Identification of broadly neutralizing antibody epitopes in the HIV-1 envelope glycoprotein using evolutionary models

Background: Identification of the epitopes targeted by antibodies that can neutralize diverse HIV-1 strains can provide important clues for the design of a preventative vaccine. Methods: We have developed a computational approach that can identify key amino acids within the HIV-1 envelope glycoprotein that influence sensitivity to broadly cross-neutralizing antibodies. Given a sequence alignment and neutralization titers for a panel of viruses, the method works by fitting a phylogenetic model that allows the amino acid frequencies at each site to depend on neutralization sensitivities. Sites at which viral evolution influences neutralization sensitivity were identified using Bayes factors (BFs) to compare the fit of this model to that of a null model in which sequences evolved independently of antibody sensitivity. Conformational epitopes were identified with a Metropolis algorithm that searched for a cluster of sites with large Bayes factors on the tertiary structure of the viral envelope. Results: We applied our method to ID50 neutralization data generated from seven HIV-1 subtype C serum samples with neutralization breadth that had been tested against a multi-clade panel of 225 pseudoviruses for which envelope sequences were also available. For each sample, between two and four sites were identified that were strongly associated with neutralization sensitivity (2ln(BF) > 6), a subset of which were experimentally confirmed using site-directed mutagenesis. Conclusions: Our results provide strong support for the use of evolutionary models applied to cross-sectional viral neutralization data to identify the epitopes of serum antibodies that confer neutralization breadth

Environmental and socioeconomic dynamics of the Indian Ocean tsunami in Penang, Malaysia

This paper addresses some of the environmental and socioeconomic dimensions of the 2004 Indian Ocean tsunami on Penang, Malaysia. We aim to offer wide access to unique and perishable data, while at the same time providing insight to ongoing debates about hazards, vulnerability and social capital. Our social survey examines some of the dynamics that shaped the tsunami impact, response and recovery process. While in terms of lives lost Penang may not conform to arguments surrounding vulnerable environments, the recovery process is more marked by social disparities in terms of the ability to access resources. Our physical survey records local topography, flow depth\ud and flow direction, and charts the differential impact of the tsunami. Yet measuring hazards is not a straightforward process, and relies on reflexive methodologies and eyewitness accounts