One Large Plague Against Humanity, One Small Step Towards Immunity

By: Linda Huang, Shivani Seth, Shawn Kripalani, Anasua Bandyopadhyay and Nikita Maddineni

Imagine you’re living in the middle ages welding steel swords, leading your mundane life. Suddenly, your child is overcome with a horrid fever. Distraught, you also start to notice your child developing shockingly large lumps all over his body. What is going on? Soon, you learn that this nightmare is not only endangering your son’s life, but also the communities around you. Two weeks later, everyone around you has passed away, but for some reason you managed to survive. Why?

This so-called curse was actually known as the Black Plague that spread throughout Europe. The black death killed 75 to 200 million people and it peaked in Europe between the years of 1346 and 1353. It began with a rat infected with the bacterium Yersinia pestis. The bacteria infect humans by attacking the lymph nodes. They then begin to rapidly replicate, causing the lymph nodes to swell and become buboes. These buboes cause the immune system to go into septic shock, which is multiple-organ failure. This was one of the darkest points of European history, as 30-60% of Europe’s total population was killed. The methods of treatment ranged from visiting witch doctors to bathing in urine to turning to the church. Communities even started to live in the sewage systems after they became aware that it could be airborne. However, there was a small percentage of the population that was able to survive the plague.  In the population that survived, researchers found that there was a mutation in the gene for the CCR5 cell membrane receptor called CCR5-∆32.

This is an example of natural selection, where the bubonic plague acted as the selection pressure for individuals with the mutation. These individuals with the delta-32 mutation had a higher fitness because they were able to survive and reproduce better compared to individuals who were susceptible to the black plague.

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Figure 1: Top map shows regions of Europe during the black plague where the CCR5-∆32 mutation was present vs. regions where it was not present. Bottom map shows regions of Europe that were affected by the Black Plague vs regions that were not.

Coincidentally, research has shown that this mutation can also provide protection against HIV infection. In order for HIV to enter cells, the CCR5 receptor must be present on the surface of the cell. However, in individuals with the CCR5-∆32 mutation, the CCR5 receptor is not present on the cell membrane. Due to this mutation, individuals are resistant to HIV. This relationship between HIV and the CCR5-∆32 mutation is a way to debunk the misconception that all mutations are detrimental. In this case, having the mutation leads to increased fitness.

The protective effects of the CCR5 delta32 mutation against HIV infection are also being investigated as a potential long-term treatment option. Currently, antiretroviral therapy (ART) is the most widely used treatment for HIV, consisting of a combination of drugs that suppress progression of the disease and for reduce rates of transmission. However, ART is not a cure and individuals must rely on daily drug regimens for the entirety of their lives. Furthermore, the virus can eventually develop resistance to ART, leading to a need for more long-term treatment options.

In 2009, Hutter and other researchers identified an innovative approach using stem-cell transplantation. In a case study, a patient had HIV infection for ten years and acute myeloid leukemia. Researchers performed a stem-cell transplantation from bone marrow from an immune-compatible donor whose cells lacked expression of CCR5. The donor, who was homozygous for the CCR5 delta32 mutation, was resistant to the HIV infection. Researchers hoped that transplanting these cells with the mutation to the HIV-infected patient would confer resistance. After two transplantations, there was no recurrence of leukemia or detectable HIV in the bloodstream. The CD4+ T-cells in this patient have returned to the normal range and all carry the donor’s CCR5 gene. This patient has remained without any evidence of HIV infection for more than 8 years after discontinuation of ART, providing encouragement for stem cell transplantation as a more long-term treatment for HIV.

Normal cell that has the CCR5 receptor. HIV can enter and infect the cell.

Figure 2A: Normal cell that has the CCR5 receptor. HIV can enter and infect the cell.

Figure 2B: Mutated cell without the CCR5 receptor. HIV is not able to enter and infect the cell, thus making the individual immune to the virus.

Figure 2B: Mutated cell without the CCR5 receptor. HIV is not able to enter and infect the cell, thus making the individual immune to the virus.

To learn more:

Petz, L.D., et al. 2015. Progress toward curing HIV infection with hematopoietic cell transplantation. Stem Cells Cloning 8: 109-116.

Cohn, S.K., & Weaver, L.T. 2006. The Black Death and AIDS: CCR5-Δ32 in genetics and history. Q J Med 99: 497-503.

