Law Laboratory

THE SCRIPPS RESEARCH INSTITUTE

RESEARCH

Challenges in understanding and generating protective antibodies to highly variable human viruses

Highly variable viruses including hepatitis C virus (HCV) and human immunodeficiency virus (HIV) have developed structural features in their envelope spikes to escape antibodies.  In natural infection, most antibodies elicited to the envelope spikes are directed to highly variable regions of non-neutralizing epitopes. These antibodies are ineffective against viral quasispecies. Consequently, vaccine candidates designed to mimic natural infection will not likely elicit protective antibodies.  To overcome the challenge of viral diversity, the humoral components of any candidate vaccines should aim to elicit neutralizing antibodies targeting conserved regions on the envelope spikes.  Broadly neutralizing antibodies, i.e. antibodies that can cross-neutralize diverse viral isolates, define critical epitopes for antibody protection against highly variable viruses.

In our laboratory, we are interested in the strategies and technologies to discover novel broadly neutralizing antibodies and to elicit them in immunization.

Current research topics are:

(1) Discovery and improvement of broadly neutralizing antibodies to HCV and other highly variable viruses.

(2) Dissecting antibody responses to HCV in natural infection and vaccination.

(3) Understanding molecular mechanisms of virus neutralization by antibodies.

We believe the above research efforts will allow us to identify more broadly neutralizing epitopes in disease-causing viruses and the expanding list of epitopes should improve our chance of developing immunogens to elicit protective antibody responses.

MANSUN LAW, PH.D.

 

 

 

Associate Professor
Department of Immunology & Microbiology

Education
B.Sc., Biotechnology, University of Hong Kong
M.Phil., Molecular Biology, University of Hong Kong
D.Phil., Virology, University of Oxford

PERSONNEL

ALUMNI

Name Position Date
SHAUN CASTILLO STUDENT INTERN / RESEARCH ASSISTANT 2012 - 2018
FERNANDO ALEMAN (PH.D.) RESEARCH ASSOCIATE 2014 - 2018
RADHIKA GOPAL (PH.D) RESEARCH ASSOCIATE 2016 - 2017
KALIFA STRINGFIELD SURF STUDENT 2017
MATTHEW WANG SUMMER HIGHSCHOOL STUDENT 2017
ALEX SWEY-SHEN CHEN (D.SC.) VISITING SCIENTIST 2015 - 2017
ANDREW HONDA RESEARCH ASSISTANT 2013 - 2017
DEVAN CHEA STUDENT INTERN 2014 - 2016
MICHELLE ZHI XU (M.D./PH.D.) VISITING SCIENTIST 2015 - 2016
JESSICA REINHARD VISITING STUDENT 2015
KELLI JACKSON GRAD STUDENT 2013 - 2015
JUDY JUN STUDENT INTERN 2011 - 2014
TINASHE RUWONA (PH.D.) RESEARCH ASSOCIATE 2010 - 2014
TRAVIS NIEUSMA STUDENT INTERN / RESEARCH ASSISTANT 2009 - 2012
JUSTIN ROBBINS (PH.D.) RESEARCH ASSOCIATE 2009 - 2012
KRISTIN COGBURN RESEARCH ASSISTANT 2009 - 2012
ANNE DUE (PH.D.) RESEARCH ASSOCIATE 2010 - 2012
NANCY FONG STUDENT INTERN 2011 - 2012
JILL ROUGHAN (PH.D.) RESEARCH ASSOCIATE 2009 - 2012
KATHRYN REARDON SURF STUDENT / RESEARCH ASSISTANT 2009 - 2011
ARTHUR KIM STUDENT INTERN 2009 - 2011
ROSA CARDOSO (PH.D.) RESEARCH ASSOCIATE 2009 - 2010

PHOTOS

CONTACT

Law Laboratory
Department of Immunology and Microbiology
The Scripps Research Institute

10550 N. Torrey Pines Rd.
Room/Mailcode: IMM33
La Jolla, CA 92037
Phone - (858) 784-2383
Fax - (858) 784-7842

 

