Influenza Research Pause

REFERENCE: Fouchier et al. “Pause on avian flu transmission studies.”  Nature (2012)

LINK directly to published letter

                As I discussed in my American Society for Cell Biology Meeting post, I don’t want to repeat work that has already been discussed outside of the initial scientific publication, however this topic is interesting, especially considering the letter was signed by 39 authors and published in both Nature and Science magazines.  

                Work being performed at the University of Wisconsin-Madison and Erasmus MC in the Netherlands has suspended important research on a highly transmittable influenza virus due to fears of viral escape from their laboratories.  They have imposed a 60 day “pause” on their work while the scientific community and the community at large have time to discuss some of the new issues this type of research presents.

Ebolaviruses

REFERENCE: Dias et al. “A shared structural solution for neutralizing ebolaviruses.” (2011) Nature Structural and Molecular Biology 18(12) pgs 1424 – 1427.

                Five types of ebolaviruses have been identified: Sudan, Ebola, Reston, Bundibugyo, and Tai Forest.  The Sudan and Ebola forms cause the predominant amount of human deaths and recently a new variant of the Sudan virus has been found in the Gulu district of Uganda.  While many monoclonal antibodies exist, only a handful can neutralize Ebola virus and none can neutralize Sudan virus.  In a recent Nature Structural and Molecular Biology publication, Dias et al. discuss their development of a neutralizing antibody for Sudan virus and a subsequent crystal structure of it bound to the Gulu-Sudan variant protein GP_1,2.

                GP_1,2 (glycoprotein) is a viral trimeric receptor solely responsible for bringing ebolavirus into a host cell.  The protein is so named because the entire amino acid sequence is expressed then cleaved to create GP₁ and GP₂.  However, these two proteins remain attached to each other via a disulfide bond until the viral membrane fuses with the endosomal membrane.   

                The monoclonal antibody developed here, referred to as 16F6, recognized native Sudan virus GP_1,2 and their work indicated that binding of 16F6 alone was enough to block infection.  The epitope for the antibody was revealed by X-ray crystallography to be at the base of the trimer (Figure 11.1).  Further work showed that Sudan virus could still attach to host cells and be internalized, which left the authors to speculate that the antibody is either inhibiting another unidentified factor or it is blocking an additional necessary conformational change in GP_1,2 that leads to successful infection.  

                The final sentence of their paper summarizes a possible far-reaching conclusion from their work as “...for viruses in general, successful immunotherapy and vaccine design may depend on targeting antibodies that anchor glycoprotein subunits together and prevent the conformational changes required for fusion.”

VEEV

Reference: Zhang et al. “4.4 Å cryo-EM structure of an enveloped alphavirus Venezuelan equine encephalitis virus” EMBO (2011) 30(18), pgs 3854 – 3863.

VEEV = Venezuelan equine encephalitis virus

Fast Facts

-                Capable of infecting both humans and all species of equine (horses, zebras, donkeys)

-                Mosquito-borne pathogen

No human vaccine or antivirual drugs are available to treat VEEV.  Instead, an attenuated virus exists known as TC-83, which is given to laboratory workers and military personnel as a vaccine.  Because of its inability to be treated, high infection rate, and ease of production, VEEV has the potential to be used in bioterrorism.  In fact, the United States and a few other countries have developed VEEV as a biological weapon.  

In a recent issue of The EMBO Journal, Zhang et al. published the 4.4 Å electron cryo-microscopy structure of TC-83.  Partial X-ray crystallography structures were known of the viral coat proteins E1 and E2, but this data allowed researchers to determine reasonable models for both entire proteins.  

Figures 3.1 and 3.2 are taken directly from the paper and show the reported structure for one viral particle in 3D and a cross section of the virus.

Researchers say their data partially explains why TC-83 is attenuated compared with other VEEVs and offers insights on host recognition and initial nucleocapsid core formation.  For a virus we need to understand better, this structure and their work is definitely a step forward. 

The reference is above if you’d like to read more!