The Bay Area Reporter - August 28, 1995
Marcos E. García-Ojeda and Jeff Getty, ACT UP/Golden Gate Writers Pool

Current HIV therapies involving anti-viral agents that target various enzymes essential for HIV's viral life cycle are rendered ineffective by the virus's ability to mutate and become resistant to anti-viral agents. Furthermore, long-term exposure to anti-viral drugs like AZT has toxic side-effects.

Cell Genesys Inc., a company located in Foster City, California, developed a non-toxic gene therapy approach for targeting HIV-infected cells by arming CD8 T-cells with Universal T-cell receptors. This approach could circumvent the problems caused by the virus's ability to mutate.

CD8 T-cells, also called cytotoxic T-cells or CTLs, have T-cell receptors (TCR) at their surface that specifically allow them to recognize and kill virally-infected cells. Recognition occurs in three steps: first, the infected cell breaks down viral proteins into small protein fragments called peptides; then it mounts these peptides on specialized presenting proteins called HLA; finally, the T-cell receptors on the CTLs recognize these peptide/HLA complexes on the surface of the infected cell, eventually leading to its death.

This process of HLA presentation is essential for the development and maintenance of immunity against viruses.

HIV-infected individuals have HIV-specific CTLs. Laboratory studies have demonstrated that these HIV-specific CTLs are capable of inhibiting HIV replication. Still, the virus is capable of evading CTL killing by mutating the peptides recognized by the HIV-specific CTLs. The transfer of HIV-specific CTLs from a twin, or expanded from one's own self, has been considered as treatment for HIV. Transfer of these cells requires the isolation and growth of large quantities of HIV-specific CD8 T-cells, which can be a very laborious, lengthy, and expensive process.

The zeta chain

CD4 T-cells (helper T-cells) have CD4 molecules on their surface. All T-cells have a signaling protein, called zeta chain, on their T-cell receptors. The zeta chain is needed for giving T-cells the signals required to gain their function: helper function for CD4 T-cells or killer function for CD8 T-cells. HIV has a protein on its surface, called gp120, that uses CD4 molecules on helper T-cells to infect them.

Using techniques of molecular biology, scientists at Cell Genesys generated CD4-zeta chain fusion proteins called CD4-UR (for CD4-Universal Receptor). Universal T-cell receptors (UR) could counteract HIV's ability to evade the immune system. These engineered receptors recognize portions of HIV's gp120 that do not mutate. They also recognize the intact viral protein, avoiding the necessity of breaking it into peptides and presenting these peptides on HLA complexes.

How does the CD4-UR work? The CD4-UR uses gp120's own need to bind CD4 to kill infected cells. As part of HIV's life cycle, the infected cell is turned into a virus-producing factory, making all the viral proteins required to produce new viruses. The infected cells will produce gp120 and display it on their surface. CTLs armed with CD4-UR will use the CD4 molecule of the receptor to recognize gp120 on the surface of the infected cell. Upon recognition, the zeta chain will then give the T-cell the signal to kill the infected cell.

How would this technology be applied to the patient? First, a donor with similar HLA proteins (HLA-matched) is required to be the source of CTLs. Alternatively, one's own CTLs could be used. CTLs will be isolated and modified with the CD4-UR using gene therapy. Scientists have developed a way to use benign retroviruses (called retroviral vectors) to deliver the genes needed to grow CD4-UR molecules onto CD8 T-cells. Because all CTLs will have the same CD4-UR, they will be easy to isolate and grow in large quantities. Once large quantities of the CD4-UR bearing T-cells are obtained, they will be reinfused back into the HIV-positive individual.

Preliminary in vitro data indicates that CTLs endowed with CD4-URs are capable of recognizing gp120 on the surface of HIV-infected cells. Recognition leads to activation and reproduction of these killer cells. It is interesting to note that free-floating HIV proteins in the blood of HIV+ donors did not block the Universal Receptor's ability to recognize gp120 on target cells or inhibit CTLs from killing their targets.

No detrimental effects yet

Currently, the Universal Receptors are undergoing human clinical safety studies. A small number of late stage disease patients have been infused with the modified CTLs from twins and are being carefully monitored. As of now, these UR-bearing CTLs show no detrimental effects on the patients participating in this study.

Doctors at UC San Francisco General Hospital will most likely be initiating a small Phase I - Phase II study later this year. Inside sources indicate that there will be up to 20 patients involved, and the study will use autologous (one's own) immune cell expansion. Only six months ago, Cell Genesys was technically able to vector and expand only enough Universal Receptor T-cells for their safety clinical study. This spring, activists learned that there might be a significant advance in this type of gene therapy that would allow for large-scale applications. It seems Cell Genesys has achieved that advance.

Gene therapy has shown great promise for slowing or stopping HIV, but is also thought by some to be potentially dangerous. Human-engineered immune cells could run amok or worse yet, the retroviral vectors could somehow mutate, causing more harm. To ensure its safety, the FDA has carefully regulated Cell Genesys' vectors, slowing the development of this gene therapy by more than one year. Still, the first patients must understand that there is real risk for injury or long-term effects from this exciting new technology.
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