Tag Archives: Drug Resistance

Evolution in Influenza

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Contributed by Runako Aranha-Minnis

Evolution is not only limited to the organisms we are able to see with the naked eye. Viruses like influenza are able to evolve, and this can be very dangerous to human populations. Though it is true that influenza is not the danger that it once was, it still can not be ignored. Viral resistance to treatment can lead to many deaths globally, especially during flu seasons. During these times, doctors usually see a rise in cases of viruses resistant to the treatments available at the time. One type of resistance that influenza can develop is Oseltamivir resistance. Oseltamivir is an important antiviral defense against the flu. It is found in drugs like Tamiflu, and can be rendered ineffective if resistance is developed.

Influenza and its neuraminidase

The DNA change that in the virus that occurs is related to the neuraminidase enzyme activity. The enzyme cleaves salicylic acid moieties that can be bound by the viral hemagglutinin. In essence the enzyme’s job is to help release newly formed viral particles. Imagine the enzyme as little Pac-Men just going about and eating the connections of new virus particles to let them spread. Oseltamivir works by inhibiting the activity of the neuraminidase enzyme. This limits the infectiousness of the virus.

Resistance requires changes in the DNA of the virus. Mutations, changes in the DNA, can change genes, often leading to changes in the organism. For Oseltamivir resistance, a point mutation, the change of a single base of DNA, is all that is necessary. A change in the genes leads to a change in the amino acids produced. This change in the amino acids is just one amino acid at the 274th spot in the chain leads to a change in the activity of the virus. This line of reasoning is why the mutation is called H274Y.

The H274Y mutation that gives influenza resistance usually does not spread through the population.  In early clinical tests, the mutation meant the virus was unaffected by oseltamivir, but had associated decreased viral fitness. So even though viruses with resistance would be selected for, their lower chance of survivability because of the mutation meant it did not matter. The influenza virus is able to evolve with Oseltamivir only when an associated mutation occurs. These associated mutations that allow oseltamivir resistance to keep going are permissive mutations. More recently, permissive mutations have arisen that allow influenza to be resistant to Oseltamivir without losing any fitness. Imagine a population of influenza like a game of “Where is Waldo?”:

No permissive mutations. In the absence of permissive mutations, all viruses, including Waldo, die. 

With permissive mutations. If Waldo has a permissive mutation, he survives to reproduce and the whole populations becomes Waldos because all other viruses died. 

Waldo in the first cartoon has H274Y with no permissive mutations. Without permissive mutations, there is no evolution under treatment. After treatment, the viruses are killed. There are no viruses left so the picture goes black. In the second cartoon, With permissive mutations, there is evolution for Waldo and a new viral population arises. This population only has Waldo because only Waldo has the H274Y mutation that conferred resistance.

For Further Reading:

Jesse D. Bloom, Lizhi Ian Gong, David Baltimore. 2010. Permissive Secondary Mutations Enable the Evolution of Influenza Oseltamivir Resistance Science. 328: 1272-1275

Nicholas Renzette, Daniel R. Caffrey, Konstantin B. Zeldovich, Ping Liu, Glen R. Gallagher, Daniel Aiello, Alyssa J. Porter, Evelyn A. Kurt-Jones, Daniel N. Bolon, Yu-Ping Poh, Jeffrey D. Jensen, Celia A. Schiffer, Timothy F. Kowalik, Robert W. Finberg, Jennifer P. Wang. 2013. Evolution of the Influenza A Virus Genome during Development of Oseltamivir Resistance In Vitro 88: 272-281

The Sad History of HIV and its Persistence against Drug Therapy

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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.

Rise of Antibiotic Resistance

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Contributed by Richard Parilla

https://www.youtube.com/watch?v=gXisYehVXUk

In 1928 a discovery made by Scottish scientist Alexander Fleming would change modern medicine. Fleming observed that the fungus Penicillium was able to kill disease causing pathogens. This discovery won Fleming a Nobel Prize in 1945 and led to development of antibiotics. The effectiveness of these drugs, once referred to as “miracle drugs”, led them to become used very regularly to treat a variety of illnesses. However, these lifesaving antibiotics have become far less effective due to the increasingly more common bacterial strains that are antibiotic resistant.

Antibiotics function by either directly killing bacteria themselves or by inhibiting their growth and reproduction. So how does bacterial strains resistance to certain antibiotics come about? Well an easy way to think about this is in evolutionary terms. The use of antibiotics selects for bacterial strains that are resistant to the mechanism by which the antibiotic targets the pathogen. Since all the non-resistant bacteria are wiped out by the antibiotic, only the resistant bacteria can reproduce and spread. This is an interesting perspective since it shows that humans can have an impact on the evolution of a species through implementation of novel selective pressures such as antibiotics.

Over the past decade antibiotic resistance has become a very threatening problem to society. It is has been a topic which has continually made headlines over the past few years. Why has the threat of antibiotic resistant microbes risen? The World Health Organization points to the misuse of antibiotics and over prescription as the cause of the accelerated emergence of the resistant bacteria strains. Due to the nature of this problem it would seem that it will be a frequent topic of discussion in the near future.

For Further Further Reading:

“Antimicrobial Resistance.” WHO. N.p., May 2013. Web. 20 Apr. 2014.

Austin, D. J. “The Relationship between the Volume of Antimicrobial Consumption in Human Communities and the Frequency of Resistance.” Proceedings of the National Academy of Sciences 96.3 (1999): 1152-156. Print.

Bonhoeffer, S. “Evaluating Treatment Protocols to Prevent Antibiotic Resistance.” Proceedings of the National Academy of Sciences 94.22 (1997): 12106-2111. Print.
Centers for Disease Control and Prevention. Centers for Disease Control and Prevention, 16 Sept. 2013. Web. 20 Apr. 2014.

“General Background: About Antibiotic Resistance.” Tufts University. N.p., n.d. Web. 20 Apr. 2014.

Hampton, L. M., M. M. Farley, W. Schaffner, A. Thomas, A. Reingold, L. H. Harrison, R. Lynfield, N. M. Bennett, S. Petit, K. Gershman, J. Baumbach, B. Beall, J. Jorgensen, A. Glennen, E. R. Zell, and M. Moore. “Prevention of Antibiotic-Nonsusceptible Streptococcus Pneumoniae With Conjugate Vaccines.”Journal of Infectious Diseases 205.3 (2012): 401-11. Print.

Levy, Stuart B. “The Challenge of Antibiotic Resistance.” Diss. Texas U, 1998. Web.

Lupo, Agnese, Sébastien Coyne, and Thomas Ulrich Berendonk. “Origin and Evolution of Antibiotic Resistance: The Common Mechanisms of Emergence and Spread in Water Bodies.” Frontiers in Microbiology 3 (2012): n. pag. Print.

Stöppler, Melissa C., M.D. “Antibiotics 101 – MedicineNet.com.” MedicineNet. N.p., 3 Sept. 2012. Web. 20 Apr. 2014.

Woodford, Neil, Jane F. Turton, and David M. Livermore. “Multiresistant Gram-negative Bacteria: The Role of High-risk Clones in the Dissemination of Antibiotic Resistance.” FEMS Microbiology Reviews 35.5 (2011): 736-55. Print.

HIV/AIDS and the Evolution of Drug Resistance

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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.”  – aids.gov

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.