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.
Department of Immunology & Microbiology
B.Sc., Biotechnology, University of Hong Kong
M.Phil., Molecular Biology, University of Hong Kong
D.Phil., Virology, University of Oxford
Team Finds Promising Vaccine Targets on Hepatitis C Virus
Department of Immunology and Microbiology
The Scripps Research Institute
10550 N. Torrey Pines Rd.
La Jolla, CA 92037
Phone - (858) 784-2383
Fax - (858) 784-7842
Native Folding of a Recombinant gpE1/gpE2 Heterodimer Vaccine Antigen from a Precursor Protein Fused with Fc IgG. 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. J Virol. 2016 Dec 16;91(1):e01552-16.
Structural flexibility at a major conserved antibody target on hepatitis C virus E2 antigen. 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. Proc Natl Acad Sci U S A. 2016; In Press.
Hypervariable region 1 shielding of hepatitis C virus is a main contributor to genotypic differences in neutralization sensitivity. Prentoe J, Velázquez-Moctezuma R, Foung SK, Law M, Bukh J. Hepatology. 2016 Dec;64(6):1881-1892.
Low-Cost Peptide Microarrays for Mapping Continuous Antibody Epitopes. McBride R, Head SR, Ordoukhanian P, Law M. Methods Mol Biol. 2016;1352:67-83.
Prevention of hepatitis C virus infection using a broad cross-neutralizing monoclonal antibody (AR4A) and epigallocatechin gallate. 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. Liver Transpl. 2016 Mar;22(3):324-32.
A Lentiviral Vector Allowing Physiologically Regulated Membrane-anchored and Secreted Antibody Expression Depending on B-cell Maturation Status. Fusil F, Calattini S, Amirache F, Mancip J, Costa C, Robbins JB, Douam F, Lavillette D, Law M, Defrance T, Verhoeyen E, Cosset FL. Mol Ther. 2015 Nov;23(11):1734-47.
Approaching rational epitope vaccine design for hepatitis C virus with meta-server and multivalent scaffolding. He L, Cheng Y, Kong L, Azadnia P, Giang E, Kim J, Wood MR, Wilson IA, Law M, Zhu J. Sci Rep. 2015 Aug 4;5:12501.
Structure of Hepatitis C Virus Envelope Glycoprotein E1 Antigenic Site 314-324 in Complex with Antibody IGH526.Kong L, Kadam RU, Giang E, Ruwona TB, Nieusma T, Culhane JC, Stanfield RL, Dawson PE, Wilson IA, Law M. J Mol Biol. 2015 Aug 14;427(16):2617-28.
Editorial overview: Preventive and therapeutic vaccines (B cell epitope vaccine). Law M. Curr Opin Virol. 2015 Apr;11:viii-x.
Capitalizing on knowledge of hepatitis C virus neutralizing epitopes for rational vaccine design. Kong L, Jackson KN, Wilson IA, Law M. Curr Opin Virol. 2015 Apr;11:148-57.
Broadly neutralizing antibodies abrogate established hepatitis C virus infection.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. Sci Transl Med. 2014 Sep 17;6(254):254ra129.
Breadth of neutralization and synergy of clinically relevant human monoclonal antibodies against HCV genotypes 1a, 1b, 2a, 2b, 2c and 3a. Carlsen TH, Pedersen J, Prentoe JC, Giang E, Keck ZY, Mikkelsen LS, Law M, Foung SK, Bukh J. Hepatology, 2014 2014 Nov;60(5):1551-62.
Fine mapping of murine antibody responses to immunization with a novel soluble form of hepatitis C virus envelope glycoprotein complex. Ruwona T, Giang E, Nieusma T, Law M. J Virol. 2014 Nov;88(22):13517.
Production and characterization of high-titer serum-free cell culture grown hepatitis C virus particles of genotype 1-6. Mathiesen CK, Jensen TB, Prentoe J. Krarup H, Nicosia A, Law M, Bukh J, Gottwein JM. Virology. 2014 Jun;458-459:190-208.
Hepatitis C virus e2 envelope glycoprotein core structure. Kong L, Giang E, Nieusma T, Kadam RU, Cogburn KE, Hua Y, Dai X, Stanfield RL, Burton DR, Ward AB, Wilson IA, Law M. Science. 2013 Nov 29;342(6162):1090-4.
Optimization of peptide arrays for studying antibodies to hepatitis C virus continuous epitopes. Ruwona TB, McBride R, Chappel R, Head SR, Ordoukhanian P, Burton DR, Law M. J Immunol Methods. 2013. In Press
Completion of the entire hepatitis C virus life cycle in genetically humanized mice. 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. Nature. 2013 Sep 12;501(7466):237-41.
Neutralization resistance of hepatitis C virus can be overcome by recombinant human monoclonal antibodies. Pedersen J, Carlsen TH, Prentoe J, Ramirez S, Jensen TB, Forns X, Alter H, Foung SK, Law M, Gottwein J, Weis N, Bukh J. Hepatology. 2013. In Press
Structure of hepatitis C virus envelope glycoprotein E2 antigenic site 412 to 423 in complex with antibody AP33. Kong L, Giang E, Nieusma T, Robbins JB, Deller MC, Stanfield RL, Wilson IA, Law M. J Virol. 2012 Dec;86(23):13085-8.