PUBLICATIONS

  1. Aleman F, Tzarum N, Kong L, Nagy K, Zhu J, Wilson IA, Law M. (2018) Immunogenetic and structural analysis of a class of HCV broadly neutralizing antibodies and their precursors. Proc Natl Acad Sci U S A. https://doi.org/10.1073/pnas.1802378115
  2. Tzarum N, Wilson IA, Law M. (2018) The Neutralizing Face of Hepatitis C Virus E2 Envelope Glycoprotein. Front Immunol 9:1315. https://doi.org/10.3389/fimmu.2018.01315
  3. Gopal R, Jackson K, Tzarum N, Kong L, Ettenger A, Guest J, Pfaff JM, Barnes T, Honda A, Giang E, Davidson E, Wilson IA, Doranz BJ, Law M. (2017) Probing the antigenicity of hepatitis C virus envelope glycoprotein complex by high-throughput mutagenesis. PLoS Pathog 13:e1006735. https://doi.org/10.1371/journal.ppat.1006735
  4. Velazquez-Moctezuma R, Law M, Bukh J, Prentoe J. (2017) Applying antibody-sensitive hypervariable region 1-deleted hepatitis C virus to the study of escape pathways of neutralizing human monoclonal antibody AR5A. PLoS Pathog 13:e1006214. https://doi.org/10.1371/journal.ppat.1006214
  5. Morris CD, Azadnia P, de Val N, Vora N, Honda A, Giang E, Saye-Francisco K, Cheng Y, Lin X, Mann CJ, Tang J, Sok D, Burton DR, Law M, Ward AB, He L, Zhu J. (2017) Differential Antibody Responses to Conserved HIV-1 Neutralizing Epitopes in the Context of Multivalent Scaffolds and Native-Like gp140 Trimers. MBio 8. https://doi.org/10.1128/mBio.00036-17
  6. Logan M, Law J, Wong JA, Hockman D, Landi A, Chen C, Crawford K, Kundu J, Baldwin L, Johnson J, Dahiya A, LaChance G, Marcotrigiano J, Law M, Foung S, Tyrrell L, Houghton M. (2017) Native Folding of a Recombinant gpE1/gpE2 Heterodimer Vaccine Antigen from a Precursor Protein Fused with Fc IgG. J Virol 91. https://doi.org/10.1128/JVI.01552-16
  7. Kong L, Lee DE, Kadam RU, Liu T, Giang E, Nieusma T, Garces F, Tzarum N, Woods VL, Jr., Ward AB, Li S, Wilson IA, Law M. (2016) Structural flexibility at a major conserved antibody target on hepatitis C virus E2 antigen. Proc Natl Acad Sci U S A. https://doi.org/10.1073/pnas.1609780113
  8. McBride R, Head SR, Ordoukhanian P, Law M. (2016) Low-Cost Peptide Microarrays for Mapping Continuous Antibody Epitopes. Methods Mol Biol 1352:67-83. https://doi.org/10.1007/978-1-4939-3037-1_6
  9. Prentoe J, Velazquez-Moctezuma R, Foung SK, Law M, Bukh J. (2016) Hypervariable region 1 shielding of hepatitis C virus is a main contributor to genotypic differences in neutralization sensitivity. Hepatology 64:1881-92. https://doi.org/10.1002/hep.28705
  10. O'Shea D, Law J, Egli A, Douglas D, Lund G, Forester S, Lambert J, Law M, Burton DR, Tyrrell DL, Houghton M, Humar A, Kneteman N. (2016) Prevention of hepatitis C virus infection using a broad cross-neutralizing monoclonal antibody (AR4A) and epigallocatechin gallate. Liver Transpl 22:324-32. https://doi.org/10.1002/lt.24344
  11. Kong L, Kadam RU, Giang E, Ruwona TB, Nieusma T, Culhane JC, Stanfield RL, Dawson PE, Wilson IA, Law M. (2015) Structure of Hepatitis C Virus Envelope Glycoprotein E1 Antigenic Site 314-324 in Complex with Antibody IGH526. J Mol Biol 427:2617-28. https://doi.org/10.1016/j.jmb.2015.06.012
  12. Law M. (2015) Editorial overview: Preventive and therapeutic vaccines (B cell epitope vaccine). Curr Opin Virol 11:viii-x. https://doi.org/10.1016/j.coviro.2015.05.003
