article Fall 2016

HIV: The Master of Mutation

By Edwin Neumann

Viruses have been around for eons — possibly close to 3.5 billion years, according to many scientists. Some viral proteins even predate the divergence of life into the three domains: bacteria, archaea (ancient bacteria), and eukarya (plant, animal, and fungus cells). These ubiquitous microbes, which are not classified under any of the domains, have stood the test of time where a myriad of other life forms have long since gone extinct. This suggests rapid evolution has enabled viruses to endure all the challenges and catastrophic events in Earth’s history. Viral evolution is essentially Darwin’s theory of natural selection condensed into a much shorter time scale than what we typically imagine.

Humans have learned to prevent infection from dangerous viruses with the development of vaccines. Vaccines were first widely used to stop and eventually eradicate smallpox. An English physician named Edward Jenner observed that milkmaids would never get smallpox, however, since they worked closely with cows, they often contracted a milder illness called cowpox. This led to the discovery that people who were inoculated with the cowpox virus became immune to smallpox. In fact, the word “vaccine” was derived from vacca, which is Latin for cow. Unfortunately, sometimes vaccines simply aren’t enough in situations where the virus evolves at an absurdly rapid rate. This is the case with the infamous Human Immunodeficiency Virus (HIV).

Dr. Matthew Reynolds is an associate scientist in the UW-Madison School of Medicine and Public Health’s Department of Pathology and Laboratory Medicine. Dr. Reynolds specializes in HIV research and has received a $2 million grant from the National Institute of Health (NIH) to study and take on the onerous task of disease prevention research. To put prevention efforts into perspective, think about the flu. Influenza is widespread and infects many different species. The flu virus’ genetic drift (the random fluctuation in genetic makeup of a population) forces us to get a new flu shot each year. However, when the virus jumps from one species to another in a genetic shift (as is the case with swine or avian flu), an entirely new flu vaccine has to be created. Although this seems like a pretty major nuisance, it pales in comparison to HIV. According to Dr. Reynolds, “Approximately the same amount of diversity occurs in one individual with HIV as occurs worldwide in influenza in a single year.” This is astounding, and it means the virus is mutating extremely fast.

The culprit behind the frightening mutation rate of HIV is an enzyme called reverse transcriptase, which was discovered by Nobel Prize-winning scientist Howard Temin at UW–Madison in 1970. This enzyme is responsible for producing DNA from an RNA template as opposed to the ordinary transcriptase that makes RNA from a DNA template. Most life forms use transcriptase, but retroviruses such as HIV use reverse transcriptase. They integrate the new DNA into the host cell’s genome while the cell translates and transcribes as usual, generating viral proteins along with its own. However, this is where HIV’s signature variability occurs. “Going from RNA to DNA with reverse transcriptase is very error-prone… [the virus’s replication process] makes a mistake about once every 10,000 base pairs while ours only makes maybe one in a billion. It just turns out the HIV genome is about 10,000 base pairs long, so every new virus that’s made has one mistake,” Dr. Reynolds says. Most of these mutations will be detrimental to the virus, but some will be beneficial. “All it takes is one little change to make a big effect. When [HIV] is making millions if not billions of viral copies every day…evolution is going to be happening really quickly,” Dr. Reynolds explains. Thus, traditional vaccines may be a hopeless endeavor against HIV. The virus will mutate so the immune system can no longer recognize it as it continues to infect the Helper T-Cells that make up the human immune system. These immune system cells will dwindle to lower levels until the disease degenerates into AIDS. Individuals with AIDS are thus left with a very thin line of defense against common pathogens — and even commonplace illnesses such as the cold or the flu may become deadly.

With standard HIV vaccines rendered useless by the virus’s rapid mutation and antiretroviral drugs being met with more and more resistance from the virus, alternative HIV prevention methods must be pursued. The solution may lie with something called alloimmunity, or immune recognition of different cellular proteins derived from the same species. An example of this type of immune response is an attack on a transplanted organ that doesn’t quite “match” the patient. Researchers in the late 80s thought they had discovered a true HIV vaccine, but further experimentation revealed that their results were due to an alloimmune response against major histocompatibility complex (MHC) molecules. “It turns out there is more MHC from the [infected] cell on the virus than there are actual virus proteins,” Dr. Reynolds says. Much like blood types, everyone has one of a few “flavors” of MHC molecules in their bodies. Antibodies will attack foreign MHC proteins, so different variants of MHC could be incorporated into the outer coatings of HIV as it buds off from infected cells.

Alloimmunization as a new prophylactic vaccine for HIV/AIDS provides a way around the incredible variability of the virus. “MHC is always going to be a part of us; it’s never going to change…that’s the attractive part of it,” Dr. Reynolds says. Since the immune system would be targeting MHC proteins on the virus rather than the virus itself, it can essentially operate independent of any viral mutation. These vaccines would be tailored to specific regions of the world to accommodate the different MHC varieties that commonly appear there, and they could then be distributed to high-risk areas like sub-Saharan Africa. However, there is a drawback to this work-around; having a lot of anti-MHC antibodies would make it more difficult to receive organ transplants. Research regarding these alloimmunity vaccines is only in its beginning stages, but there is evidence that it would work despite these obstacles. For instance, pregnant women and people who have a lot of blood transfusions, such as those with sickle-cell anemia, have elevated anti-MHC antibody levels, and this has been linked with antiviral properties in cell culture studies.

Dr. Reynolds and his lab team are currently working on this HIV prevention research and have even had another NIH grant approved that focuses on finding a way to actually cure HIV altogether. This is based on the fluke case of Timothy Ray Brown, who is the only person ever to be completely cured of the disease.

HIV is an extraordinary example of evolution, and it is the most mutation-prone virus known. Finding a way to prevent and cure a terrible disease like HIV will improve global health significantly and change the way modern medicine deals with emerging deadly viruses.

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