Paul A Macary

Publications (2)11.42 Total impact

• Article: Resistance analysis of an antibody that selectively inhibits dengue virus serotype-1.

  Gang Zou, Petra Kukkaro, Shee-Mei Lok, Jowin K W Ng, Grace K Tan, Brendon J Hanson, Sylvie Alonso, Paul A MacAry, Pei-Yong Shi
  [show abstract] [hide abstract]
  ABSTRACT: The four serotypes of dengue virus (DENV) are the causative agents of the most prevalent mosquito-borne viral disease in human. No clinically approved antiviral therapy is currently available. Therapeutic antibodies represent a viable approach for potential treatment of DENV infection. We recently isolated a human monoclonal antibody (HM14c10) that selectively neutralizes DENV serotype 1 (DENV-1), but not serotypes 2, 3, and 4. Here we report the resistance profile of DENV-1 against HM14c10 in cell culture. Escape mutant viruses readily emerged by culturing wild-type DENV-1 in the presence of the HM14c10 antibody. Sequencing of resistant viruses revealed a single T51K substitution in the domain I/II hinge region of the viral envelope protein. Residue T51 is located within the HM14c10 epitope and is highly conserved among various DENV-1 isolates. Recombinant DENV-1 containing the T51K mutation could not be neutralized by HM14c10 in vitro or in vivo. Biochemical assay revealed that the T51K mutation completely abolished the antibody binding to the DENV-1 virion. Collectively, the results demonstrate that a single amino acid change in DENV envelope protein can confer resistance to a potent antibody through abolishing the antibody-virus interaction.
  Antiviral research 07/2012; 95(3):216-23. · 3.61 Impact Factor
• Article: The structural basis for serotype-specific neutralization of dengue virus by a human antibody.

  Ee Ping Teoh, Petra Kukkaro, En Wei Teo, Angeline P C Lim, Tze Tong Tan, Andy Yip, Wouter Schul, Myint Aung, Victor A Kostyuchenko, Yee Sin Leo, [......], D Michael Kemeny, Grace K Tan, Jowin K W Ng, Mah Lee Ng, Sylvie Alonso, Dale Fisher, Pei-Yong Shi, Brendon J Hanson, Shee-Mei Lok, Paul A MacAry
  [show abstract] [hide abstract]
  ABSTRACT: Dengue virus (DENV) is a mosquito-borne flavivirus that affects 2.5 billion people worldwide. There are four dengue serotypes (DENV1 to DENV4), and infection with one elicits lifelong immunity to that serotype but offers only transient protection against the other serotypes. Identification of the protective determinants of the human antibody response to DENV is a vital requirement for the design and evaluation of future preventative therapies and treatments. Here, we describe the isolation of a neutralizing antibody from a DENV1-infected patient. The human antibody 14c10 (HM14c10) binds specifically to DENV1. HM14c10 neutralizes the virus principally by blocking virus attachment; at higher concentrations, a post-attachment step can also be inhibited. In vivo studies show that the HM14c10 antibody has antiviral activity at picomolar concentrations. A 7 Å resolution cryoelectron microscopy map of Fab fragments of HM14c10 in a complex with DENV1 shows targeting of a discontinuous epitope that spans the adjacent surface of envelope protein dimers. As found previously, a human antibody specific for the related West Nile virus binds to a similar quaternary structure, suggesting that this could be an immunodominant epitope. These findings provide a structural and molecular context for durable, serotype-specific immunity to DENV infection.
  Science translational medicine 06/2012; 4(139):139ra83. · 7.80 Impact Factor