How Plagues of the Past are Helping Scientists Cure HIV

Serious plagues consistently swarmed the globe for much of human history. The past prevalence of these diseases plays an important role in the health of humans today and even contains secret keys to discovering a potential cure for HIV. This article explores how past epidemics enable some Europeans to carry a gene mutation that enables them to be HIV resistant or immune. It is important to promote awareness and research in this area, because this field is currently enabling us to be closer than ever to actually finding a cure for HIV and AIDS.

CCR5 Delta 32 is the name of the mutation that shows up in Northern European populations and enables individuals a certain immunity to HIV. Modern scientists are now trying to manipulate it in gene therapy in an attempt to create artificial immunity in people today. But where does this mutation come from, and why does it specifically show up in Northern European populations? What is clear is that plagues of the past somehow caused pressured selection in populations, which enabled the gene to show up more readily in subsequent populations. For example, if the mutation enabled people to survive epidemics in the past, then obviously those survivors would be most likely to live and pass that mutation on to their children, while those who did not have the mutation were more likely to die out. It is estimated that the delta 32 mutation was once found in 1 in 20,000 individuals, and that over the course of thousands of years this pressured selection caused it to become increasingly frequent in populations. Today, it is estimated that in Finland and Sweden (where the mutation is believed to have originated) as many in 1 in 10 people carry the mutation. 1% of the overall European population carries two copies of the mutation. This means that the mutation was inherited from both parents and those individuals would actually be immune to HIV. Up to 20% of the European population carries one copy of the mutation, meaning that it was inherited from one parent, and that these individuals are resistant to HIV. They are able to contract the virus, but their bodies do exceptionally well in handling it and they have a very good prognosis, even without medication (Cohn, 2005).

Many scientists and the media have given credit largely to the Black death, caused by Y. Pestis as the main culprit for creating this mutation. Scientific historians point out that this is actually unlikely for a number of reasons, and say that the mutation most likely comes from other plagues. It was originally believed (back in the late 90s) that because Black Death was so prevalent in Northern Europe, this caused the bottle neck of pressured selection, resulting in a high incidence rate of the mutation in those populations. However, historians point out that the black death was actually much worse in other places, like the Mediterranean and Asia, and that in these areas the mutation is not present. Also, in mice experiments it is clear that having the mutation does not actually keep one from dying of Y. Pestis. Afterall, Y.Pestis is a bacteria and not a virus like HIV. Interesting to note is that delta 35 DOES prevent people from catching smallpox (also a virus), which also came in waves to humanity over the course of thousands of years: dating back considerably further than the black death plagues which occurred AD (Cohn, 20015).

“Geneticists, archaeologists and physical anthropologists are revising the conclusions drawn in the late 1990s; they are now finding ancient DNA with the mutant gene CCR5-Δ32 in skeletal remains in northern Europe as early as 2900 years ago. Some have estimated its age at 5075 years, and have argued that ‘the high frequency of the allele cannot be attributed solely to a strong selective event within the past millennium’.”

While we may have heard in the past through numerous media outlets that the Black death was responsible for modern HIV immunity. Scientists now have evidence to believe that this mutation does not come from an event that occurred in the last thousand years. Instead, this very old mutation is something that resulted from pressured selection over the course of thousands of years.

“Maybe smallpox is the reason. Smallpox killed 3 in 10 infected people for thousands of years in Europe. Recent studies suggest that smallpox, like HIV, can't infect someone with the CCR5-delta 32 mutation. (Staar 2004)”

Understanding how the mutation works in the cell opens the door to modern implications in gene therapy. CCR5 is a protein on a normal human cell, and it essentially functions as a lock for HIV, which has a key to open that protein and access to the cell inside. Once a cell is infected with HIV the virus replicates inside of that cell, and eventually explodes infecting other cells with its copies. The CCR5 Delta 32 mutation changes the regular version of CCR5, so that HIV and some other viruses (like Smallpox) cannot access the cell any longer. In a sense, the mutation changes the lock and HIV no longer has the key.

You may have heard of the Berlin patient, Timothy Brown. Brown is now famous as the gold standard of HIV treatment. At the time of his life altering treatment he was extremely sick from AIDS and cancer. He received a bone marrow transplant from a donor who carried both copies of CCR5 Delta 32, and within time the virus was completely eradicated from his system. Keep in mind that blood cells are created in the bone marrow, and so by receiving donor marrow his body began to produce cells that had the mutation. This caused a surge of hope among doctors and patients all over the globe, because it showed the promising potential that CCR5 Delta 32 has to potentially cure AIDS and HIV. Unfortunately, this was not an instant solution. A bone marrow transplant is extremely hard on the body and it is considered to be a high risk procedure that is only performed under extreme circumstances. Timothy had cancer, and this was the reason that he actually needed the dangerous procedure. Doctors cannot simply begin giving everyone with HIV a bone marrow transplant form a CCR5 Delta 32 carrier and hope for the best.

Since this form of inserting the mutation into a patients cells is too invasive and dangerous, the job of modern scientists and doctors is to figure out how they can insert this age old mutation into the cells of the majority of people who are not born with it. There are many on going experiments attempting to understand how this can be done with gene therapy.

“CCR5 is the Achilles’ heel,” said Dr. Paula Cannon, a University of Southern California stem cell researcher and a member of defeatHIV. “You can take out people’s cells, take out CCR5 and pop the cells back in – their own cells, but an improved version that’s now resistant to HIV.” (Engel 2014)

Currently, scientists have had some success with what is called a viral vector. This means they infect the immune system with a harmless virus that acts as a gene delivery system for the mutation. At this point scientists are not confident that this kind of work will result in a sterilizing cure like Timothy Brown saw, however they are hopeful that it is the key to a successful future of HIV treatments. Timothy Brown's case was very complicated and he was undergoing a series of treatments. While it is clear that the bone marrow transplant was the game changer, it is unclear how the other numerous treatments he underwent at the time also came into play. While this kind of therapy is still in its trial phase, it is probably the most hopeful candidate that we have for actually curing HIV. However, these trials are being done slowly and cautiously and so it could be a a few years before we start seeing definitive results, or before we have these treatments available to humans.

The story is not yet complete and there are still a lot of questions that remain unanswered. While we are still not totally sure of the origins of the mutation, we know that it is something deeply rooted in our history that was caused by the plagues our ancestors once regularly faced. Today, this mysterious mutation holds the key to treating the most prolific plague of our times; HIV. Scientists are hard at work to try and understand how we can safely use Delta 32 to help patients who are not born with it. We aren't there yet, but the findings are so far optimistic. In a few years time we may have some of the long sought after answers that we have been looking for since AIDS surfaced in 1980.

Sources:

Engel, Mary. "HIV Cure Research Today: Gene Therapy, Molecular Scissors and Where’s Waldo." Fred Hutch. N.p., 14 Aug. 2015.

University Of Liverpool. "Biologists Discover Why 10 Percent Of Europeans Are Safe From HIV Infection." ScienceDaily. ScienceDaily, 3 April 2005.

Cohn, SK. "The Black Death and AIDS: CCR5-Delta32 in Genetics and History." National Center for Biotechnology Information. U.S. National Library of Medicine, n.d.

Starr, B. "Understanding Genetics." Understanding Genetics. Stanford, 2014. Web. 03 May 2016.

Pappas, Stephanie, and LiveScience. "Black Death Survivors and Their Descendants Went On to Live Longer." Scientific American. N.p., May 2014.

Reardon, Sarah. "Gene-editing Method Tackles HIV in First Clinical Test."Nature.com. Nature Publishing Group, Mar. 2015.