TreatmentUpdate 68, Volume 8, No 4; May-June 1996
Sean Hosein

HIV infection decreases the ability of the immune system to respond to attacks by bacteria, fungi, parasites and viruses. Over time, levels of CD4+ cells fall, as do CD8+ cells that target and destroy HIV-infected cells. The loss of CD4+ cells is in part due to direct attack by HIV. Researchers have also found that non-HIV-infected CD4+ cells are also destroyed. In an attempt to maintain and increase levels of CD4+ cells, research teams are testing a number of strategies, one of which is gene therapy.

Gene therapy

Cells contain "blueprints" for making copies of themselves, repairing damage, regulating how they function and so on. These blueprints are called genes. When HIV infects a cell, it changes the cell's blueprints replacing them with its own genes. Using this new information, HIV converts cells into virus factories and in the process of making and releasing new viruses, the HIV-infected cell dies.

One research team at the Howard Hughes Medical Institute (Ann Arbor, Michigan) has been studying ways to help CD4+ cells withstand HIV infection. Their strategy is to infect CD4+ cells with the instructions (genes) necessary to make an anti-HIV protein called Rev M10. In laboratory experiments with cells this anti-HIV protein can:

* stop HIV from turning cells into virus factories

* allow T cells to carry out their duties

Study details

Researchers used three HIV-infected subjects who had CD4+ cell counts ranging between "400 - 500 cells." Blood from the subjects was removed and processed. Non-CD4+ cells were removed from the blood samples and the remaining cells were kept in a liquid containing nutrients and two anti-HIV drugs, delavirdine and CD4-PE40. This last drug destroys HIV-infected CD4+ cells. In this way, the researchers hoped to reduce the spread of HIV infection amongst the cells. The surviving CD4+ cells were then infected with the genes for the anti-HIV protein Rev M10. Technicians also infected some of the cells with a dummy gene. This gene had no anti-HIV activity but it allowed researchers to compare the effect of HIV infection on cells with and without the anti-HIV gene.

Treatment of the cells with anti-HIV agents continued for ten days. During this time the cells were bathed with the T cell growth stimulant IL-2 (interleukin-2), causing more CD4+ cells to form. The ability of technicians to infect the T cells with the anti-HIV genes was low. Only about 10% of cells exposed to the anti-HIV genes received it and added it to their existing genes. Billions of both sets of CD4+ cells (with and without Rev M10 genes) were infused back into subjects over "a 30-minute period".

Results

In as little as 7 days after being infused with the CD4+ cells, researchers found 10 times as many CD4+ cells with the anti-HIV genes than CD4+ cells with the dummy gene. In one subject the level of protected CD4+ cells fell by 50% 15 days after infusion. In other subjects CD4+ cells containing the anti-HIV gene were 4 to 5 times more likely to survive than cells without the anti-HIV gene.

Other issues

There are a number of issues to consider about future use of this form of gene therapy.

- efficiency of infection

The efficiency rate of infecting cells with the anti-HIV gene was only 10%. If this could be improved, perhaps more protected cells could be infused into people in less time. This may also decrease the number of infusions needed.

- More time and different subjects

The results of this experiment are promising but now researchers need to find out if the results benefit people with HIV/AIDS.

- Delavirdine and protease inhibitors

Experiments will probably be extended to subjects taking delavirdine and protease inhibitors.

- Other anti-HIV genes

There are other anti-HIV genes that could be used in addition to Rev M10. Should these be used instead of Rev M10 or in combination?

Type of immune response

One issue that this team has not considered is the type of response these CD4+ cells would make when faced with attack by microbes that cause many of the life-threatening complications seen in AIDS. These chemicals appear to be the product of an inappropriate immune response to the infections seen in AIDS and do not help in the fight against those infections.

REFERENCES:

1. Gougeon M-L, Lecoeur H, Ouliost A, et al. Programmed cell death in peripherial lymphocytes from HIV-infected persons: increased susceptibility to apoptosis of CD4+ and CD8+ cells correlates with lymphocyte activation and with disease progression. Journal of Immunology 1996;156:3509-3520.

2. Woffendin C, Ranga U, Yang Z-Y, and Nabel GJ. Expression of a protective gene prolongs survival of T cells in human immunodeficiency virus-infected patients. Proceedings of the National Academy of Sciences USA 1996;93:2889-2894.

3. Landay AL, Clerici M, Hashemi F, Kessler H et al. In vitro restoration of T-cell immune function in Human Immunodeficiency Virus - positive persons: effects of Interleukin (IL)-12 and anti-IL-10. The Journal of Infectious Diseases. 1996;173:1085-1091.

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Copyright © 1996 - TreatmentUpdate. Reproduced with permission. Reproduction of this article (other than one copy for personal reference) must be cleared through the Editor, The Canadian AIDS Treatment Information Exchange, 555 Richmond St. West, Suite 505, Box 1104, Toronto, ON, M5V 3B1 • Phone: 416-203-7122 • Toll Free: 1-800-263-1638 • Fax: 416-203-8284  http://www.catie.ca