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Targeted Antibody Blocking by a Dual-Functional Conjugate of Antigenic Peptide and Fc-III Mimetics (DCAF)
Published on: September 17, 2019
Resistance analysis of an antibody that selectively inhibits dengue virus serotype-1
Gang Zou1, Petra Kukkaro, Shee-Mei Lok
1Novartis Institute for Tropical Diseases, Singapore, Singapore.
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.
Insights
A single mutation in dengue virus type 1 (DENV-1) can cause resistance to a neutralizing antibody. This T51K change in the envelope protein prevents antibody binding, impacting potential DENV therapies.
Area of Science:
- Virology
- Immunology
- Infectious Diseases
Background:
- Dengue virus (DENV) causes a widespread mosquito-borne illness with no approved antiviral treatments.
- Therapeutic antibodies are a promising strategy for combating DENV infections.
- A human monoclonal antibody, HM14c10, was identified that specifically neutralizes DENV serotype 1 (DENV-1).
Purpose of the Study:
- To investigate the resistance profile of DENV-1 against the neutralizing antibody HM14c10.
- To identify the genetic basis of DENV-1 escape from HM14c10 neutralization.
- To characterize the impact of identified mutations on antibody-virus interactions.
Main Methods:
- DENV-1 was cultured in the presence of HM14c10 to select for escape mutants.
- Resistant viral isolates were sequenced to identify genetic mutations.
- Recombinant DENV-1 with specific mutations were generated for further testing.
- In vitro and in vivo neutralization assays were performed.
- Biochemical assays assessed antibody binding to viral particles.
Main Results:
- DENV-1 rapidly generated escape mutants when exposed to HM14c10.
- A single amino acid substitution, T51K, in the DENV-1 envelope protein was identified in resistant viruses.
- This T51K mutation is located within the HM14c10 epitope and is conserved in DENV-1.
- Recombinant DENV-1 with the T51K mutation showed complete resistance to HM14c10 neutralization in vitro and in vivo.
- The T51K mutation abolished HM14c10 binding to the DENV-1 virion.
Conclusions:
- A single amino acid change (T51K) in the DENV-1 envelope protein is sufficient to confer complete resistance to the neutralizing antibody HM14c10.
- This mutation abrogates antibody binding, highlighting the critical role of this residue in the antibody-epitope interaction.
- Understanding these resistance mechanisms is crucial for developing effective antibody-based therapies against dengue virus.
