New approach to gene therapy against HIV
It is a problem to develop gene constructs that are effective against HIV. The other difficulty lies in transporting this construct to where it can take effect: into the infected cells. A new way seems to be the use of a retroviral vector. The use of combination preparations against HIV has now proven to be promising. In some cases, the virus was no longer detectable due to the treatment. However, it seems that the virus is not completely destroyed by these treatments, but some viruses remain "hidden" in the immune system cells. The patients can therefore not be considered cured and the therapy must be continued indefinitely. New approaches to treating HIV infection, particularly those with the potential for a real cure, are still urgently needed.
Now researchers at the University of Pennsylvania Medical Center announce the development of a novel gene therapy to target HIV-infected cells. The new strategy takes the molecular tools used by HIV to enter and infect cells and applies them against the virus. The necessary genes are only transported into those cells that actually harbor the virus. The technique could also be used against many other viruses that use mechanisms similar to those used by HIV to infect cells. The results have been published in Science (November 21, 1997).
“Viruses carry molecules on their envelopes that allow them to attach themselves to the receptors on the cell type they infect,” explains Dr. James AHoxie, professor of medicine and lead author of the study. "We have loaded the relevant receptors into a retroviral vector specifically targeting HIV-infected cells."
In the first stage of HIV infection, the envelope proteins of the virus bind to two cell surface receptors: the well-known CD4 receptor and – depending on the cell type that is being attacked – one of the new receptors that are only were discovered in the past year. The most important of these so-called co-receptors are CCR5 and CXCR4. CCR5 is used along with CD4 by the HIV strains that infect macrophages at the earliest stage of infection; they are also known as M-tropic viruses. CXCR4, in turn with CD4, is used by the T-tropic viruses, which are the viruses that infect the T-cells in the later stages of infection and are associated with the progression of the disease.
After binding to a cell and subsequent entry, HIV incorporates its genetic material into the cell's genome. These cells then start making viral proteins along with their own proteins. As with all cells, some of the proteins produced are incorporated on the cell surface. The scientists took advantage of this fact.
The researchers integrated into the surface of a replication-defective retroviral vector the receptor complexes commonly found on the cells that HIV attacks. They suspected that this would allow the vector to bind to the viral proteins on the infected cells. By integrating reporter genes into the vectors, researchers were able to show that a viral vector with CD4 and CCR5 receptors can seek out and enter cells infected by M-tropic viruses; a vector carrying CD4 and CXCR4 did the same in cells infected with T-tropic virus. Also, the vector actually only infected the cells it intended to target.
"Scientists have developed a number of genetic constructs that could be used to block HIV replication," said Dr. Michael J. Endres, researcher in Hoxie's lab and co-author of the Science study. "The problem so far has been that nobody knew how to get this material into infected cells efficiently - and that's what we're talking about here." I can well imagine that one or more of the anti-viral constructs could be integrated into this new vector for therapeutic purposes.”
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