  13. Kong L, Jackson KN, Wilson IA, Law M. (2015) Capitalizing on knowledge of hepatitis C virus neutralizing epitopes for rational vaccine design. Curr Opin Virol 11:148-57. https://doi.org/10.1016/j.coviro.2015.04.001
  14. He L, Cheng Y, Kong L, Azadnia P, Giang E, Kim J, Wood MR, Wilson IA, Law M, Zhu J. (2015) Approaching rational epitope vaccine design for hepatitis C virus with meta-server and multivalent scaffolding. Sci Rep 5:12501. https://doi.org/10.1038/srep12501
  15. Fusil F, Calattini S, Amirache F, Mancip J, Costa C, Robbins JB, Douam F, Lavillette D, Law M, Defrance T, Verhoeyen E, Cosset FL. (2015) A Lentiviral Vector Allowing Physiologically Regulated Membrane-anchored and Secreted Antibody Expression Depending on B-cell Maturation Status. Mol Ther 23:1734-47. https://doi.org/10.1038/mt.2015.148
  16. Ruwona TB, McBride R, Chappel R, Head SR, Ordoukhanian P, Burton DR, Law M. (2014) Optimization of peptide arrays for studying antibodies to hepatitis C virus continuous epitopes. J Immunol Methods 402:35-42. https://doi.org/10.1016/j.jim.2013.11.005
  17. Ruwona TB, Giang E, Nieusma T, Law M. (2014) Fine mapping of murine antibody responses to immunization with a novel soluble form of hepatitis C virus envelope glycoprotein complex. J Virol 88:10459-71. https://doi.org/10.1128/JVI.01584-14
  18. Mathiesen CK, Jensen TB, Prentoe J, Krarup H, Nicosia A, Law M, Bukh J, Gottwein JM. (2014) Production and characterization of high-titer serum-free cell culture grown hepatitis C virus particles of genotype 1-6. Virology 458-459:190-208. https://doi.org/10.1016/j.virol.2014.03.021
  19. de Jong YP, Dorner M, Mommersteeg MC, Xiao JW, Balazs AB, Robbins JB, Winer BY, Gerges S, Vega K, Labitt RN, Donovan BM, Giang E, Krishnan A, Chiriboga L, Charlton MR, Burton DR, Baltimore D, Law M, Rice CM, Ploss A. (2014) Broadly neutralizing antibodies abrogate established hepatitis C virus infection. Sci Transl Med 6:254ra129. https://doi.org/10.1126/scitranslmed.3009512
  20. Carlsen TH, Pedersen J, Prentoe JC, Giang E, Keck ZY, Mikkelsen LS, Law M, Foung SK, Bukh J. (2014) Breadth of neutralization and synergy of clinically relevant human monoclonal antibodies against HCV genotypes 1a, 1b, 2a, 2b, 2c, and 3a. Hepatology 60:1551-62. https://doi.org/10.1002/hep.27298
  21. Kong L, Giang E, Nieusma T, Kadam RU, Cogburn KE, Hua Y, Dai X, Stanfield RL, Burton DR, Ward AB, Wilson IA, Law M. (2013) Hepatitis C virus E2 envelope glycoprotein core structure. Science 342:1090-4. https://doi.org/10.1126/science.1243876
  22. Dorner M, Horwitz JA, Donovan BM, Labitt RN, Budell WC, Friling T, Vogt A, Catanese MT, Satoh T, Kawai T, Akira S, Law M, Rice CM, Ploss A. (2013) Completion of the entire hepatitis C virus life cycle in genetically humanized mice. Nature 501:237-41. https://doi.org/10.1038/nature12427
  23. Pedersen J, Carlsen TH, Prentoe J, Ramirez S, Jensen TB, Forns X, Alter H, Foung SK, Law M, Gottwein J, Weis N, Bukh J. (2013) Neutralization resistance of hepatitis C virus can be overcome by recombinant human monoclonal antibodies. Hepatology 58:1587-97. https://doi.org/10.1002/hep.26524
  24. Giang E, Dorner M, Prentoe JC, Dreux M, Evans MJ, Bukh J, Rice CM, Ploss A, Burton DR, Law M. (2012) Human broadly neutralizing antibodies to the envelope glycoprotein complex of hepatitis C virus. Proc Natl Acad Sci U S A 109:6205-10. https://doi.org/10.1073/pnas.1114927109
