Thursday 6 February 2014
RSV-directed therapeutic strategies and evolutionary dynamics
Promotor: Prof. dr E.J.H.J. Wiertz
Defence: 6 February 2014
Human Respiratory Syncytial Virus (RSV) is the main causative agent of airway infections among neonates, but is also more frequently found in elderly people and immuno-compromised patients with serious lower respiratory tract infections. RSV may cause or enhance airway sensitization that could result in asthma on the long term. Prophylactic treatment with RSV neutralizing antibodies may therefore reduce the amount of wheezing days and intervene with asthma development.
Thus far we have not succeeded to develop cost-effective therapeutic strategies, nor an effective and safe vaccine. This study describes RSV whole genome variability and evolutionary dynamics based on Bayesian genealogical inference for a broad set of RSV subgroup A and B strains and describes the virus neutralization efficacy of two antibody strategies on a selection of these strains.
Substitutions in RSV genes and proteins that have been plotted in order to determine mutational hotspots showed that the G, SH and M2-2 gene were most variable together with non-coding regions. Several of these mutations influence glycosylation potential and could therefore influence antibody recognition, but also protein functionality and even the course of infection. The rate of evolution, which is the footprint of mutational changes over time, gives us an indication on the need for viral adaptation in order to “survive”. Both RSV subgroups have similar evolutionary rates and selective pressure analysis revealed that the majority of mutational sites in RSV genes are under neutral selection. This indicates that RSV does not require a strong selection of advantageous genomic changes for optimal infection, virus transmission or adaptation. These findings are not only important for the development of an effective immunologic therapy, but are also valuable for future structure-function studies in gene and protein specific roles relating viral gene products to virus viability, adaptability and putative immune escape.
Both antibody strategy studies with monoclonal human B-cell-derived antibodies directed against the pre-fusion form of RSV F and multi-epitope targeting via bi-specific and combinatorial antibodies covered all strain variants tested. Some antibodies were even more efficient than one of the currently used clinical antibodies, Palivizumab. The combination of strong neutralizing antibodies and multi-epitope targeting will not only effectively dampen RSV infections in future antibody prophylaxis, but also most likely diminish the occurrence of antibody escape mutants. In addition, the smaller amount of inflammatory cell infiltrates observed upon antibody treatment may reduce pathology and on the long term decrease the risk of developing wheezing and/or asthma.