Certain Mutations Significantly Impair Hepatitis C Virus Replication

 

Two new studies reveal that a key phenomenon of an individual’s ability to control Hepatitis C Virus (HCV) is their ability to target critical regions of the virus. These studies, led by researchers at the Ragon Institute in collaboration with scientists at the Broad Institute and the University of Freiburg, appear in recent articles in the Journal of Virology and the journal Hepatology.

Efforts to develop vaccines against highly variable pathogens such as HIV and HCV have been thwarted in large part due to the ability of these viruses to rapidly mutate to avoid host immune responses. However, certain individuals are able to uniquely control each pathogen through proteins that orchestrate host immunity (termed HLA-B57 and HLA-B27).

In these studies, individuals expressing the protective alleles HLA-B57 or HLA-B27 were both found to elicit immune responses against regions of the HCV polymerase protein that are critical to the ability of the virus to replicate. These immune responses force the virus to develop highly deleterious escape mutations that significantly impair virus replication, even resulting in the development of secondary ‘compensatory’ mutations by the virus in an attempt to minimize the effects of these escape mutations.

Importantly, HLA-B57 and HLA-B27 function to control HIV through a similar mechanism of selecting for highly deleterious mutations in critical regions of HIV.

“The susceptibility of each of these viruses to the same mechanism of immune control reveals that the key to controlling highly variable pathogens may lie in the ability to develop vaccines that able to redirect immune responses towards more critical regions of these viruses” says Todd Allen, PhD, of the Ragon Institute and Massachusetts General Hospital (MGH) and an Associate Professor of Medicine at Harvard Medical School, the senior author of the two reports.

Efforts are underway at the Ragon Institute to harness these findings to develop and test novel vaccine approaches against each of these human pathogens for which vaccines are still unavailable.

Articles

“HLA-B27 Selects for Rare Escape Mutations that Significantly Impair Hepatitis C Virus Replication and Require Compensatory Mutations” – Neumann-Haefelin et al, Hepatology

“Compensatory Mutations Restore the Replication Defects Caused by CTL Escape Mutations in HCV Polymerase” – Oniangue-Ndza et al, Journal of Virology