GLPG0634 Supplier The complex interplay between viral escape

The complex interplay between viral escape and Env conformation observed by Bradley et al. and others gives some pause to reductionist approaches focussing on recapitulating single bNAb specificities by immunisation. Favourable GLPG0634 Supplier interactions between different bNAb epitopes, shown here for the MPER and the CD4 binding site or V3 loop, suggests vaccines simultaneously targeted to multiple epitopes may be advantageous. While targeting the MPER by vaccination may be difficult due to described self-mimicry and frequent generation of autoantibodies (), the results suggest effective MPER responses may complement neutralisation at alternative epitopes by constraining potential pathways of viral escape. This is supported by observations that combinations of two or more HIV bNAbs may drive some synergistic neutralisation activity beyond the simply additive (). Similarly, rapid emergence of neutralisation resistance following bNAb monotherapy in HIV infected individuals was recently reported (), further highlighting how synergistic bNAb combinations will be required for HIV therapy. From the perspective of vaccine immunogen design, the study by Bradley et al. highlights the importance of gp41 MPER residues near the viral membrane in maintaining the stability of the closed native trimer state. However, it is notable that the exceptionally well-characterised stabilised Env trimer BG505 SOSIP (truncated at residue 664) lacks this MPER region and has been experimentally confirmed to exist in a closed, neutralisation resistant state (). Future studies aimed at accurately defining the complex determinants of neutralisation sensitivity will be informative for both preventive HIV vaccine immunogen design and for the application of combination HIV bNAb therapy in HIV infected subjects. Conflicts of Interest
Acknowledgements We thank Rebecca Lynch for helpful discussions. Supported by Australian National Health and Medical Research Council awards 1052979 and 1041832 and the Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology (CE140100036).
Cutaneous abscesses are some of the most common manifestations of bacterial infections. Abscesses can present as transient painful lumps that resolve without medical intervention, or in severe cases as large deep abscesses associated with bloodstream dissemination. Although many Gram-positive and Gram-negative bacteria cause abscesses, . , in particular community-associated MRSA, is the most common causative agent. Once formed, the pus in the walled-off lesion can significantly interfere with the activity of antibiotics to the extent to make antibiotic treatment moderately ineffective when an abscess exceeds a certain size, with scarring posing as an additional problem. In this issue of (), Hancock and colleagues describe a cationic peptide that primarily targets the formation of abscesses. The peptide was developed from a screen of -biofilm peptides () and in vitro prevented or eradicated biofilms formed by both Gram-positive and Gram-negative bacteria. In non-vertebrate models of . infection, it enhanced survival of the host (). The target of the cationic peptide is the conserved bacterial stringent stress response mediator (p)ppGpp (). Cellular concentrations of pppGpp and ppGpp increase when bacteria are exposed to stresses, specifically nutrient limitation. (p)ppGpp, as a pleiotropic transcriptional regulator, orchestrates reprogramming of cellular processes by slowing the growth rate and pushes energy to be used for maintenance and stress-defense, including biofilm formation (). This is known as the stringent response and is an important bacterial survival mechanism. The enzymes responsible for synthesizing and degrading (p)ppGpp are highly conserved among bacteria. In Gram-negative bacteria, (p)ppGpp is synthesized by RelA and degraded by SpoT (). In Gram-positive bacteria, the RelA/SpoT Homologue (RSH) bifunctional proteins are the main enzymes responsible for synthesizing (p)ppGpp from ATP and GTP/GDP and hydrolyzing (p)ppGpp into GTP/GDP and pyrophosphate ().