  25. Kong L, Giang E, Robbins JB, Stanfield RL, Burton DR, Wilson IA, Law M. (2012) Structural basis of hepatitis C virus neutralization by broadly neutralizing antibody HCV1. Proc Natl Acad Sci U S A 109:9499-504. https://doi.org/10.1073/pnas.1202924109
  26. Roughan JE, Reardon KM, Cogburn KE, Quendler H, Pockros PJ, Law M. (2012) Chronic hepatitis C virus infection breaks tolerance and drives polyclonal expansion of autoreactive B cells. Clin Vaccine Immunol 19:1027-37. https://doi.org/10.1128/CVI.00194-12
  27. Kong L, Giang E, Nieusma T, Robbins JB, Deller MC, Stanfield RL, Wilson IA, Law M. (2012) Structure of hepatitis C virus envelope glycoprotein E2 antigenic site 412 to 423 in complex with antibody AP33. J Virol 86:13085-8. https://doi.org/10.1128/JVI.01939-12
  28. Kim Y, Vaughan K, Greenbaum J, Peters B, Law M, Sette A. (2012) A meta-analysis of the existing knowledge of immunoreactivity against hepatitis C virus (HCV). PLoS One 7:e38028. https://doi.org/10.1371/journal.pone.0038028
  29. Brown RJ, Hudson N, Wilson G, Rehman SU, Jabbari S, Hu K, Tarr AW, Borrow P, Joyce M, Lewis J, Zhu LF, Law M, Kneteman N, Tyrrell DL, McKeating JA, Ball JK. (2012) Hepatitis C virus envelope glycoprotein fitness defines virus population composition following transmission to a new host. J Virol 86:11956-66. https://doi.org/10.1128/JVI.01079-12
  30. Montero A, Gastaminza P, Law M, Cheng G, Chisari FV, Ghadiri MR. (2011) Self-assembling peptide nanotubes with antiviral activity against hepatitis C virus. Chem Biol 18:1453-62. https://doi.org/10.1016/j.chembiol.2011.08.017
  31. Dorner M, Horwitz JA, Robbins JB, Barry WT, Feng Q, Mu K, Jones CT, Schoggins JW, Catanese MT, Burton DR, Law M, Rice CM, Ploss A. (2011) A genetically humanized mouse model for hepatitis C virus infection. Nature 474:208-11. https://doi.org/10.1038/nature10168
  32. Gastaminza P, Dryden KA, Boyd B, Wood MR, Law M, Yeager M, Chisari FV. (2010) Ultrastructural and biophysical characterization of hepatitis C virus particles produced in cell culture. J Virol 84:10999-1009. https://doi.org/10.1128/JVI.00526-10
  33. Roberts KL, Breiman A, Carter GC, Ewles HA, Hollinshead M, Law M, Smith GL. (2009) Acidic residues in the membrane-proximal stalk region of vaccinia virus protein B5 are required for glycosaminoglycan-mediated disruption of the extracellular enveloped virus outer membrane. J Gen Virol 90:1582-91. https://doi.org/10.1099/vir.0.009092-0
  34. Law M, Maruyama T, Lewis J, Giang E, Tarr AW, Stamataki Z, Gastaminza P, Chisari FV, Jones IM, Fox RI, Ball JK, McKeating JA, Kneteman NM, Burton DR. (2008) Broadly neutralizing antibodies protect against hepatitis C virus quasispecies challenge. Nat Med 14:25-7. https://doi.org/10.1038/nm1698
  35. Law M, Hangartner L. (2008) Antibodies against viruses: passive and active immunization. Curr Opin Immunol 20:486-92. https://doi.org/10.1016/j.coi.2008.06.005
  36. Law M, Cardoso RM, Wilson IA, Burton DR. (2007) Antigenic and immunogenic study of membrane-proximal external region-grafted gp120 antigens by a DNA prime-protein boost immunization strategy. J Virol 81:4272-85. https://doi.org/10.1128/JVI.02536-06
  37. Putz MM, Midgley CM, Law M, Smith GL. (2006) Quantification of antibody responses against multiple antigens of the two infectious forms of Vaccinia virus provides a benchmark for smallpox vaccination. Nat Med 12:1310-5. https://doi.org/10.1038/nm1457
