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HCV is a positive strand RNA viruse that has ben classified as the genus  Hepacivirus in the Flaviviridae  family. The HCV genome is uncapped,linear molecule with a leanth of 9600 nucleotides.it carries a long open reading frame that is flanked at the 5’- and 3’- ends by short highly structure non-translated regions(NTRs). 5’-NTR  has a lenth of about 340nt and contains an internal ribosome entry site (IRES) required for  translation  of the HCV genome.Prat of the  IRES(domain II)  overlaps with RNA signals essential for viral  replication .
[object Object],[object Object],[object Object],[object Object],Genetic studies have shown that a  poly(U/UC)  as well as the complete  X-tail  are required for RNA replication in cell culture and for infectivity of the viral genome  in vivo. An additional  cis- acting RNA element ( CRE )has been identified in the 3’-terminal coding region of  NS5B .this CRE (designated  5BSL3.2 )form a long distance RNA-RNA interaction with SL2 in the X-tail which is indispensable for RNA replication.
Expression of the viral proteins from the monocistronic genome is primarily achieved by production of a polyprotein that is proteolytically cleaved into the structural protien ( core , envelope proteins E1  and  E2 )the hydrophobic peptid  p7 ,and nonstructural(NS) proteins  NS2 , NS3 , NS4A , NS4B , NS5A  and  NS5B . Processing of the core to  p7  region is mediated by  host cell signalases  , and in the case of the  core protein  , in addition by signal  peptide peptidase .  ,[object Object],[object Object],[object Object]
COMPONENTS OF THE HCV REPLICATION COMPLEX Since the minimum components required for HCV RNA translation and replication are the  NTRs  and the  NS3  to  NS5B  coding region. NS3-serin-type protease: And its Cofactor  NS4A-NS3  is a bifunctional molecule  that carries the N-terminal 180 amino acids a serine-type protease.this enzyme has a typical chymotrypsin-like fold. NS3: Although NS3  possesses intrinsic proteolytic activity, polyprotien cleavage is dramatically   enhanced by the NS4A cofactor. 1. Anchors the protease to intracellular membranes via an N-terminal transmembrane segment present in NS4A 2. Cotributes one-strand to the N-terminal protease domain and thereby allows its complete folding 3. It stabilize the protease against proteolytic degradation 4. Activates protease activity by changing the geometry of the catalytic traid.
NS3 helicase : The C-terminal 400 amino acids of NS3 form a superfamily  2DE×H/D-box RNA helicase that is capable of unwinding RNA-RNA duplexes in an ATP-dependent manner.the protein binds to homopolymeric RNAs with a preference for poly(U) In fact , it was found that NS3 can cleave two components of the dsRNA signaling pathway ,[object Object],[object Object],Both adaptor Phosphorylation  of IFN regulatory factor-3 (IRF-3)  Transcription of IFN And Other antiviral genes
 
NS4B : Inducer of a membrane scaffold for the viral RC( replicase complex ) ? ,[object Object],[object Object]
 
 
1: Introduction 2: HCV associated SLVL: the beginning of the story 3:  HCV & mixed cryoglobulinemia 4:  Indirect transformation by protracted antigenic stimulation 5:HCV-associated large B Cell Lymphomas 6:Direct transformation of B cells by HCV 7: Conclusion 1: Introduction 2:HCV associated SLVL: the beginning of the story
DC CD81 BAFF/BLyS Anti-E2 IgM/RF B cell 3:  HCV & mixed cryoglobulinemia HCV
IgH-bcl2 ? Other oncogenic event INF α +Ribavirin INF α +Ribavirin
EBV  ( B, T, NK Cell Lymphoma ) Herpes virus ( kaposi sarcoma )  HTLV Helicobacter pylori Campylobacter jejuni ( immunoprolifrative small intestinal disease ) EBV Naïve resting B cell Activated B cell Immortalized  B cell Polyclonal prolifration Trasformed B cell;secondary oncogenic events 4:  Indirect transformation by protracted antigenic stimulation
5:HCV-associated large B Cell Lymphomas Aside from SLVL & other low-grade B cell NHL , HCV is Epidemiologically associated with DLBCL
HCV BCR E2 CD81 core NS3/4 NOS Mutations:Bcl6-Beta Catenin-P53 B CELL 6:Direct transformation of B cells by HCV
HCV E2 BCR CD81 CD21 CD19 Proliferation AID Somatic hypermutation of immunoglubolins B CELL Activation –induced deaminase
7: Conclusion
 

