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The Connection Between Bubonic Plague and Hiv Resistance

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The Connection Between Bubonic Plague and HIV Resistance

When the name Yersinia pestis (Y. pestis) is mentioned, most know it to be the cause of the Bubonic Plague. The last thought is that this bacterium could be in anyway linked to a resistance to Human Immunodeficiency Virus (HIV). Nor is there a thought that HIV has a possible link with the Variola Major Virus, which causes Small Pox. Nevertheless, there are geneticists who agree and disagree with both theories. One such geneticist with the National Institutes of Health that believes in a connection between Y. pestis and HIV resistance is Dr. Steven O'Brien, who studied why some individuals who were exposed to the plague either recovered, or never became ill. His curiosity and that of others led him to find an abnormal version of the gene known as CCR5. A mutation called delta 32 showed it provided those exposed to the plague a form of protection. When doing his research, he found that a good majority of those survivors had to be carriers of the delta 32 mutation in order for them to have survived, and following this theory believed that they must have passed this genetic anomaly onto their offspring. O'Brien was following a theory that because England alone was besieged by plague on and off for approximately 300 years he understood the way Y. pestis is spread and that the bacteria should have killed more of the population than it did.

To understand what and how CCR5-delta 32 works, not only in a cell but also in conjunction with HIV infection an explanation is necessary. HIV is a retrovirus. An enveloped RNA virus that is duplicated in a host's cell using an enzyme called reverse transcriptase. This enzyme helps make DNA out of an RNA genome. The DNA is then incorporated into the hosts DNA with the help of another enzyme called integrase. From there on the virus is replicated as part of the host cell's DNA. In order for one to have HIV, three things must be in play. First, the person must have a decreased CD4 count, and an opportunistic infection must be present and finally there must be the presence of the virus. AIDS is an immunodeficiency disease that is caused by HIV. This disease has been in the public eye for more than two decades, and as of December 2001, over 40 million people are infected worldwide with either HIV or AIDS (13). Many research hours have been spent trying to find a cure for this virus. For Dr. O'Brien his search was personal because he lost his brother to AIDS in 1996. I too found his theory interesting because my brother also died of AIDS in 1994. The virus attacks the patients T-cells because it has sites on it to which the virus can bind. As shown in picture 1 these sites

allow HIV to enter the T-cell and replicate by using the CD4 and CCR5, protein receptors that protrude out of the surface of the T-cell. In picture 2, you will see the CD4 and CCR5 protein receptors that protrude off the surface of a macrophage, the large white blood cells that can engulf and kill viruses and bacteria within the immune system. The GP-120 protein on an HIV virus must first bind loosely to the CD4 protein, and then secures itself to the T-cell by binding to the CCR5 receptor. Without this second binding, the virus does not bind closely enough to infect the T-cell. The recent discovery of the mutation in the CCR5 protein shows that the alteration of the structure prohibits the binding of HIV. As Dr. Barbara Goldrick said, "The CCR5 gene encodes the CD4 T-lymphocyte surface receptor for chemokines and it serves as a coreceptor for HIV-1, providing a molecular gateway where the virus can invade the cell. The delta 32 deletion mutation reduces cell surface expression of CCR5 thus protecting the cell against the virus" (1).

Consequently, like HIV, the bacterium responsible for bubonic plague also attacks macrophages. Y. pestis binds to the membranes by attaching to the cellular surface and injecting toxins into the cell via the Type Three Secretion System (T3SS), a protein appendage found in several gram-negative bacteria, and the toxins secreted restrict the cells' vital role in ordering the body's immune response to attack (3).

Therefore, to understand where Dr. O'Brien first got this idea he went back to his original research and used his theory of a connection between the delta 32 mutation and Y. pestis being an inherited trait. He then decided he needed to track down some of the surviving descendants of the bubonic plague. He used his original theory and found the small mountain town of Eyam, England. This town had the largest population of survivor descendant's in one area. He also chose Eyam because in the 1600s this small mountain village closed their gates from the rest of the community to prevent further spread of the plague that had taken root in their town. O'Brien found that those who were direct descendants of the plague victims of 300 years ago still living in Eyam had a 14 percent mutation of the gene known as CCR5. Dr. O'Brien stated, "This is a high percentage in genetic terms" (2). So why does a defective gene for CCR5 make HIV unable to spread in the blood? The answer is simple, because without that CCR5 protein receptor, the virus cannot bind and infect the T-cells and macrophages.

O'Brien's research found convincing evidence that pointed to a connection between the delta 32 mutations and HIV resistance from inherited genes passed down by survivors of the bubonic plague in Europe. He found that resistance to HIV varied according to the number of mutated CCR5 genes inherited, but if a person was to obtain two mutated CCR5 genes then they were immune to HIV. However, someone who has only one mutated CCR5 gene would be resistant to HIV but not necessarily immune. The research showed that the person with one mutated CCR5 gene who became infected has a slower course of infection than someone without the mutated delta 32 gene.

An example of someone who obtained two mutated CCR5 genes is a man named Steve Crohn. He is not only homosexual, but repeatedly was exposed to HIV and is not infected. Dr. O'Brien used the results obtained by another researcher named Bill Paxton of the Aaron Diamond Center for AIDS Research in New York. Paxton took samples of Crohn's immune cells and then "bombards these cells with 3,000 times the amount of virus that typically causes infection" (2), but the virus could not penetrate his immune cells. With further genetic testing Paxton showed that Mr. Crohn had not just one but two copies of the delta-32 mutation, the same mutation found by that of Dr. O'Brien with the population of Eyam and their 14 percent mutation rate in descendants of bubonic plague survivors. Following this discovery, many geneticists began looking for a way to isolate this mutation in the hopes that they could



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