| Trojan Horse vs. HIV
By Sean Henahan, Access Excellence
New Haven, CT (9/5/97) Borrowing a page from the classics, AIDS
researchers have devised a viral trojan horse that appears to target HIV-infected
cells while leaving the rest of the immune system alone.
Researchers at Yale University modified livestock virus known as vesicular
stomatitis virus (VSV) so it would target the CD4 T-cells selectively infected
by HIV. In in vitro studies the modified VSV successfully targeted HIV-infected
cells and destroyed them.
"This is a completely new approach, targeting a virus to an infected
cell," explains the study's senior scientist, John K. Rose, Ph.D., from
Yale's Departments of Pathology and Cell Biology. "The concept could be
used to develop a whole new class of agents that are useful for controlling
disease."
"Although additional in vitro and animal studies need to be performed
before this novel virus can be tested in humans, this concept of cell-targeted
delivery has enormous potential applications for HIV, cancer or other diseases"
said Anthony S. Fauci, M.D., Director of the National Institutes for Allergic
and Infectious Diseases.
The researchers modified the vesicular stomatitis virus (VSV) genome,
deleting its envelope gene and replacing it with the genes for a pair of
cell surface receptor -- CD4 and the coreceptor CXCR4. These receptors
are normally found on human T cells and allow HIV to attach to, enter and
infect T cells.
These receptors also permit cell-to-cell HIV infection to occur. HIV-infected
cells flag themselves for destruction by the body's immune system by displaying
HIV's outer coat protein. But this protein, HIV gp120, is the same one
that attaches to the T-cell receptors and leads to infection. Cell-to-cell
infection occurs when the HIV gp120 on an infected cell first hitches up
to the receptors on an uninfected T cell, resulting in the fusion of the
cell and viral membranes, and transfer of virus from the infected to the
uninfected cell.
In a cleverly engineered reversal of nature, the remodeled shell of
VSV -- which now looks like an uninfected T cell -- tricks HIV-infected
cells into fusing with it instead. This enables VSV, which easily kills
cells, to gain entry into the HIV-infected cell and destroy it. The modified
VSV cannot infect normal cells because it lacks its normal surface protein.
Thus, it targets, enters, multiplies in and kills only Tcells that, through
the display of HIV gp120, signal that they are infected, Rose explained.
In their initial laboratory experiments, the researchers infected human
T cell lines with a laboratory strain of HIV. They then added the modified
VSV at different times following infection. The VSV appeared to do the
job, reducing infectious HIV levels to barely detectable levels, at least
300-fold to10 thousand-fold lower than the levels of HIV produced in control
cells.
"Until there are data from animal models," Dr. Rose cautions, "we cannot
gauge how well the potential treatment might work in people." But he regards
it as "likely to be safe," and would like to see the concept tested in
human clinical trials as soon as possible. Such discussions are already
under way, but Dr. Rose estimates the possibility is at least a year away
and that trials in animal models are a necessary first step.
If the trojan horse virus proves safe and effective in humans
it would probably be used first to treat patients with advanced AIDS. Progress
is already underway to develop other novel VSV forms that might prove useful
in earlier stages of HIV infection.
VSV is known to cause a blistering disease called vesicular stomatitis
in livestock. It is rarely fatal in animals. Human infection is rare and
no deaths have been reported. The researchers believe the modified VSV
would be particularly harmless in humans because it lacks its normal protein
envelope, so could not enter normal cells.
The new research also represents an important development in the field
of gene therapy generally. Most attempts at gene therapy have involved
removing and reinserting modified somatic cells back into the body, an
expensive and inefficient approach. The new approach allows direct, in
vivo delivery of a vector that can find its destined target in the body,
eliminating the need for ex-vivo manipulation of cells
Nava Sarver, Ph.D., chief of the targeted interventions branch in NIAID's
Division of AIDS says, "This is a very exciting advance. We are getting
closer to solving one of the major problems in targeted delivery of genes
to specific cells for treatment and possibly disease prevention: specifically,
how to deliver what you want to the cell you want it to go to."
The research appears in the Sept. 5, 1997 issue of the journal
Cell.
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