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Monoclonal antibody mapping of a vaccine-induced escape mutant of HBV
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50
ZZFECTIVENESS 6F LONG TEIGI LY1BHOBL.ABTOID IRTER1EROU (L-IFN) TREKCRERT IN CRROUSC HEPATITIS C (CHC1. J. Camps. A. Castilla, JI. Riezu-Boi.Up. Civeira. J. Priato Dpt. of Bcdicina. University of Novarra. Punplono.Spain.
INSULlN-LlKE GROWTHFACTOR II (IW-II) mRNAAS A IWIKEAOF DIFFERENTIATION 1N HvII\NPRIMARY LlVCRCAWCR.
1E C-riani Ic. Las4ePEe % France ‘C. Wchot. ‘IHKRM “wkker. Paris. *Dep&ent :f Swwy and Pathology, Hopi&l Louise M&l, Evry, France. ICF-*I fiNpI exprerrsionis deuelcmentally regulated in humanliver. In the Fetus. two major ndlM.4~ of 6 and 5 kb are synthesized whereas a mique nRW of 5.5 kb is expressed in the adult. we previw?ily repo*ted the diwerentia1 erpression of IGF-II mRNA.3in huaun primary liver cancer, benign liver tumors and cirrhositr. In mast or cancers, ye observed the reexpression of fetal W-11 MNAs, that were also detected in somecirrhotic adjacent tissue. Conversely, roost of cirrhosis not associated with a cerciwna and benign twrs contained the adult tiNA of 5.3 kb, seldom associated with the fetal transcript of 5 kb. The shift of IGF-II nANI to the Fetal pattern might then represent a marker of early steps OP hape-
Thirty six patients (pts) with CRC were randomized to receive L-IFN (Gl. n=lE> or no treatrent (CZ, n=lB). HCV ab. &-i positive in all of them. L-IF0 schedule: 3 kGJN/d frx 2 mo. 3 I4U/tiw for 3 mo. and 1.5 !N/tiw for 7 mo. Pts in Gl and 62 were comparable in all features. Liver biopsies and serum procollaRen III peptide (P-III-P) were obtained prior to the entry into the trial and after one year in both groups. Hean followup after finishins the trial is ll.Sk3.08 (ran6e:7-15). Results: complete rasponsc (CR)= no=malizstion of 6LT . Partial response (PR) = .lLT < 60 IV. CR: E/l8 (44.4%) in Gl vs 1118 (5.5%) in C2 pc.005; PR: 1110 (38.9%) in Gl VB 0118 in GZ p<.OOl and no response: 3118 (16.6%) in Cl vs 17118 (94.4%) in G2 pc.001. Liver histology iaproved in 15118 (83.3%) in Cl vs 1118 (5.5%) in G2 pc.001). P-III-P levels disminishcd significantly in Cl pc.05. Of 8 pts with CR. 6 remain with nonal ALT after 15.14.13.11.9 and 7 mo. follow-up. Conclusions: L-Iti 1; aale to induce P sustained biochemical improvement in P sirnifi+ant proportion of pts (Li3.3,). HistoloGic~i5 provwent is achieved in the majority of pts. even in those with PR. MooreprolonR6.dadministration of L-IPU can be necessary in some pts.
tocyte dedifferentiatim end/or trmsfcxeatim. andalphafetoprotein ratiwly analyzed ICF-II a series of hman primary liver cameos, mst
differentiated. Hepatitis 0 virus (IBY) RN% uere also studied xn the fvnon fmm HIV chronic carriers. AFP n2M was detected in only 4/16 tllnrorsand l/17 nontlllnorws cirrhotic tissues these sarnplas alto displayed IGF-II fetal MXAs. Furthermore, Fetal IGF-11 mRQ%s wrs observed in 5 tumorouaand 6 n~nt~rn~r~~~ cirrhotic areas not expressing AFP mRXA.The presence of HBVRN.&was only observed in tissues not expressing AFP or fetal IW-II nR*.
, F.
:
F&al IGP-II nrwA5al.0 expressed mare freConclusion -,qvently than RFP nRNplin hiqhly differentiated liver cancers and surrwndlnq cirrhotic areas. The detection of Fetsl Iw-II tiNAs might ‘hen represent a cowlementsry tool for the identiFication oi sarly steps in liver transformation and the evalurkinn of psemaliqnsnt crmditiom S&I 85 liver cirrhosis.
MONOCLONAL ANTIBODY MAPPING OF A VACCINEINDUCEDESCAF'EMUTANTOFHBV Carmao WF$ WatersJi,ZaneniA$ ZuckermanAJZ and ThomasHd. 1. Department of Medicine, St Mary’s Ho&%
!&?a.
II.lhivenity
London. 2. Department of Microbiology, London 3. Institute of Virology, Milao.
Fl-~*~~edica~liv.~engia.~~,uV
Isolated Fwa A23l87 w w c 0.2: 4%7 2.0: 76zl3 7lsl w
Aal&/
2s:
5%!i
;
all
??
