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Can Gene Therapy Cure AIDS?BY: Padma Kumar | Category: Healthcare | Submitted: 2010-09-02 22:09:23
When antiretroviral drugs came on the scene it was widely believed that they would kill all the cells with HIV and thus it was touted as a cure for AIDS. But things went wrong because HIV has a tendency to fuse with the patient's DNA. There it could lie dormant for many years yet have the capacity to cause infection.
Antiretroviral drugs only prevent the virus from replicating. This means the moment you stop taking the drug, the virus will spring to life. So antiretroviral drugs have to be taken every day in a patient's life and that's expensive for most AIDS patient's who come from poor countries
It is in this regard the announcement of German doctors in 2007 that they had cured a 42 year old leukemia patient of AIDS through bone marrow transplants was indeed stunning.
Immune-system cells are generated in the bone marrow. The basic concept behind this treatment was the fact that a patient could be rendered immune to HIV using mutant bone-marrow cells that did not have CCR5 cell surface protein(without this protein the HIV cannot get inside the cell).
In a specific instance, an American living in Germany was supposedly cured of AIDS when given a bone marrow transplant for curing his leukemia. The bone marrow was transplanted from another person who had a natural immunity to HIV. After being given the transplant, the patient has lived without any signs of HIV. He is no more on conventional AIDS medication and so far there has been no AIDS virus in his blood. Normally when a patient stops taking AIDS drugs, the virus stampedes through the body within weeks, or even days.
In other word, Dr Hutter (not an AIDS specialist) who conducted this procedure could replace his patient's bone marrow cells with donor cells that had immunity to HIV.
At first the patient was made to stop taking antiretroviral drugs lest it undermined the transplanted cells ability to survive in the host. Then the patient's own hematopoietic stem cells (stem cells that can become any type of blood cells) were killed using a combo of drugs and radiation and instead a donor's tissue marrow (after doing tissue-type matches) that contains hematopoietic stem cells from donors who were HIV resistant was put in place. These newly introduced cells created healthy RBCs and WBCs and shored up the patient's immune systems.
The doctors had intended that the patient would be put back on anti retrovirals if and when HIV reappeared. But this never happened. Usually HIV hides in blood, brain or rectal tissues but even after several years this has never happened.
Researchers affiliated to the nonprofit Foundation for AIDS Research, or amFAR have concluded that although some HIV could still be lingering in the patient it couldn't spring to infection levels as most of target cells had become impenetrable mutants(meaning they did not have CCR5 cell surface protein). So they concluded that the patient was functionally cured.
What is striking about this procedure is the fact that donor's stem cells weren't genetically modified. These were from a patient whose cells did not have CCR5 cell surface protein which is a point of entry for HIV to infect T-cells. This mutation is referred to as a CCR5 double deletion (when both parents of the donor have this).
Who has these mutations? 1% of Europeans have it especially north Europeans possibly as a consequence of plague or other epidemics that would have lasted for a long while. African, Asian and South American people do not have the CCR5 mutation. People with this mutation do not have CCR5 on the cell surface. If this gene mutation comes from both parents then the offspring is totally resistant to HIV. Without binding to CCR5, HIV strains cannot enter cells.
The German effort has been rightly hailed as a genetic engineering pathway for curing AIDS
However there could be some concerns regarding this bone marrow transplant procedure to cure AIDS.
There are millions of people worldwide suffering from HIV. Is Bone marrow transplant a viable solution for them despite the costs? The answer is certainly no. Apart from the risk of infection and fatality (due to chemotherapy) as the patients await their immune system to prime and regenerate cells on their own, the availability of HIV resistant donors in relation to millions of infected individuals is improbable, especially if they required donor cells that were all CCR5 double deleted (meaning donors who had inherited the CCR5 mutation from both parents). That apart, whether ablative chemotherapy plus radiation to devour the existing immune cells could be given to a patient on retrovirals is a moot point.
Since the donor was another person and as the procedure did not involve transplanting the patient's own cells after replacement of existing cells, the mild graft versus host disease phenomenon could have come into play---which means the donor cells could have actively killed whatever HIV infected cells were there.
Interestingly it has been noted that people with CCR5 mutation were susceptible to West Nile virus. That apart this transplantation procedure itself has a more than twenty five percent mortality rate. Besides, there is a possibility that the initial round of drugs (ablative chemotherapy) and radiation to kill the existing immune cells may have killed cells containing HIV as well and probably contributed to the overall success.
Other Research Efforts
1) Theoretically AIDS could be cured if normal immune cells could be substituted with HIV-resistant cells. Already there are several anti-HIV genes developed. These could be put into induced pluripotent stem cells and could be given to a patient the same way a bone marrow transplant is done. Researchers at UC Davis have followed this interesting path. In order to instill immunity in patients suffering from HIV, human skin cells were genetically engineered to have properties akin to IP stem cells (induced pluripotent stem cells) which have the capacity to differentiate into other cell types like hematopoietic stem cells.
2) Some researchers have stitched in genes (to outwit the virus) to the immune stem cells removed from HIV infected patients. These cells when transplanted to the patients showed that the stitched in genes did show some good effects. The altered stem cells also matured and diversified into different types of immune system cells that HIV infects. In this way anti-HIV genes could technically make the virus ineffective.
3) Research is underway to create bone marrow stem cells without the crucial CCR5 gene akin to what the Berlin patient had received. This is by using genetic scissors. Genetic scissors are Zinc finger nucleases which can cut DNA at any particular point. So for example if CCR5 gene were cut half length and if the cell was made to glue the gene back then there would invariably be a mistake in that process causing the gene to be defective and work no longer the way it usually does.
4) Although this route is seldom taken, others are working on therapeutic viruses they could inject into a patient as easily as a flu vaccine. If re engineered viruses have to carry therapeutic genes to the cells then the former has to be absolutely safe. Currently cells are removed, genetically reengineered in vitro (outside the body) and transfused back.
5) Yet another approach is to use HIV itself, make it harmless by genetic engineering and use that to deliver 3 genes to the WBCs of the patient. One of the genes would disarm CCR5 while the other 2 deactivates HIV.
The newer gene-therapy protocols relating to research enumerated in this article are in clinical trial stages. If scientists can use gene therapy to confer the same sort of protection against HIV as CCR 5 deletions provides, then they may be able to stop the virus replicating. Perhaps the safer alternative to reengineer a patient's own cells is a promising possibility but past experience has linked this with mortality as well.
The HIV virus attacks cells that are successors of hemopoeitic stem cells. So anti-HIV genes take advantage of how HIV works and a cure for AIDS will come only if each and every hematopoietic stem cell could be replaced. Besides over a period of time, there is always the possibility that the lingering HIV could find a way to surpass the ostensible invulnerability of the mutant cell. Nevertheless gene-therapy might someday cure the dreaded disease
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