National Institute of Allergy and Infectious Diseases (NIAID)grantees at Yale University have converted a common livestock virusinto a Trojan horse that selectively targets HIV-infected cells and thendestroys them. As reported Sept. 5 in the journal Cell, this strategyeffectively controlled HIV infection in laboratory-grown T cells anddramatically reduced infectious HIV to levels that were barely or nolonger detectable.
"This is a completely new approach, targeting a virus to aninfected cell," explains the study's senior scientist, John K. Rose,Ph.D., from Yale's Departments of Pathology and Cell Biology. "Theconcept could be used to develop a whole new class of agents thatare useful for controlling disease."
"Although additional in vitro and animal studies need to be performed before this novel virus can be tested in humans," comments NIAID Director Anthony S. Fauci, M.D., "this concept of cell-targeted delivery has enormous potential applications for HIV, cancer or other diseases."
In their report, Dr. Rose, Matthias J. Schnell, Ph.D., and theircolleagues describe how they modified the vesicular stomatitis virus(VSV) genome, deleting its envelope gene and replacing it with thegenes for a pair of cell surface receptor -- CD4 and the coreceptor CXCR4 -- normally found on human T cells. These receptors enableHIV 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'simmune system by displaying HIV's outer coat protein. But thisprotein, HIV gp120, is the same one that attaches to the T-cellreceptors and leads to infection. Cell-to-cell infection occurs whenthe HIV gp120 on an infected cell first hitches up to the receptors onan uninfected T cell, resulting in the fusion of the cell and viralmembranes, and transfer of virus from the infected to the uninfectedcell.
Turning around what occurs naturally, the remodeled shell ofVSV -- 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.
In their experiments, the Yale team infected human T cell lineswith a laboratory strain of HIV. To these cells lines -- in which abouthalf of the cells were now HIV-infected -- they added the novel VSV ateither three or five days postinfection. This ultimately slashedinfectious HIV to extremely low or undetectable levels, at least 300-fold to10 thousand-fold lower than the levels of HIV produced incontrol cells.
"Until there are data from animal models," Dr. Rose cautions,"we cannot gauge how well the potential treatment might work inpeople." But he regards it as "likely to be safe," and would like to seethe concept tested in human clinical trials as soon as possible. Suchdiscussions are already under way, but Dr. Rose estimates thepossibility is at least a year away and that trials in animal models area necessary first step.
The report says the novel VSV described would be mostappropriate for limiting HIV production in people with late-stagedisease, but the Yale team has moved on to develop VSV constructsthat incorporate other HIV coreceptors such as CCR5 and CCR3 inan attempt to affect HIV strains that target macrophages and typicallypredominate in early HIV infection.
The virus involved, VSV, causes vesicular stomatitis, adisease mainly of cattle, horses and pigs that causes blister-likebumps on the hoofs and tongue. Nearly all animals recovercompletely from the illness.
Occasionally, people become infected with VSV through closecontact with infected livestock or via laboratory exposure. Manypeople with VSV have no symptoms, and those who become illusually have a mild, limited flu-like disease. No human deaths linkedto VSV infection have been reported.
The modified VSV is defective because it no longer has itsnormal coat protein. Therefore, it can not enter normal cells andcause infection in livestock or humans.
In their paper, the authors note several positive features oftheir system. For example, levels of the novel VSV would beexpected to decline as HIV declines, since the VSV only targets andmultiples in HIV-infected cells. Moreover, resistance to the novel VSVwould not be expected to develop, because that "would require loss of HIV's ability to bind CD4 or [the] coreceptor and would therefore not be selected," the authors write.
Nava Sarver, Ph.D., chief of the targeted interventions branchin NIAID's Division of AIDS says, "This is a very exciting advance. We are getting closer to solving one of the major problems in targeteddelivery of genes to specific cells for treatment and possibly diseaseprevention: specifically, how to deliver what you want to the cell youwant it to go to."
Currently, most gene delivery is done by removing certaincells from the body, modifying and then growing more of them, and,finally, reintroducing them back into the body. "This is a very labor-intensive, time-consuming task," says Dr. Sarver. In addition, there'sa tremendous dilution effect because the amount of cells reintroducedis very small.
She adds, "The Yale group has crossed a major hurdle thatmay allow direct, in vivo delivery of a vector that can find its destinedtarget in the body. There should be no need for ex-vivo manipulationof cells." She envisions many potential applications of this research. Surface-modified live vectors like VSV could be used to shuttle intothe body viruses or toxins to destroy infected or cancerous cells, ortherapeutic genes to protect uninfected cells against an invadingvirus. Moreover, such vectors could be used as novel vaccines todeliver antigenic genes to antigen-presenting cells, such as dendriticcells, for mounting immune protection against an invading pathogensuch as HIV.
NIAID, a component of the National Institutes of Health (NIH),supports research on AIDS, malaria and other infectious diseases, aswell as allergies and asthma. NIH is an agency of the U.S.Department of Health and Human Services. ###Press releases, fact sheets and other NIAID-related materials areavailable on the Internet via the NIAID home page athttp://www.niaid.nih.gov.
Reference:Schnell MJ, Johnson JE, Buonocore L and Rose JK. Construction ofa novel virus that targets HIV-1-infected cells and controls HIV-1infection. Cell 1997;90(5):849-857.
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