Allers, K., et al. 2011. Evidence for the cure of HIV infection by CCR5Δ32/Δ32 stem cell transplantation. Blood 117(10): 2791-99.

Galvani, A.P., & Slatkin, M. 2003. Evaluating plague and smallpox as historical selective pressures for the CCR5-Δ32 HIV-resistance allele. PNAS 100(25): 15276-79.

Shariff, Mohammed. “10 Crazy Cures for the Black Death- Listverse.” List verse. N.p., 21 Jan. 2013. Web. 06 Dec. 2015.

Libert, F., et al. 1998. The CCR5 mutation conferring protection against HIV-1 in Caucasian populations has a single and recent origin in Northeastern Europe. Human Molecular Genetics 7(3): 399-406.

Stumpf, M.P., & Wilkinson-Herbots, H.M. 2004. Allelic histories: positive selection on a HIV-resistance allele. Trends in Ecology and Evolution 19(4): 166-8.

Hutter, G., et al. 2009. Long-Term Control of HIV by CCR5 Delta32/Delta32 Stem-Cell Transplantation. New England Journal of Medicine 360: 692-698.

The Sad History of HIV and its Persistence against Drug Therapy

Contributed by Oliver Ting, Jackson Fritz and Milan Patel

According to a report from the World Health Organization, human immunodeficiency virus (HIV) infected about 2.7 million new people in 2010 alone. Broken down, HIV destroys the immune system in humans, allowing opportunistic diseases to come in and kill the patient. HIV spreads through bodily fluid from person to person. Once inside a patient, HIV targets certain cells within the immune system called T-cells. HIV forces these cells to create new copies of the virus and destroys the T-cells in the process. As the virus grows exponentially, the immune system loses its ability to fight other diseases, leading to acquired immune deficiency virus (AIDS).

HIV cannot be cured. The main problem in creating a drug that treats HIV is that the virus is constantly changing. HIV is a retrovirus, meaning it uses RNA and then converts that into DNA when it infects cells. Retroviruses use an enzyme called reverse transcriptase to do this. However, unlike DNA enzymes, this enzyme cannot proofread itself, allowing more mutations (changes in the genetic code) to occur. This causes the virus to produce a base mismatch roughly every 10, 000–30, 000 bases during the replication. This differs significantly from regular viruses that typically have a range of one base mismatch per one million to one billion base pairs. When these base mutations occur in specific regions of the HIV DNA, new types or subtypes of the virus can be created. HIV builds up drug resistance because a drug that was effective for a previous variation of HIV may not be effective against a new variant of the virus. In addition, the virus builds cross-resistance, and becomes resistant to multiple types of HIV drugs within the same class. This further limits the number of drugs that can be used to treat the virus.

HIV is a prime example of evolution in action. HIV’s high rate of DNA mutation creates many variants. When HIV is selected against through antiviral drugs, certain variants survive that are resistant to the drug. These drug-resistant strains of HIV survive to reproduce and can be transmitted to other individuals. This constantly changing HIV population produces a substantial obstacle in trying to treat and eradicate the virus. Continued research is required to combat this evolving virus and improve the quality of life of those affected by HIV and AIDS.

Inspired by Radiolab “Patient Zero”, a fascinating tale about how HIV began, where it came from, and who “Patient 0” may have been. The podcast further reinforces how the virus has been able to combat so many challenges to its existence as well as it has.

Further Reading:

Bao, Yi, et al. “Characteristics Of HIV-1 Natural Drug Resistance-Associated Mutations In Former Paid Blood Donors In Henan Province, China.” Plos ONE 9.2 (2014): 1-9.

Bennett, Diane E . et al. “Drug Resistance Mutations for Surveillance of Transmitted HIV-1 Drug-Resistance: 2009 Update.” Ed. Douglas F. Nixon. PLoS ONE 4.3 (2009): E4724.

Sanjuan, R. et al. “Viral Mutation Rates.” Journal of Virology 84.19 (2010): 9733-748.

Shilts, Randy. And the Band Played On: Politics, People, and the AIDS Epidemic. New York: St. Martin’s, 1987.

