AIDS TREATMENT UPDATE, December 1995
Raffi Babakhanian

* How genes work

Our genetic material is present in every cell in the form of two strands of DNA (deoxyribonucleic acid) as a double helix. These strands of DNA are very long and contain our entire biological blueprint. Particular parts of the DNA strand contain the instructions for making specific enzymes or proteins, and each of these parts is called a gene.

When a cell needs enzymes or proteins to carry out a particular function, the relevant gene which contains the instructions for making them is activated. The activated gene is then converted (transcribed) into RNA (ribonucleic acid), a single-stranded copy of that gene's DNA. The RNA molecule then leaves the nucleus of the cell and attracts specific amino acids, so forming the required protein or enzyme. Instead of forming a single protein or enzyme, sometimes the RNA molecule is converted into a large strip of protein, which is then cut up (spliced) by enzymes such as protease to form several smaller, functional proteins.

* Gene therapy and HIV

Most current research is investigating the potential for gene therapy in treating inherited genetic disorders. Researchers hope that it may be possible to correct genetic abnormalities which can cause diseases previously regarded as untreatable. HIV infection is not an inherited genetic disorder, but in many ways it can be viewed as an acquired genetic disorder. HIV belongs to the family of retroviruses, which carry their genetic material in the form of RNA. Once the virus has infected a cell, it converts its RNA into DNA using reverse transcriptase (the enzyme that anti-HIV drugs such as AZT inhibit) and inserts its DNA into the DNA of the infected cell. Gene therapy approaches may thus be able to target the HIV genes in infected cells in a similar manner to the way in which they target faulty human genes in inherited genetic disorders.

* Types of gene therapy for HIV

There are three general ways in which gene therapy could potentially be tested for treating HIV infection: - as an anti-viral, targeting the HIV genes in infected cells - as a protective, by trying to alter uninfected cells so that HIV is unable to infect them - as an immune booster, by increasing the immune system's own ability to detect and attack HIV-infected cells

Several research teams are trying the anti-viral approach. One form uses small molecules called anti-sense oligonucleotides. These bind to the RNA strands before they can attract the necessary amino acids to form the functional proteins. Another strategy is to use molecules that can detect specific parts of HIV's RNA within infected cells and splice it (cut it up), thus inactivating it. These molecules are called ribozymes. Ribozymes can be created that splice HIV RNA in several different locations, so that one ribozyme may simultaneously prevent the formation of several different HIV proteins. Even if HIV mutates against one splicing site, the ribozyme will still be effective at others. In addition, ribozymes can attack HIV RNA soon after the virus enters a new cell and before it has incorporated its genetic information into the cell's DNA, theoretically stopping the infection process in its tracks.

Another strategy involves creating mutant forms of essential viral proteins. These defective proteins effectively compete with real HIV viral proteins within the body but do not carry out their proper function, thus interfering with the ability of HIV to reproduce. These altered proteins are called transdominant mutant proteins.

* Immune-based gene therapy

Other researchers are trying to use gene therapy either to boost the immune system's CD8 cells, which can kill HIV-infected cells, or to protect CD4 cells from being infected. In each of these two approaches, immune cells are taken from people with HIV and a gene is inserted that either protects them from HIV or activates them against HIV. The enhanced cells are then cloned to increase their numbers and reinfused back into the patient. This is called adoptive cell therapy.

Several clinical trials of both these approaches have taken place. To protect participants against unexpected side-effects from this novel treatment, in some trials the cloned cells also had another gene inserted which made them susceptible to ganciclovir, allowing doctors to kill all the altered cells at the first sign of any problems by administering ganciclovir. However, when these cells were re-infused into trial participants no benefits were seen because the cells were rapidly identified as 'foreign' and destroyed by the recipients' immune systems.

Adoptive cell therapy requires the removal, alteration and cloning of cells individually for each patient and for this reason is unlikely to be a practical or cost-effective way of treating large numbers of HIV-positive people.

* Delivering the therapies

The main problem with all these strategies is how to deliver the new genes into cells.

The most common approach is to use genetically altered viruses to carry the gene therapy into the target cells and 'infect' them with it. These altered viruses are called viral vectors.

Some researchers think it could prove hard to get gene therapy into all the parts of the body infected by HIV, such as the lymph nodes and the central nervous system. One approach is to use altered HIV itself as a viral vector. But no-one knows the long-term consequences of combining 'therapeutic' HIV with 'normal' HIV within the body.

* Conclusion

Gene therapy is still at an early stage of development. No-one can be sure that these therapies will not cause unforeseen side-effects. The insertion of the 'foreign' gene therapies into the genetic material of normal cells could affect their normal functions, or lead them to mutate. The body's immune system could also identify protein-based gene therapy as 'foreign' and try to eliminate it from the body.

No form of gene therapy has yet produced clear beneficial results, but they are all still in the early stages of development, having been transformed in just the past five years from theoretical science into practical forms for testing. Clinical trials for people with HIV may begin in the UK as early as next year.

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