Chikungunya virus (CHIKV) has the potential to create a major public health impact should it be introduced into the United States, as seems likely following a large and sustained outbreak in the Caribbean. CHIKV causes extensive human and economic damage, primarily due to acute fever and arthralgia and post-viral chronic joint pain/arthritis. Currently no licensed therapeutic treatments or vaccines exist for CHIKV. We will address the important public health threat posed by CHIKV by identifying lead candidate monoclonal antibodies (mAbs) for development into treatments capable of being used both prophylactically and therapeutically. Importantly, we have demonstrated the ability of mAbs directed against CHIKV to block viral assembly/budding - probably by preventing the envelope glycoprotein-driven membrane curvature required to form particles. We will characterize new antibodies targeting this mechanism, as well as describe the full B-cell repertoire in response to infection - both in acutely infected patients and recovered individuals. Finally, we will characterize CHIKV genetic diversity and evolution with emphasis on detecting variation and signatures of selection at B-cell epitopes. In order to achieve these goals we will perform three Specific Aims:
Aim 1. Identification and characterization of potent human monoclonals capable of budding inhibition. We will derive and screen B-cell clones from recovered CHIKV patients specifically for inhibition of CHIKV virus release/budding. Resulting mAbs will be characterized for in vitro and in vivo potency, and their epitopes will be mapped using escape mutants and mutagenesis.
Aim 2. Characterize acute and memory B-cell responses to CHIKV infection. Using immune repertoire capture (IRC) technology, we will fully map B-cell repertoires during CHIKV infection. Common epitopes will be identified by looking for convergent evolution of B-cell paratopes in multiple individuals, and the relationship between entry neutralization and budding inhibition will be characterized in acutely infected and recovered individuals.
Aim 3. Characterization of CHIKV envelope glycoprotein diversity and evolution. In order to assess the potential for the antibodies derived in Aims 1 and 2 to be broadly cross reactive, we will characterize the nature and extent of CHIKV envelope sequence variation in viral isolates derived from individuals enrolled in the study (over three years) together with CHIKV sequences from the wider global population. Data sets will be screened for signatures of selective pressure, particularly from the humoral response. In summary, we hope to develop novel mAbs, targeting specific stages of the viral lifecycle. The humoral responses during infection will be mapped and related to viral diversity and evolution.
The recent large outbreak of chikungunya virus (CHIKV) in the Caribbean demonstrates the potential of this virus to become the next major viral epidemic to spread to the United States, in a similar fashion to West Nile virus. In this proposal we will identify multiple novel monoclonal antibodies targeting both entry and virus budding. We will characterize the epitopes targeted by these antibodies, both during infection and after recovery, and also investigate the genetic diversity and evolution of antibody targets.
| Jin, Jing; Liss, Nathan M; Chen, Dong-Hua et al. (2015) Neutralizing Monoclonal Antibodies Block Chikungunya Virus Entry and Release by Targeting an Epitope Critical to Viral Pathogenesis. Cell Rep 13:2553-2564 |