  38. Law M, Sanna PP, Burton DR. Viral subversion of humoral immune responses. In: Lachmann PJ, Oldstone MB, editors. Microbial Subversion of Immunity: Current Topics: Caister Academic Press; 2006. p. 177-210.
  39. Law M, Carter GC, Roberts KL, Hollinshead M, Smith GL. (2006) Ligand-induced and nonfusogenic dissolution of a viral membrane. Proc Natl Acad Sci U S A 103:5989-94. https://doi.org/10.1073/pnas.0601025103
  40. Selvarajah S, Puffer B, Pantophlet R, Law M, Doms RW, Burton DR. (2005) Comparing antigenicity and immunogenicity of engineered gp120. J Virol 79:12148-63. https://doi.org/10.1128/JVI.79.19.12148-12163.2005
  41. Law M, Putz MM, Smith GL. (2005) An investigation of the therapeutic value of vaccinia-immune IgG in a mouse pneumonia model. J Gen Virol 86:991-1000. https://doi.org/10.1099/vir.0.80660-0
  42. Carter GC, Law M, Hollinshead M, Smith GL. (2005) Entry of the vaccinia virus intracellular mature virion and its interactions with glycosaminoglycans. J Gen Virol 86:1279-90. https://doi.org/10.1099/vir.0.80831-0
  43. Smith GL, Law M. (2004) The exit of vaccinia virus from infected cells. Virus Res 106:189-97. https://doi.org/10.1016/j.virusres.2004.08.015
  44. Law M, Smith GL. (2004) Studying the binding and entry of the intracellular and extracellular enveloped forms of vaccinia virus. Methods Mol Biol 269:187-204. https://doi.org/10.1385/1-59259-789-0:187
  45. Law M, Hollinshead M, Lee HJ, Smith GL. (2004) Yaba-like disease virus protein Y144R, a member of the complement control protein family, is present on enveloped virions that are associated with virus-induced actin tails. J Gen Virol 85:1279-90. https://doi.org/10.1099/vir.0.79863-0
  46. Smith GL, Murphy BJ, Law M. (2003) Vaccinia virus motility. Annu Rev Microbiol 57:323-42. https://doi.org/10.1146/annurev.micro.57.030502.091037
  47. Carter GC, Rodger G, Murphy BJ, Law M, Krauss O, Hollinshead M, Smith GL. (2003) Vaccinia virus cores are transported on microtubules. J Gen Virol 84:2443-58. https://doi.org/10.1099/vir.0.19271-0
  48. Smith GL, Vanderplasschen A, Law M. (2002) The formation and function of extracellular enveloped vaccinia virus. J Gen Virol 83:2915-31. https://doi.org/10.1099/0022-1317-83-12-2915
  49. Law M, Hollinshead R, Smith GL. (2002) Antibody-sensitive and antibody-resistant cell-to-cell spread by vaccinia virus: role of the A33R protein in antibody-resistant spread. J Gen Virol 83:209-22. https://doi.org/10.1099/0022-1317-83-1-209
  50. Law M, Smith GL. (2001) Antibody neutralization of the extracellular enveloped form of vaccinia virus. Virology 280:132-42. https://doi.org/10.1006/viro.2000.0750
  51. Cao YC, Yeung WS, Law M, Bi YZ, Leung FC, Lim BL. (1998) Molecular characterization of seven Chinese isolates of infectious bursal disease virus: classical, very virulent, and variant strains. Avian Dis 42:340-51.
  52. Brown F, Meyer RF, Law M, Kramer E, Newman JF. (1998) A universal virus inactivant for decontaminating blood and biopharmaceutical products. Biologicals 26:39-47.
  53. Cao YC, Bi YZ, Law M, Yeung WS, Leung FC, Lim BL. (1997) Identification and cloning of the major immune antigen of infectious bursal disease virus variant strain. Chin J Vet Med 23:3-5.
  54. Law MS, Cheng KW, Fung TK, Chan YH, Yu KL, Chan KM. (1996) Isolation and characterization of two distinct growth hormone cDNAs from the goldfish, Carassius auratus. Arch Biochem Biophys 330:19-23. https://doi.org/10.1006/abbi.1996.0221