V. Carla-&. G. laffi. P. Gre& E. Cuex~ G.G. Newi ?? . P. Gmtilini. Clinic” Medico
Thus ue bodeWFP) rRi.4 in of vhich highly
Royal Free Hospit&
Patients with replicadog HBV in the prcsencc of adequate levels of vaccine-induced anti-HBs have bezn described from Italy. We now show that one of these patients, a3 infant born to a carrier mother, has a mutation in the “a” determinant of HBsAg. This gives rise to an amino acid substitution from glycine to argioine, increasing the hydrophilicity of lhis area @nificdy. The mother had the uwaf seouencc. Binding studies on’tbis HBsAg with a mapped set of monoclonats have been ocrformed: the AUSRIA-2 kit (Abbott) was used for all reactions. F;rw, a ddutioa series of serum from the child and mother were tested using the standard proioc01. Then, amibodies RFHBs-i sod -2 (which bind to aa l27-l37) and 7 (aa 138.147) were bound to beads and iocubatcdwith the scra at the same dilutions as above. Reactions were completed using radiolabelled a&HBs from the kit. Sample to negative ratios for the zxhcr, at a dilution of 1 in SO, were g7 (Au?&), 129 (RF-l), 25 (RF-21 and 140 IRF-7). For the child the corresoondios ratios ie;e 27,&Z and ‘27 1; [hechild, binding IORF-iand-?was4 and 10 fold decreased respcctivety compared to the Ausria The precise conformation of the “a” determinant of HBsAg is nor-known but the mulation at aa 145 ha altered the hinding of monoclonals reactive with both regions of this dclcrminant. perlicularly RF-7, which has been mapped to the rcsion of the mulaion. This supports the hypothesis lhat the mum&x is rcsponaible for escape from the immuneresponse.
Wlo1e Dlad
3x4 *m
0xszlusia-s: A defective LIB rp3zxtim by isolated Ftas in C *sscbservedir.~ to 8.2 $4 A23187, ticb is cmcidered a critical CorentIatim (1). An evident defect UBS also denastrated by aperimsrts carried cut m *hole blood. Fati-, m inwxellular defect of Fwk a-d an alter-& cell-cell inter-aim cm catrib& to the inpaired mtbsis of L1B Defective LlB prc&ztion w be imrolved in the altered d fLncticn &se& in C. 1) NisbiaJg Y.. Nature lEB4; 3% bE-633
.
SlS
50
ZZFECTIVENESS 6F LONG TEIGI LY1BHOBL.ABTOID IRTER1EROU (L-IFN) TREKCRERT IN CRROUSC HEPATITIS C (CHC1. J. Camps. A. Castilla, JI. Riezu-Boi.Up. Civeira. J. Priato Dpt. of Bcdicina. University of Novarra. Punplono.Spain.
INSULlN-LlKE GROWTHFACTOR II (IW-II) mRNAAS A IWIKEAOF DIFFERENTIATION 1N HvII\NPRIMARY LlVCRCAWCR.
1E C-riani Ic. Las4ePEe % France ‘C. Wchot. ‘IHKRM “wkker. Paris. *Dep&ent :f Swwy and Pathology, Hopi&l Louise M&l, Evry, France. ICF-*I fiNpI exprerrsionis deuelcmentally regulated in humanliver. In the Fetus. two major ndlM.4~ of 6 and 5 kb are synthesized whereas a mique nRW of 5.5 kb is expressed in the adult. we previw?ily repo*ted the diwerentia1 erpression of IGF-II mRNA.3in huaun primary liver cancer, benign liver tumors and cirrhositr. In mast or cancers, ye observed the reexpression of fetal W-11 MNAs, that were also detected in somecirrhotic adjacent tissue. Conversely, roost of cirrhosis not associated with a cerciwna and benign twrs contained the adult tiNA of 5.3 kb, seldom associated with the fetal transcript of 5 kb. The shift of IGF-II nANI to the Fetal pattern might then represent a marker of early steps OP hape-
Thirty six patients (pts) with CRC were randomized to receive L-IFN (Gl. n=lE> or no treatrent (CZ, n=lB). HCV ab. &-i positive in all of them. L-IF0 schedule: 3 kGJN/d frx 2 mo. 3 I4U/tiw for 3 mo. and 1.5 !N/tiw for 7 mo. Pts in Gl and 62 were comparable in all features. Liver biopsies and serum procollaRen III peptide (P-III-P) were obtained prior to the entry into the trial and after one year in both groups. Hean followup after finishins the trial is ll.Sk3.08 (ran6e:7-15). Results: complete rasponsc (CR)= no=malizstion of 6LT . Partial response (PR) = .lLT < 60 IV. CR: E/l8 (44.4%) in Gl vs 1118 (5.5%) in C2 pc.005; PR: 1110 (38.9%) in Gl VB 0118 in GZ p<.OOl and no response: 3118 (16.6%) in Cl vs 17118 (94.4%) in G2 pc.001. Liver histology iaproved in 15118 (83.3%) in Cl vs 1118 (5.5%) in G2 pc.001). P-III-P levels disminishcd significantly in Cl pc.05. Of 8 pts with CR. 6 remain with nonal ALT after 15.14.13.11.9 and 7 mo. follow-up. Conclusions: L-Iti 1; aale to induce P sustained biochemical improvement in P sirnifi+ant proportion of pts (Li3.3,). HistoloGic~i5 provwent is achieved in the majority of pts. even in those with PR. MooreprolonR6.dadministration of L-IPU can be necessary in some pts.
