Posts Tagged ‘replication’

Elusive HIV Shape Change Revealed; Key Clue to How Virus Infects Cells

Thursday, October 1st, 2009

From: Science.com

Structural biologists at Children’s Hospital Boston and Harvard Medical

School have shown how a key part of the human immunodeficiency virus

(HIV) changes shape, triggering other changes that allow the AIDS virus

to enter and infect cells. Their findings, published in the Feb. 24 issue of

the journal Nature, offer clues that will help guide vaccine and treatment

approaches.

Researchers led by Howard Hughes Medical Institute Investigator Ste-

phen Harrison, PhD, and Bing Chen, PhD, focused on the gp120 protein,

part of HIV’s outer membrane, or envelope. gp120’s job is to recognize

and bind to the so-called CD4 receptor on the surface of the cell HIV

wants to infect. Once it binds, gp120 undergoes a shape change, which

signals a companion protein, gp41, to begin a set of actions that enable

HIV’s membrane to fuse with the target cell’s membrane. This fusion of

membranes allows HIV to enter the cell and begin replicating.

The structure of gp120 after it binds to the CD4 receptor and changes its

shape was solved several years ago by another group. Harrison and Chen

have now described gp120’s structure before the shape change, yielding

vital before-and-after information on how the molecule rearranges itself

when it encounters the CD4 receptor.

‘’Knowing how gp120 changes shape is a new route to inhibiting HIV – by

using compounds that inhibit the shape change,’’ says Harrison. He notes

that some HIV inhibitors already in development seem to inhibit the shape

change; the new findings may help pin down how these compounds work

and hasten their development into drugs.

‘’The findings also will help us understand why it’s so hard to make an

HIV vaccine, and will help us start strategizing about new approaches to

vaccine development.’’

The studies, performed in the Children’s Hospital Boston Laboratory of

Molecular Medicine, used the closely related simian immunodeficiency

virus (SIV) as a stand-in for HIV. By aiming an X-ray beam through a crystallized form of gp120, they obtained the first high-resolution three-

dimensional images of the protein in its unbound form. They surmounted

considerable technical challenges, including difficulty in getting gp120 to

form good crystals.

‘’Without very well-ordered crystals you get a very blurry picture,’’

explains Harrison. ‘’It took a very long time, and lots of computational

work, to get that picture to sharpen up enough to get an answer.’’

One of the lab’s first steps will be to determine which shape of gp120

- bound to the CD4 receptor, or unbound – is recognized by a person’s

antibodies. gp120’s shape change is an important ‘’escape mechanism’’

for HIV, allowing the virus to bind to and enter a cell before the immune

system can ‘’see’’ it, notes Harrison.

‘’We can now compare the bound and unbound forms and try to unders-

tand whether there are any immunologic properties that differ and that

might provide a route to new vaccine or drug strategies,’’ Harrison says.