB 3a V....E.....T.DV.P.....CFK.PP.Y NZL1 3a LESWKSPDYVPPAVHGCPLPPTTGPPIPPPRKKRTVVLTESTVSSA HC-J4 1b.A...D....H.V KA R RF.....D......V KA..V....R M21 RF I....D......V KA R k1-s2 1b..P..D......V KA b V....R...Q.AT.A..A...PKKT.T....RR...G.S..SIAD. HC-J6 2a V.T..R...D..T.S..A...RVTA.T....RR.AL..SQ.N.GE. VAT-96 2k.DR..A......T....A...RGA..V....R...IQ.DG.N..A. CB 3a.DR..A......T....A...RGA..V....R...IQ.DG.N..A. NZL1 3a LAELATKTFGSS-----GSSAVDSGTATAPPDQTSDDGDKESDVES HC-J4 1b S..QN...N...TG RF YN...N...AG..... M21 RF E...A P.N...AG..... k1-s2 1b E A b.QQ..I.S..QPPPSGDSGLSTGADA.DSG-SR.PP.ELAL.ETG. HC-J6 2a.QA..I.S..QLPPSCDSGRSTGMD.TD.T-..PALKESTD.EAG. VAT-96 2k.RA..E.S.P.LKPQEENN.SSGVD.QSSTTSKVPPSPGG...S.. CB 3a..A..E.S.P..KPQEEN..SSGVD.QSSTTSKVPPSPGG...S.. NZL1 3a LSAPSLKATCTTHHDSPDADLIEANLLWRQEMGGNITRVESENKVV HC-J4 1b RF M21 RF R k1-s2 1b R C A b......R......GKAY.V.MVD...F DV..I...S... HC-J6 2a......R....A.AKNYAVEMVD..FF----..SDV..I...T..L VAT-96 2k Q..RPH...E.VN S T... CB 3a Q..RPH...E.VD S T... NZL1 3a Interferon sensitivity-determining region ISDR/PKR binding domain V3 variable domain

12 Outcome of Hepatitis C Infection  HCV sensitivity to interferon therapy mainly depends on genotype and is the poorest for HCV 1b.  Genotype accounting for recombination is important for selection the therapy approach(es) and prognosis the response

13 Outcome of Recombinant RF1_2k/1b Hepatitis C Infection Patients  N 1763 men, 51 years old, chronic hepatitis C, revealed as a contact person with patient N 1764 with patient N 1764  N 1764 feminine, 34 years old, acute hepatitis C, icteric form, 20 days after onset biochemical level became normal after onset biochemical level became normal  M21 (sampled in France) men, 30 years old, IVDU, chronic hepatitis C, known as infected by HCV genotype 3a ( Morel et al., 2010)

14 Outcome of Recombinant RF1_2k/1b Hepatitis C Infection Patients N 1764, feminine, 34 years old, acute hepatitis C, icteric form, 20 days after onset biochemical level became normal 20 days after onset biochemical level became normal  During the following 12 months she was positive for RNA HCV, had increasing level of liver enzyme and progressed to chronic hepatitis  After one year from onset of disease patient received mono-therapy by α2a-interferon: Units three times per week  by week 12, it was observed early virological response. Following 36 weeks patient received the same therapy  by week 48, it was sustained virological and biochemical responses (also after 5 years later)

15 Outcome of Recombinant RF1_2k/1b Hepatitis C Infection Patients N 1763, men, 51 years old, chronic hepatitis C  patient received mono-therapy by α2a-interferon: Units three times per week  by week 12, it was observed only biochemical responses but not virological  after that patient received α2a-interferon + RIBA  by week 16, it was still not virological response  no progression of fibrosis stage for 6 years  elastography (Fibroscan Echosens) in 2007 Fibrosisscore - F1,  elastography (Fibroscan Echosens) in 2007 Fibrosis score - F1, in 2010 Elastography - F2 in 2010 Elastography - F2  at 2010 patient received Peg IFN + RIBA, by week 24, it was not virological and biochemical responses

16 Outcome of Recombinant RF1_2k/1b Hepatitis C Infection M21 (sampled in France) men, 30 years old, chronic hepatitis C, known as infected by HCV genotype 3a (Morel et al., 2010)  patient received combination therapy by pegylated interferon and ribavirin  by week 24, it was observed virological response. One month later HCV RNA didn’t also detected in the serum HCV RNA didn’t also detected in the serum  Three months post-treatment, it was noted virological relapse with increasing level of ALT with increasing level of ALT  HCV strain belonged to genotype 3a was no longer found. In the same time in the serum samples HCV strain was subtypes In the same time in the serum samples HCV strain was subtypes as recombinant RF1_2k/1b as recombinant RF1_2k/1b

17 CONCLUSIONS II  At present HCV recombinant RF1_2k/1b has to be considered as “difficult-to-treat” genotype  Further studies are emergency needed to define the long-term outcome and strategy for antiviral therapy in the case of RF1_2k/1b

18 Acknowledgements IN THE EPIDEMIOLOGY STUDY PARTICIPATED Lars O Magnius, Helene Norder Swedish Institute for Infectious Disease Control Tatjana Tallo Sergey MukomolovSt. Petersburg Pasteur Institute Olga ZnoikoMoscow State University of Medicine and Dentistry Maria Isaguliants Swedish Institute for Infectious Disease Control Ivanovsky Institute, Moscow Valentina Tchakharian State Centre for Epidemiological Surveillance Konstantin Zhdanov Medical Military Academy, St. Petersburg Denis GusevMedical Military Academy, St. Petersburg Timophei Vetrov St. Petersburg Pavlov Medical University Pavel Kislii St. Petersburg Metchnikov Medical Academy

19 Acknowledgements THANK YOU for YOUR ATTENTION


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