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HCV & SLVL

  • 1.  
  • 2.  
  • 3.  
  • 4. HCV is a positive strand RNA viruse that has ben classified as the genus Hepacivirus in the Flaviviridae family. The HCV genome is uncapped,linear molecule with a leanth of 9600 nucleotides.it carries a long open reading frame that is flanked at the 5’- and 3’- ends by short highly structure non-translated regions(NTRs). 5’-NTR has a lenth of about 340nt and contains an internal ribosome entry site (IRES) required for translation of the HCV genome.Prat of the IRES(domain II) overlaps with RNA signals essential for viral replication .
  • 5.
  • 6.
  • 7. COMPONENTS OF THE HCV REPLICATION COMPLEX Since the minimum components required for HCV RNA translation and replication are the NTRs and the NS3 to NS5B coding region. NS3-serin-type protease: And its Cofactor NS4A-NS3 is a bifunctional molecule that carries the N-terminal 180 amino acids a serine-type protease.this enzyme has a typical chymotrypsin-like fold. NS3: Although NS3 possesses intrinsic proteolytic activity, polyprotien cleavage is dramatically enhanced by the NS4A cofactor. 1. Anchors the protease to intracellular membranes via an N-terminal transmembrane segment present in NS4A 2. Cotributes one-strand to the N-terminal protease domain and thereby allows its complete folding 3. It stabilize the protease against proteolytic degradation 4. Activates protease activity by changing the geometry of the catalytic traid.
  • 8.
  • 9.  
  • 10.
  • 11.  
  • 12.  
  • 13. 1: Introduction 2: HCV associated SLVL: the beginning of the story 3: HCV & mixed cryoglobulinemia 4: Indirect transformation by protracted antigenic stimulation 5:HCV-associated large B Cell Lymphomas 6:Direct transformation of B cells by HCV 7: Conclusion 1: Introduction 2:HCV associated SLVL: the beginning of the story
  • 14. DC CD81 BAFF/BLyS Anti-E2 IgM/RF B cell 3: HCV & mixed cryoglobulinemia HCV
  • 15. IgH-bcl2 ? Other oncogenic event INF α +Ribavirin INF α +Ribavirin
  • 16. EBV ( B, T, NK Cell Lymphoma ) Herpes virus ( kaposi sarcoma ) HTLV Helicobacter pylori Campylobacter jejuni ( immunoprolifrative small intestinal disease ) EBV Naïve resting B cell Activated B cell Immortalized B cell Polyclonal prolifration Trasformed B cell;secondary oncogenic events 4: Indirect transformation by protracted antigenic stimulation
  • 17. 5:HCV-associated large B Cell Lymphomas Aside from SLVL & other low-grade B cell NHL , HCV is Epidemiologically associated with DLBCL
  • 18. HCV BCR E2 CD81 core NS3/4 NOS Mutations:Bcl6-Beta Catenin-P53 B CELL 6:Direct transformation of B cells by HCV
  • 19. HCV E2 BCR CD81 CD21 CD19 Proliferation AID Somatic hypermutation of immunoglubolins B CELL Activation –induced deaminase
  • 21.  

Editor's Notes

  1. Splenic lemphoma with villous lymphocytes,mixed cryoglobulinemia and HCV infection:deciphering the role of HCV in B-cell lymphomagenesis