HIV/AIDS and the Evolution of Drug Resistance

Contributed by June Tzu-Yu Liu, Akanksha Samal and Amy Jeng

“Currently, the CDC estimates that more than 1.1 million people in the United States are living with HIV infection and around 180,900 people are unaware that they are infected. It has been observed that people diagnosed with HIV are increasing annually, around 50,000 new incidences per year.”  –

What is HIV? What is AIDS?

HIV (Human Immunodeficiency Virus) is a retrovirus that attacks the human immune system, more specifically, CD4+ T cells. These cells are essential components of the body’s defense system against infections and diseases. HIV invades T cells, uses them for replication and destroys them. The terms HIV and AIDS are often used interchangeably, however there is an important distinction. HIV is the name of the retrovirus that invades cells, while AIDS (Acquired Immunodeficiency Syndrome) is the most advanced stage of the HIV infection. People with healthy immune systems are able to fight off infections, however, people with HIV have compromised immune systems and are highly susceptible to opportunistic infections. Opportunistic infections refer to infections that do not cause serious health threats in healthy individuals, but cause life threatening illnesses in HIV positive individuals.

How does HIV replicate?

HIV mainly targets the T CD4+ cells in our bodies. When HIV enters the host, it binds to receptors on the surface of T cells. It is analogous to using a key to unlock a door. If the HIV has the right key, it can fuse with the T cell and release its genetic material into the cell. The genetic material in HIV is RNA, thus it must change its genetic material into DNA so that the host cell can replicate the genetic material. An enzyme called reverse transcriptase changes RNA into DNA. The virus’ genetic material can now integrate with the host’s. The host cell will unknowingly replicate the virus’ genetic material. Then, the virus will push itself out of the host cell, killing it in the process.

Drug Resistance?

There is high genetic diversity in HIV because of its rapid replication and high mutation rate. Currently, doctors are using a combination of different antiretroviral drugs to inhibit various steps in the HIV life cycle, leading to a synergistic effect. One major drawback to this approach, however, is drug resistance.  Scientists have found that using antiretroviral therapy (ART) increases the rate of drug resistance. According to a case study from China, prevalence of drug-resistant variants in therapy patients increased significantly to 45.4% in three months and 62.7% in six months. Alarmingly, drug resistant variants can replace the wild type variants completely within 14-28 days of treatment. Similar results were found in a case study in South Africa in which a large percentage of patients who did not respond to treatment harbor viruses with drug-resistance mutations. The effectiveness of therapeutic regimens to control the HIV pandemic are compromised due to drug resistance.

A common misconception is that evolution is a chance event. Evolution of HIV is not a chance event; it is driven by drug selective pressures. Also, organisms are commonly perceived as  getting “better” through evolution. The HIV virus isn’t getting better. It’s becoming more adapted to it’s environment. Resistant HIV is not “better” than the non-resistant strains. They have just evolved to be better suited for their environment.

For more information please see the following papers:

Hegreness, M. et al. 2008. Accelerated evolution of resistance in multidrug environments. Proceedings of the National Academy of Sciences of the United States of America 105 (37): 13977-13981.

Li, J.Y., et al. 2005. Prevalence and evolution of drug resistance HIV-1 Variants in Henan, China. Cell Research 15: 843–849.

Mammano, F., et al. 2000. Retracing the Evolutionary Pathways of Human Immunodeficiency Virus Type 1 Resistance to Protease Inhibitors: Virus Fitness in the Absence and in the Presence of Drug. Journal of Virology 74 (18): 8524-8531.

Mansky, L. M. 2002. HIV mutagenesis and the evolution of antiretroviral drug resistance. Drug Resistance Updates 5 (6), 219-223.

Marconi, V.C. et al. 2008. Prevalence of HIV-1 Drug Resistance after Failure of a First Highly Active Antiretroviral Therapy Regimen in KwaZulu Natal, South Africa. Clinical Infectious Diseases 46: 1589-1597.

Peeters, M., et al. 2002. Risk to Human Health from a Plethora of Simian Immunodeficiency Viruses in Primate Bushmeat. Emerging Infectious Disease 8: 451-457.

Sarkar, I., et al. 2007. HIV-1 Proviral DNA Excision Using an Evolved Recombinase. Science 316: 1912-1915.

Smith, R. J., et al. 2010. Evolutionary Dynamics of Complex Networks of HIV Drug-Resistant Strains: The Case of San Francisco. Science 327: 697–701.