tocyte dedifferentiatim end/or trmsfcxeatim. andalphafetoprotein ratiwly analyzed ICF-II a series of hman primary liver cameos, mst
differentiated. Hepatitis 0 virus (IBY) RN% uere also studied xn the fvnon fmm HIV chronic carriers. AFP n2M was detected in only 4/16 tllnrorsand l/17 nontlllnorws cirrhotic tissues these sarnplas alto displayed IGF-II fetal MXAs. Furthermore, Fetal IGF-11 mRQ%s wrs observed in 5 tumorouaand 6 n~nt~rn~r~~~ cirrhotic areas not expressing AFP mRXA.The presence of HBVRN.&was only observed in tissues not expressing AFP or fetal IW-II nR*.
, F.
:
F&al IGP-II nrwA5al.0 expressed mare freConclusion -,qvently than RFP nRNplin hiqhly differentiated liver cancers and surrwndlnq cirrhotic areas. The detection of Fetsl Iw-II tiNAs might ‘hen represent a cowlementsry tool for the identiFication oi sarly steps in liver transformation and the evalurkinn of psemaliqnsnt crmditiom S&I 85 liver cirrhosis.
MONOCLONAL ANTIBODY MAPPING OF A VACCINEINDUCEDESCAF'EMUTANTOFHBV Carmao WF$ WatersJi,ZaneniA$ ZuckermanAJZ and ThomasHd. 1. Department of Medicine, St Mary’s Ho&%
!&?a.
II.lhivenity
London. 2. Department of Microbiology, London 3. Institute of Virology, Milao.
Fl-~*~~edica~liv.~engia.~~,uV
Isolated Fwa A23l87 w w c 0.2: 4%7 2.0: 76zl3 7lsl w
Aal&/
2s:
5%!i
;
all
??
V. Carla-&. G. laffi. P. Gre& E. Cuex~ G.G. Newi ?? . P. Gmtilini. Clinic” Medico
Thus ue bodeWFP) rRi.4 in of vhich highly
Royal Free Hospit&
Patients with replicadog HBV in the prcsencc of adequate levels of vaccine-induced anti-HBs have bezn described from Italy. We now show that one of these patients, a3 infant born to a carrier mother, has a mutation in the “a” determinant of HBsAg. This gives rise to an amino acid substitution from glycine to argioine, increasing the hydrophilicity of lhis area @nificdy. The mother had the uwaf seouencc. Binding studies on’tbis HBsAg with a mapped set of monoclonats have been ocrformed: the AUSRIA-2 kit (Abbott) was used for all reactions. F;rw, a ddutioa series of serum from the child and mother were tested using the standard proioc01. Then, amibodies RFHBs-i sod -2 (which bind to aa l27-l37) and 7 (aa 138.147) were bound to beads and iocubatcdwith the scra at the same dilutions as above. Reactions were completed using radiolabelled a&HBs from the kit. Sample to negative ratios for the zxhcr, at a dilution of 1 in SO, were g7 (Au?&), 129 (RF-l), 25 (RF-21 and 140 IRF-7). For the child the corresoondios ratios ie;e 27,&Z and ‘27 1; [hechild, binding IORF-iand-?was4 and 10 fold decreased respcctivety compared to the Ausria The precise conformation of the “a” determinant of HBsAg is nor-known but the mulation at aa 145 ha altered the hinding of monoclonals reactive with both regions of this dclcrminant. perlicularly RF-7, which has been mapped to the rcsion of the mulaion. This supports the hypothesis lhat the mum&x is rcsponaible for escape from the immuneresponse.
Wlo1e Dlad
3x4 *m
0xszlusia-s: A defective LIB rp3zxtim by isolated Ftas in C *sscbservedir.~ to 8.2 $4 A23187, ticb is cmcidered a critical CorentIatim (1). An evident defect UBS also denastrated by aperimsrts carried cut m *hole blood. Fati-, m inwxellular defect of Fwk a-d an alter-& cell-cell inter-aim cm catrib& to the inpaired mtbsis of L1B Defective LlB prc&ztion w be imrolved in the altered d fLncticn &se& in C. 1) NisbiaJg Y.. Nature lEB4; 3% bE-633
.
SlS