In the early 1980’s, clinicians in New York and California were faced with a growing epidemic. Men were presenting with severe immune system compromisation and, as similar cases started to emerge around the world, scientists raced to identify the cause of the disease (1). Three years later they identified the human immunodeficiency virus (HIV). Today, HIV is estimated to affect nearly 37 million people worldwide (2). While the cure for HIV remains elusive, the management of HIV has achieved huge strides in the past few decades thanks to work of dedicated scientists, including Argentinean-Canadian physician Dr. Julio Montaner.
Much of the difficulty in treating HIV lies within its ability to hide within the host’s genetic material. In most biological systems, genetic information is encoded by deoxyribonucleic acid (DNA) molecules, a stable biological media that is normally transcribed into ribonucleic acid (RNA) molecules for protein production. HIV’s genetic material is made up of RNA, but HIV uses a protein known as a reverse transcriptase to drive transcription in the reverse direction, which generates DNA molecules from RNA (3). The newly-synthesized viral DNA is then hidden in the host’s own genetic material, evading immune detection until there is an opportune time to activate. HIV can remain dormant and undetected in host immune cells for many years until its activation, at which point the viral DNA produces new viral particles, a process that kills the immune cell. Extensive destruction of immune cells in this manner causes acquired immunodeficiency syndrome (AIDS), an affliction that has claimed the lives of more than 35 million people worldwide since HIV’s discovery (2).
Early efforts in treating HIV focused on inhibiting the reverse transcriptase protein, the protein that was critical for the virus’ ability to infiltrate the host’s genetic material (4). The first drug approved by the FDA to treat HIV infections was azidothymidine in 1987, referred to today as zidovudine (ZDV). ZDV is similar to a nucleic acid that reverse transcriptase uses to synthesize viral DNA, but its chemical structure prematurely terminates the synthesis of DNA strands. Around the time ZDV was approved for clinical use, Julio Montaner joined St. Paul’s Hospital in Vancouver (5). Montaner began to treat patients with ZDV, but discovered that early success quickly turned to failures as patients stopped responding to treatment. Montaner had learned from his father, a tuberculosis specialist in Argentina, that single drugs were often insufficient, so he began to experiment with combinations of ZDV and didanosine (ddI), another approved drug with a similar mechanism of action (5). Disappointingly, the combination of ZDV and ddI only marginally improved outcomes and was poorly tolerated by patients due to combined toxicities (4).
The prognosis for HIV patients remained poor until the development of nevirapine (NVP), the first in a new class of antiviral drugs that inhibited reverse transcriptase through a different mechanism from ZDV and ddI. Like other antiviral drugs at the time, patient response to NVP treatment diminished quickly if it was administered alone (4). Given NVP’s alternative mechanism of action, Montaner organized an international group of clinicians and scientists from Canada, Italy, Australia, and the Netherlands to study its application in combination with ZDV and ddI. The group presented initial successes at the 11th International AIDS Conference in Vancouver and later published the full trial in 1998, which demonstrated that the triple therapy had reduced HIV levels to near-undetectable levels in nearly half of all patients over a year of treatment; the percent of patients who had similar outcomes using combinations of two of the three drugs were in the single digits (6). For its stunning efficacy, the triple therapy would go on to be referred to as Highly Active Anti-Retroviral Therapies (HAART).
Thanks to the pioneering work by Montaner, triple therapy became the standard of care for patients with HIV worldwide. ZDV, ddI, and NVP are all listed on the World Health Organization’s List of Essential Medicines and both ZDV and NVP are still recommended in first-line therapies today (7, 8). HAART has allowed patients with HIV to survive longer and enjoy a higher quality of life, even preventing the transmission of the virus to intimate partners. Montaner, motivated by the success of HAART, has continued to study HIV, characterizing the underlying factors that lead to the development of drug resistance by the virus (9). Outside of biomedical research, Montaner has been a major proponent of harm reduction and treating hard-to-reach populations. He has pioneered the concept of Treatment as Prevention (TasP), where HAART is administered to all eligible patients to decrease further transmission of HIV in the population. The strategy was implemented in 2006 by the British Columbia Centre for Excellence in HIV/AIDS with great success and is embraced today by the World Health Organizations and countries around the world (5).
HIV alarmed the world with its contagiousness and lethality, but in less than four decades it has changed from a death sentence to a manageable condition. This dramatic transformation was made possible through the pioneer research of Julio Montaner, who continues his work to alleviate the global burden of HIV to this day. There are still many issues that hinder the elimination of HIV, including multidrug resistance and adverse drug interactions in elderly patients, but firms like Cyclica are ready to employ cutting-edge technologies to help confront these challenges. Cyclica honours the contributions of Julio Montaner to the treatment and prevention of HIV/AIDS.
Stay tuned for our next blog outlining other great discoveries by Canadian scientists or check out our other blog posts for Canada150 found here.
This blog was written by Tonny Huang, a graduate student at the Princess Margaret Cancer Center. Tonny has a deep interest in the applications of protein science for the betterment of human health. You can find him here on LinkedIn.
1. Centers for Disease Control. (1981) Kaposi’s sarcoma and Pneumocystic pneumonia among homosexual men: New York City and California. Morb Mortal Wkly Rep 30, 305-308.
2. World Health Organization. (2017) HIV/AIDS Fact Sheet. Retrieved from http://www.who.int/mediacentre/factsheets/fs360/en/.
3. Zheng, Y.-H., Lovsin, N., & Peterlin, B. M. (2005) Newly identified host factors modulat HIV replication. Immunol Lett 97(2), 225-234.
4. Vella, S., Schwartlander, B., Sow, S. P., Eholie, S. P., & Murphy, R. L. (2012) The history of antiretroviral therapy and of its implementation in resource-limited areas of the world. AIDS 26(10), 1231-1241.
5. British Columbia Centre for Excellence in HIV/AIDS (2017) Dr. Julio Montaner. Retrieved from http://www.cfenet.ubc.ca/about-us/team/montaner-j.
6. Montaner, J. S. G., Reiss, P., & Cooper, D. (1998) A Randomized, Double-blind Trial Comparing Combinations of Nevirapine, Didanosine, and Zidovudine for HIV-Infected Patients. JAMA 279(12), 930-937.
7. World Health Organization. (2000) WHO Model List of Essential Medicines (19th List). Geneva, Switzerland.
8. World Health Organization. (2016) What’s new in HIV treatment. Retrived from http://www.who.int/hiv/pub/arv/arv2015-treatment-factsheet/en/.
9. Harrigan, P. R., Hogg, R. S., Dong, W. W. Y., Yip, B., Wynhoven, B., Woodward, J., Brumme, C. J., …, & Montaner, J. S. G. (2005) Predictors of HIV Drug-Resistance Mutations in a Large Antiretroviral-Naive Cohort Initiating Triple Antiretroviral Therapy. J Infect Dis 191(3), 339-347.