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Gene Genie: Can Gene Therapy Deliver a Better Fusion Blocker?

December 2003

A note from TheBody.com: Since this article was written, the HIV pandemic has changed, as has our understanding of HIV/AIDS and its treatment. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

If the daily grind of subcutaneous injection of T-20 (Fuzeon) has got you down, why not let your T-cells make their own -- with gene therapy? Dorothee von Laer and Marc Egelhofer from Georg-Speyer-Haus in Germany and colleagues recently reported on progress in constructing a vehicle for an artificial gene called C36 that produces a peptide with the same fusion-blocking sequence of T-20 (Fuzeon). The idea is to inject the gene, deliver it to blood cells, and let the cells manufacture a new protective weapon against HIV to place on their outer envelopes.

So far, the field of gene therapy has been beset by false starts and a few tragic incidents, which have left scientists understandably wary about inserting foreign genetic material into people. After all, HIV itself is nothing more than a collection of alien genes that hijack normal cellular activity in order to propagate and multiply; immunological havoc is the result. But von Laer's group has engineered an elegant bit of genetic trickery that not only blocks HIV before it can get its foot in the door, but is carefully designed to minimize unwanted side effects.

Other projects are investigating gene therapies to treat HIV by blocking the expression of viral proteins such as tat. But these approaches would only be able to minimize viral activity after a cell had already become infected. Mathematical models suggest that such downstream gene therapy strategies would cause the proportion of HIV infected cells in the body to steadily increase. Lead author Egelhofer cautions that, as the number of cells harboring integrated HIV provirus grows, the burden of controlling viral expression would become overwhelming. But a fusion-blocking gene therapy that worked upstream of infection would preserve uninfected cells, thereby increasing their proportion.

The idea is to attach the 36 amino acid peptide to a hinged transmembrane protein that would allow it to reside on the surface of a target cell. If an HIV virion attaches to the cell and begins the process of bringing its lipid envelope into contact with the cell's membrane, the C36 peptide would jam the gp41 mechanism that mediates fusion -- exactly as T-20 does. The advantage is that, rather than injecting the peptide into the body in sufficient concentrations to achieve a high rate of blocked infections, the peptides will be assembled inside target cells then exported to the cells' surface, precisely where they are needed.

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The genes that code for the production of C36, the hinge and other supporting members, are cleverly delivered to the cell by a retroviral vector that gains entry by attaching to cells bearing the CD34 cell surface protein. Once inside, the vector deposits its genetic cargo, which is then shipped to a protein processing factory in the cytoplasm. The finished gene product is delivered back to the cell surface and implanted in the membrane, where it is free to move about and interact with any encroaching gp41s.

After an initial demonstration of the concept with a construct that inhibited infection in a limited set of cell types, van Laer and colleagues have now created an optimized version of the therapy that works in a broader range of primary cells and HIV isolates. The design improvements are also intended to minimize the potential for unwanted immunogenicity. Animal toxicity studies of the vector, called M87oRRE, have been successfully conducted and plans for first human testing are now being made.

As with any HIV therapy, the emergence of resistance is a concern, especially since resistance to the C36 peptide of T-20 is known to occur clinically. But the scientists found that by extending the length of the peptide with 10 additional amino acids, the resulting C46 peptide was active against C36-resistant isolates, and may be inherently less prone to developing resistance, since the elongation covers a highly conserved region of the gp41 fusion protein missed by C36.

Although still in very early stages, and yet to be tested in humans, this simple and elegant approach to gene therapy to prevent HIV entry into uninfected cells holds exciting prospects.

This report was an update of a poster presented at the 10th Annual Retrovirus Conference (CROI) in 2003. Hopefully new progress will be reported at the upcoming conference in San Francisco.


References

  1. Egelhofer M, Brandenburg G, Martinius H, et al. Inhibition of Human Immunodeficiency Virus Type 1 entry in cells expressing gp41-derived peptides. Journal of Virology, Jan. 2004, p 568-575.
  2. vanLunzen J, Brandenburg G, Baum C, et al. A comprehensive approach to gene therapy of HIV infection. Abstract 230. 10th Conference on Retroviruses and Opportunistic Infections, Boston, 2003.

A note from TheBody.com: Since this article was written, the HIV pandemic has changed, as has our understanding of HIV/AIDS and its treatment. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!



  
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This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.
 
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