Flu question

[Michael L. Perdue]

There is an excellent summary of pH effects on processing of the HA by 
Lamb et.al. in the Cold Spring Harbor Monograph: "Cellular Receptors for 
Animal Viruses".  The drug amantadine and its analog rimantadine have two 
actions.  The first is at the level of penetration and uncoating and 
resistant mutants have alterations in the M (matrix) gene, but the second 
action against some influenza strains is at the level to which you 
refer.  Namely amantadine appears to lower the pH in the trans golgi 
lumen causing a premature transition to the fusogenic form of the HA.  
This basically gums up the works with the HA oligomers aggregating and 
virus subsequently unable to bud.  Resistance to both effects of 
amantadine is quite common and resistant variants arise rapidly in most 
strains.  It is a very effective drug but this problem precludes its 
widespread use.  The Russians have done and still do a lot of work on 
trying to develop analogs that will be more effective.

The best recent reference on the structural effects of the pH transition 
is Bullogh et. al. 1994, Nature 371, 37-43.  Any recent publication by 
Alan Hay would likely start you on a fruitful path for other reviews 
since he is one of the "gurus" in this area.

Michael L. Perdue, Ph.D.
Athens, Georgia  30605
Ph: 706-546-3435
Fx: 706-546-3161
mperdue at asrr.arsusda.gov

On Wed, 15 Nov 1995 BIE034 at news.salford.ac.uk wrote:

> I was recently reading a book on protein structure and was intrigued by the 
> influenza haemaglutinin protein. The book remarked that on the lowering 
> of the pH whilst inside the endocytotic vesicle the viral protein undergoes a 
> considerable structural change to fuse the viral membrane to that of the 
> vesicle. The book was several years old but I would assume that such a change 
> would be an ideal target for drug interactions and so should have a large 
> body of associated research. Could anyone tell me if there has been any 
> progress in determining the mechanism by which the change occurs? If so I 
> would appreciate any pertinent references which they may know!
> 
> 		I thank everyone for their help
> 		Simon.
> 
>