What does it mean to develop an HIV vaccine by rational design?

This review argues that the three popular concepts of design, rationality and reductionism, which guided vaccine research for many years, actually contributed to the inability of vaccinologists to develop an effective HIV vaccine. The strong goal-directed intentionality inherent in the concept of design together with excessive confidence in the power of rational thinking convinced investigators that the accumulated structural knowledge on HIV epitopes, derived from crystallographic studies of complexes of neutralizing antibodies bound to HIV Env epitopes, would allow them to rationally design complementary immunogens capable of inducing anti-HIV protective antibodies. This strategy failed because it was not appreciated that the structures observed in epitope-paratope crystallographic complexes result from mutually induced fit between the two partners and do not represent structures present in the free disordered molecules before they had interacted. In addition, reductionist thinking led investigators to accept that biology could be reduced to chemistry, and this made them neglect the fundamental difference between chemical antigenicity and biological immunogenicity. As a result, they did not investigate which inherent constituents of immune systems controlled the induction of protective antibodies and focused instead only on the steric complementarity that exists between bound epitopes and paratopes.

Viral species, viral genomes and HIV vaccine design: is the rational design of biological complexity a utopia?

A common logical confusion is prevalent in the whole of biology, namely that biological species are viewed both as an abstract category in an hierarchical classification and as a concrete kind of organism. This is partly due to the fact that the vast majority of living organisms do not have common names that differ from the Latin name of the species to which the organism belongs. However, it is somewhat astonishing that the same confusion exists in virology since every virus has a common name, different from the species name to which the virus belongs, which could be used to refer to the infectious viral entity as a concrete material object. The original 1991 ICTV definition of virus species stated that a virus species is a polythetic class of viruses and thus that a species is a class, namely a conceptual construction of the mind and not a physical, real object located in space and time. In 2013, the ICTV redefined a virus species no longer as a class but as a material object consisting of a monophyletic group of viruses that were all physically part of the species. This new definition is reminiscent of an earlier school of thought known as bionominalism which considered species to be concrete individuals rather than classes. Both bionominalism and the new ICTV definition are based on the logical fallacy of reification which treats abstractions such as classes as if they were concrete physical entities. The implications of this new ontology of virus species for virus taxonomy and for the possibility of incorporating nucleotide metagenomic sequences in the current ICTV classification is discussed.

Structure-activity relationships in peptide-antibody complexes: implications for epitope prediction and development of synthetic peptide vaccines.

Interaction modes and molecular surface properties for both peptide- and protein-antibody complexes have been investigated. Datasets were constituted from the IMGT database and consisted of 37 peptide-antibody (PEPT) and 155 protein-antibody (PROT) complexes. A computer approach was developed to analyze the surface of peptides and proteins using a level set method which allows the characterization of shape complementarity using surface curvature. We found that in both datasets, the interacting surfaces of the two binding partners, exhibited a moderate degree of shape complementarity at the molecular level but not at the atomic level. We also evaluated the structural similarity between peptides bound to antibodies and the corresponding regions in the 3D structures of the cognate proteins. We found that no more than 25% of Phipsi; dihedral angles were conserved between the corresponding regions in peptides and proteins. We also superimposed the parent protein structure onto that of the bound peptides and visually looked for the presence of bumps or clashes between the cognate protein and the antibody. Except for antibodies possessing neutralizing activity and for those bound to a peptide longer than 30 residues, no superimposition in peptide-antibody complexes was found to be bump or clash-free. These findings indicate that studies restricted to continuous epitopes are unlikely to provide the information needed to design short linear peptides that could be expected to mimic satisfactorily the discontinuous epitopes of native proteins and be successful as synthetic vaccines.

Rack-1, GAPDH3, and actin: proteins of Myzus persicae potentially involved in the transcytosis of beet western yellows virus particles in the aphid.

Beet western yellows virus (BWYV) is a Polerovirus that relies on the aphid Myzus persicae for its transmission, in a persistent-circulative mode. To be transmitted, the virus must cross the midgut and the accessory salivary glands (ASG) epithelial barriers in a transcytosis mechanism where vector receptors interact with virions. In this paper, we report in vitro interaction experiments between BWYV and aphid components. Using the M. persicae clone from Colmar, we showed that a set of aphid polypeptides, separated by SDS-PAGE or 2D electrophoresis (2DE), can bind in vitro to purified wild type or mutant particles. Using subcellular fractionation, we showed that the 65-kDa polypeptide identified as symbionin is a soluble protein whereas the other polypeptides seem to be associated more or less strongly to the membrane. We hypothesize that three polypeptides, identified by mass spectrometry as Rack-1, GAPDH3, and actin, may be involved in the epithelial transcytosis of virus particles in the aphid vector.