Biology 103
2000 Second Web Report
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Mutant CCR5: A Cure For AIDS?

Sujatha Sebastian

Everyone has heard about it. You know at least one person affected by it. We are bombarded by its repercussions everyday. The newspaper reports that yet another thousand people died from it yesterday. The only consolation that the medical world can provided is that it is fatal and at the present moment still incurable....

AIDS (Acquired immune deficiency syndrome) is a disease caused by the virus known as HIV-1 (Human immunodeficiency Virus Type One). HIV-1 attacks the immune system and prevents it from being able to fight off diseases and infections. When HIV-1 attacks CD4 T-cells, a type of white cell which fights infection, are destroyed. HIV does not necessarily develop into AIDS right away, but usually within 10 to 15 years the infected individual's immune system is destroyed. AIDS then allows life threatening cancers to develop and take control of the body. (2)AIDS was first officially reported in 1981. Since then over 16.3 million people have died from AIDS. At the moment there are an estimated 33.6 million people in the world living with HIV or AIDS.(1).

We are helpless and do not know what to do. Millions are dying and the only thing we can do is stand witness to the horror. The AIDS epidemic has in many ways taken over society and medicine. We are no longer in the day when AIDS was a "secret" disease, "something that could only be contracted by gay men or poor people in Africa". AIDS is no longer hidden. But our newfound openness with the disease is not due to a more accepting public, but rather the fact that we can no longer ignore it. AIDS has posed a great challenge to the medical world. While researchers clearly understand the results of HIV and AIDS, they have yet to fully figure out how the disease operates. Up until recently this lack of information has prevented the medical world from making significant progress towards a cure.

It is only now that scientists have learned how HIV infects the body. They have realized that it works in two phases, the M-tropic phase and the T-tropic phase, and that it looks for receptor sites to bond to. CCR5, a chemokine, is the second receptor site for HIV-1 in the M-tropic phase. Scientists have gained new information about this chemokine and how mutated versions have in many instances prevented individuals from contracting HIV. I decided to write about CCR5 because of the lack of significant information about it in AIDS research up until now. The new knowledge that scientists have gained through studying chemokines will be priceless in the battle against the disease. I wanted to learn how HIV enters the body, and the impact newly gained will have on the medical world. The attitude for a long time has been that AIDS is incurable. Many people feel that medicine is fighting a hopeless cause. The medical world itself has not fully acknowledged the advantages that will come from now understanding the HIV infection process. Because of this sense of despair it is important to focus on the advancements that are being made in the battle against HIV and AIDS.

HIV-1 is transmitted through blood. Though a person may become infected with the virus the body is unaware. Retro viruses, such as HIV, enter cells by binding to certain proteins which are encoded by genes in the body. Once inside the cell the retro virus then inserts its own gene into the host's chromosome. This allows the virus to be passed on to future generations of genes.(3)HIV goes through different phases of infection. Once in the host, HIV enters its first phase called the M-tropic phase. It is during this time that the virus looks for macrophages to bind to. It binds to it the molecules CD4 and CCR5 which are on the macrophage's surface. After its M-Tropic phase the virus then goes into its second stage, the T-Tropic Phase. It is during this stage that HIV mutates and looks for t-cells, also known as lymphocytes, that are part of the immune system. The T-tropic virus then destroys the t-cells which leads to the onset of AIDS. (2)

With the medical world's understanding of how HIV takes control of the body, the search for possible prevention and cures can be started. Because CCR5 is the second receptor protein for HIV in its M-tropic phase, it plays a very important role in looking for a solution. CCR5 is a chemokine receptor which is made up of seven membrane spanning molecules. It is found on the surface of cells mainly in the immune system. When the receptors bind their chemokines, the cells in the immune systems are sent to the sight of tissue damage. HIV-1 enters the cell during this process of fusion. (3). There are a small percentage of people, approximately 1% of all people who are of European descent, who are born with a mutation of the CCR5 protein. The homozygous CCR5 mutation is created when its gene contains a 32 base pair deletion. The lack of this base pair then causes a shift in the reading frame. The protein is truncated and cannot reach the cell surface. The overall result is that it slows the progression of HIV-1 into AIDS. (3)

