To All:
Please read the following article and make special reference to the comment section of this article by NIH.
Article:
NIH Scientists Find Cofactor for HIV Entry
Date:
05/17/96
Issue:
247
Author:
John S. James
Researchers at the National Institute for Allergy and Infectious Diseases (NIAID), of the U.S. National Institutes
of Health, have found a protein, named "fusin," which works together with the CD4 protein to allow HIV to fuse
with and enter CD4 cells (T-helper cells). It has long been known that HIV uses the CD4 protein in order to enter
and infect these cells. But also, it has long been known that the CD4 protein by itself is not enough, since HIV
cannot fuse with most animal cells, even if they have been genetically altered to express human CD4. Some
unknown "cofactor" must also be present. That is what has now been discovered.
This discovery of the fusin protein is widely considered to be a major advance in the understanding of how HIV
disease develops. However, it does not seem to have immediate implications for treatment. For example, while
fusin works for HIV strains that infect certain types of CD4-positive cells, it does not work for other strains that
infect other types of CD4-positive cells, for example, macrophages. Presumably another cofactor, probably a
related protein, functions for the HIV isolates that infect macrophages; in fact, there may be a whole family of
fusin-like proteins. Also, fusin exists naturally on human cells, where it must have some normal function,
although this function is unknown; therefore, simply blocking fusin with an antibody, as has been done in
laboratory tests, might not be a possible treatment.
How was fusin discovered? The procedure was described in a highly technical article(1), and less technically in a
NIAID press release written for science writers(2). Basically, the scientists started with ordinary mouse cells in a
laboratory culture. These cells were changed genetically so that they would express human CD4; this was done
by means of a specially constructed virus, called a "vector," which carried the DNA sequence for human CD4
into the cells.
Also, a "library" of many DNA sequences (expressed by a human cell type known to be infectable by HIV) was
introduced into the culture of mouse cells. It was expected that somewhere in the library must be the sequence
for the cofactor being sought. A few of the mouse cells in the culture were then able to fuse (with other cells
which expressed the HIV envelope protein on their surface), meaning that those mouse cells could fuse with (and
potentially be infected by) HIV. (The researchers devised a method by which the fused cells would turn blue
when treated with a special stain, allowing them to be easily seen and counted.) This fusion demonstrated that
the library did indeed contain the sequence for the cofactor. The researchers then divided the human DNA
library into fractions and tested again to see which fraction had the sequence of interest. By successive
divisions, they narrowed the search until they found the protein they were looking for. Later, to confirm the
discovery, the researchers genetically altering certain animal cells which normally cannot be infected by HIV, so
that they could be infected.
Comment
This research would probably never have been done by pharmaceutical companies, which focus on practical
applications of proprietary drug candidates, and seldom do the kind of basic research which prepares the
groundwork for future treatment advances. Without government support, little basic science would take place.
Pharmaceutical executives have often said that government must support such work. After potential products
have come into view, industry is usually best in developing them.
Unfortunately there is still a major gap between where basic research ends and where drug development begins.
No institution today has been effective in bridging this gap. That is why the immense discoveries in biology and
other sciences have translated poorly into better treatments and cures.
References
1. Feng Y, Broder CC, Kennedy PE, and Berger EA. HIV-1 entry co-factor: functional cDNA cloning of a
seven-transmembrane, G protein-coupled receptor. SCIENCE. May 10, 1996; volume 272, pages 872-877.
2. NIAID news releases and other materials are available at the NIAID home page on the World Wide Web,
niaid.nih.gov; select the "News releases" section to find the May 9 document, "NIAID Researchers
Identify Cofactor for Entry of HIV into Cells." |
