Friday, December 16, 2011

Hope for an HIV Vaccine

In 1984, the Health and Human Services Secretary declared that extensive research for a vaccine protecting against Human Immunodeficiency Virus, a virus that ravishes the immune system of its host, would be available in two years. Almost three decades and one billion dollars later, scientists have still not been able to develop a vaccine that can successfully protect against the virus. The reasoning for these difficulties revolve around HIV's ability to rapidly mutate, making it near impossible for the immune system to mount an effective response (class notes, 12/8/2011).
During a normal immune response, an immune system cell called a B-cell makes antibodies, a protein that neutralizes specific proteins on a pathogen called antigens, preventing it from infecting the host. When a person gets vaccinated against a pathogen, their immune system is being given a form of the pathogen that does not have the ability to infect the host. This form of the pathogen allows the host's immune system to prime itself against the virus, which includes the creation of antibodies, so that when the host comes in contact with the infectious form of the pathogen, the antibodies will be waiting ready to stop the it.
However, the problem with HIV is not that it stops the body from making these antigens, but that it mutates so quickly that it is able to circumvent the antibodies. When an antibody is made, it will bind to a specific part of the outside of the pathogen, but once antibodies against HIV are made, the virus has already changed its external characteristics such that the antibody cannot bind to the virus and neutralize it. This is the main reason why making a vaccine against HIV has been so difficult.
Instead of injecting mice with parts of the virus in hopes of causing the creation of antibodies against HIV, Alejandro Balazs used a technique called vectored immunoprophylaxis (VIP). This involves inserting DNA for an HIV antibody into a virus known to be harmless to humans, called adeno-associated virus (AAV), and then injecting this virus into the host's muscle, in the hopes that it will cause the host to make antibodies that will neutralize HIV. These scientists injected VIP into mice and found that the mice were fully protected against the HIV virus.

Scientists had tried using this technique before, but found that the immune response was not strong enough to stop the virus. Therefore, Balazs tested whether changing the proteins on the outside of the adeno-associated virus would cause a more effective immune response. They altered the virus by adding either luciferase or 4E10 HIV neutralizing antibody, and after injecting it into mice, found one week later that their blood had a detectable amount of antibodies in it. They then took DNA from HIV infected individuals and put the part of the DNA that causes the creation of HIV antibodies (referred to as b12) into these new AAVs and injected these into mice. The mice made 100 times more antibodies than were seen in mice injected with the old AAVs.
They then tested to see if the b12 antibodies created by these AAVs would be effective at combating the HIV virus. First, mice whose immune system are composed of human immune cells were injected with either a luciferase AAV without the b12 antibody DNA or a luciferase AAV with the b12 DNA. They were then exposed to HIV and the amount of CD4+ T cells in their bodies were counted. CD4+ T cells are the immune cells that the HIV virus attacks, so a depletion of these cells would mean that the HIV virus was infecting the mice. They found that the mice given the AAV with the b12 antibody had no loss of CD4+ cell, while the other group of mice had a drastic loss of CD4+ cells. This result suggested that the AAV with the b12 antibody was effective at protecting against the virus. To test how effective this AAV was at halting HIV, the same procedure was done but with other known HIV antibodies: 2G12, 4E10, and 2F5. After injection of each of these antibodies, the amount of CD4+ cells was counted weekly, and it was seen that there was a decrease in CD4+ cells when using those antibodies, but no decrease when using the b12 antibody. This showed that while the other 3 antibodies partially protected the mice from HIV, the b12 antibody completely protected the mice. Then, it was shown that in order to deplete CD4+ T cells in mice given the b12 AAV, they needed to be injected with 100 times more HIV virus than needed to deplete CD4+ T cells in seven out of eight control mice.
These results suggest that the b12 AAV not only provided protection against HIV in humans, but that it would provide a greater level of protection than would be needed to effectively combat the disease. These results provide hopeful evidence that a vaccine protecting people against the HIV virus is possible. However, humans are not mice, and while these results seem promising, many times vaccines that provide protection in model organisms do not do the same in human recipients. It is also known that people whose immune systems are naturally able to combat the HIV virus make cells called cytotoxic T cells that are able to kill host cells infected with a virus. Since the VIP used in this research does not cause the immune system to create these cells, it may not be as effective in combating the HIV virus as a vaccine that does elicit their production.

Balazs A. B., Chem, J., Hong, C.M., Rao, D.S., Yang, L., Baltimore, D., 2011. Antibody-based protection against HIV infection by vectored immunoprophylaxis. Nature, 1-4.

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