This mutation can be very useful to the medical world. Now that scientists have gained knowledge as to how HIV-1 enters the body, several hypothesis have been made as to how to prevent it. Working with CCR5, scientists believe that if they can block the joining of CCR5 with the HIV virus they can slow down the onset of AIDS. Blocking CCR5 is not dangerous to the immune system because other chemokines take its place. The problem is how one would go about the blocking. (2) The CCR5 defect cannot simply be injected into the body. One must be born with it. Scientists and researchers have been forced to consider other options. One possible option could be to block CCR5's binding site for HIV. Another possibility would be to insert synthetic antibodies which would specifically home to CCR5 and block the HIV's attachment. Another method being entertained is to vaccinate people with part of the CCR5 protein that would induce the person's immune system to create CCR5 antibodies. (3). Researchers are also looking at the possibility of using their knowledge of CCR5 to helps patients who have already developed AIDS. They are debating whether or not they should destroy all HIV infected cells in a person, through chemotherapy or radiation, and then give the patient bone marrow from donors who have the homozygous CCR5 protein. (3).

The research involving CCR5 does not provide immediate answers. There are still many problems with it. The proposals being suggested are just in the testing stages. Researchers are still not exactly how one would make an antibody for CCR5 or what the repercussions of a vaccination would be. The problem with chemotherapy it is that the procedure is not guaranteed to work and there are severe side effects. Once chemotherapy is completed there is no guarantee that the body will accept the bone marrow with the homozygous protein. (2)

Research relating to CCR5 is still in progress. There are problems that have to be dealt with. For one thing a homozygous CCR5 protein does not guarantee immunity from HIV. There have been cases where persons with the mutated protein were infected with HIV that immediately went to the T-tropic phase and did not go through the M-tropic phase.(4)(4) Another problem is that such a small percent of the population has this mutated protein. So far only a small percentage of persons of European descent have been found to have it. Communities in places such as Africa and Asia, where there are widespread AIDS epidemics, have not been found to have the homozygous protein chemokine.

Despite the fact that a cure has not been found yet, the knowledge gained through CCR5 research provides scientists with a starting point. The concept of interfering with chemokines and the retrovirus guides researchers in a new direction. Previously unconsidered options such as HIV pathogenesis and combat strategies are being looked at. (4). Now that researchers know that it is the chemokine receptor that allows HIV-1 to enter the cell they can focus on chemokine behavior, and the role receptors such as CCR5 play in inhibiting viral signals. (4) The fact that the homozygous CCR5 receptors are found only in people of Caucasian descent is unfortunate in that large communities lack this "advantage". But it is useful in that because it leads researchers to believe that the genetic mutation might be a result of a protective response to another pathogen. This means that we might be able to look at immunities to other viruses as possible sources for a solution. (4)

The study of homozygous CCR5 and the role it plays in preventing HIV is great progress in the battle against AIDS. For the first time scientists have identified genetic resistance as a way to combat HIV. The discovery of chemokine receptors for HIV-1 has opened the door for new research. It has provided researchers with new ideas as to how approach the problem. This research has also been the cause of controversy. Because so little is known about the disease, yet the need for a cure is so urgent, the medical community has gone into somewhat of a panic. Everyone is search of a solution, but no one is exactly sure where to start looking. Many researchers have not accepted the ideas that mutated CCR5 could be possible link to the solution. A big problem with AIDS research is that it is costly. The trial medications that researchers come up with are not without their side effects, and are not available to the general public. This and the lack of progress has frustrated many.

Perhaps it has been the public that has been the harshest critic of all. AIDS has just recently become a publicly discussed topic in our society. Previously ignored, because "only gay men had it", or because "only poor people in Africa contracted it", it is only now that there has been widespread education about it. Society is quick to attack new progress made in medicine because it seems to be going no where, while the death toll is rising rapidly. We are in desperate need of a magic solution and science is not providing us with it. It is this attitude, along with the disease itself, that medicine has had to combat. Therefore while one has to realize that the mutated CCR5 protein is not magic solution to AIDS, it is very important to realize the significance it holds for the battle against it.

WWW Sources

1)The Center for Disease Control

2)What is CCR5? , University of Arizona Biology Website

3)The Scientific American Website, Article on AID Resistant Genes

4)The Act Up Organization Website ,

5)Medical Sight on "Chemokines and HIV Second Receptors" ,

6)HIV Insite Website

7)AIDS Weekly Plus,

8)Memorias de Instituto de Oswaldo Cruz,

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