Hepatitis C virus envelope glycoprotein fitness defines virus population composition following transmission to a new host. 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. J Virol. 2012 Nov;86(22):11956-66.
A meta-analysis of the existing knowledge of immunoreactivity against hepatitis C virus (HCV). Kim Y, Vaughan K, Greenbaum J, Peters B, Law M, Sette A. PLoS One. 2012;7(5):e38028.
Chronic hepatitis C virus infection breaks tolerance and drives polyclonal expansion of autoreactive B cells. Roughan JE, Reardon KM, Cogburn KE, Quendler H, Pockros PJ, Law M. Clin Vaccine Immunol. 2012 Jul;19(7):1027-37.
Structural basis of hepatitis C virus neutralization by broadly neutralizing antibody HCV1. Kong L, Giang E, Robbins JB, Stanfield RL, Burton DR, Wilson IA, Law M. Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9499-504.
Human broadly neutralizing antibodies to the envelope glycoprotein complex of hepatitis C virus. Giang E, Dorner M, Prentoe JC, Dreux M, Evans MJ, Bukh J, Rice CM, Ploss A, Burton DR, Law M. Proc Natl Acad Sci U S A. 2012 Apr 17;109(16):6205-10.
Self-assembling peptide nanotubes with antiviral activity against hepatitis C virus. Montero A, Gastaminza P, Law M, Cheng G, Chisari FV, Ghadiri MR. Chem Biol. 2011 Nov 23;18(11):1453-62.
A genetically humanized mouse model for hepatitis C virus infection. 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. Nature. 2011 Jun 8;474(7350):208-11.
Ultrastructural and biophysical characterization of hepatitis C virus particles produced in cell culture. Gastaminza P, Dryden KA, Boyd B, Wood MR, Law M, Yeager M, Chisari FV. J Virol. 2010 Nov;84(21):10999-1009.
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. Roberts KL, Breiman A, Carter GC, Ewles HA, Hollinshead M, Law M, Smith GL. J Gen Virol. 2009 Jul;90(Pt 7):1582-91.
Antibodies against viruses: passive and active immunization. Law M, Hangartner L. Curr Opin Immunol. 2008 Aug;20(4):486-92.
Broadly neutralizing antibodies protect against hepatitis C virus quasispecies challenge. 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. Nat Med. 2008 Jan;14(1):25-7.
Antigenic and immunogenic study of membrane-proximal external region-grafted gp120 antigens by a DNA prime-protein boost immunization strategy. Law M, Cardoso RM, Wilson IA, Burton DR. J Virol. 2007 Apr;81(8):4272-85.
Quantification of antibody responses against multiple antigens of the two infectious forms of Vaccinia virus provides a benchmark for smallpox vaccination. Pütz MM, Midgley CM, Law M, Smith GL.Nat Med. 2006 Nov;12(11):1310-5.
Ligand-induced and nonfusogenic dissolution of a viral membrane. Law M, Carter GC, Roberts KL, Hollinshead M, Smith GL. Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):5989-94.
Comparing antigenicity and immunogenicity of engineered gp120. Selvarajah S, Puffer B, Pantophlet R, Law M, Doms RW, Burton DR. J Virol. 2005 Oct;79(19):12148-63.
Entry of the vaccinia virus intracellular mature virion and its interactions with glycosaminoglycans.Carter GC, Law M, Hollinshead M, Smith GL. J Gen Virol. 2005 May;86(Pt 5):1279-90.
An investigation of the therapeutic value of vaccinia-immune IgG in a mouse pneumonia model. Law M, Pütz MM, Smith GL. J Gen Virol. 2005 Apr;86(Pt 4):991-1000. The exit of vaccinia virus from infected cells. Smith GL, Law M. Virus Res. 2004 Dec;106(2):189-97.
Studying the binding and entry of the intracellular and extracellular enveloped forms of vaccinia virus. Law M, Smith GL. Methods Mol Biol. 2004;269:187-204.
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. Law M, Hollinshead M, Lee HJ, Smith GL. J Gen Virol. 2004 May;85(Pt 5):1279-90.
Vaccinia virus motility. Smith GL, Murphy BJ, Law M. Annu Rev Microbiol. 2003;57:323-42.
Vaccinia virus cores are transported on microtubules. Carter GC, Rodger G, Murphy BJ, Law M, Krauss O, Hollinshead M, Smith GL. J Gen Virol. 2003 Sep;84(Pt 9):2443-58.
The formation and function of extracellular enveloped vaccinia virus. Smith GL, Vanderplasschen A, Law M. J Gen Virol. 2002 Dec;83(Pt 12):2915-31.
Antibody-sensitive and antibody-resistant cell-to-cell spread by vaccinia virus: role of the A33R protein in antibody-resistant spread. Law M, Hollinshead R, Smith GL. J Gen Virol. 2002 Jan;83(Pt 1):209-22. Erratum in: J Gen Virol 2002 May;83(Pt 5):1251.