Monthly Archives: July 2015

HIV Uses Immune System’s Own Tools to Suppress Itself

Canadian scientists make a significant discovery on HIV persistence

A Canadian research team at the IRCM in Montréal, led by molecular virologist Éric A. Cohen, PhD, made a significant discovery on how HIV escapes the body’s antiviral responses. The team uncovered how an HIV viral protein known as Vpu tricks the immune system by using its own regulatory process to evade the host’s first line of defense. The findings pave the way for future HIV prevention or cure strategies.

The study’s goal was to determine how HIV manages to compromise antiviral responses in the initial period of infection, also called the acute infection stage, during which the virus establishes itself in the body. The acute infection is considered a critical period in determining the complexity, extent and progression of the disease. It is also during this stage that HIV establishes latent infection in long-lasting cellular reservoirs. These viral reservoirs, which harbor the virus out of sight from the immune system and antiviral drugs, represent the primary barrier to a cure.

“An important component in this process is a group of proteins collectively called type 1 Interferons, which are the immune system’s first line of defense against viral infections and are known to have a beneficial role in the early stages of HIV infection,” says Dr. Cohen, Director of the Human Retrovirology research unit at the IRCM. “The problem is that HIV has developed mechanisms to suppress the Interferon response and, until now, little was known about how this was achieved.”

PHIL-18143 PubDomLic SEM HIV Particles courtesy NIAID

SEM HIV Particles courtesy NIAID PHIL-18143

Most of the Interferon is produced by a very small population of immune cells called pDCs (plasmacytoid dendritic cells), responsible for providing immediate defense against infections. PDCs patrol the body to detect invaders and, when they recognize the presence of a pathogen, they secrete Interferon. The Interferon then triggers a large array of defense mechanisms in nearby cells, creating an antiviral state that prevents the dissemination and, ultimately, the expansion of the virus.

“When pDCs encounter HIV-infected cells, the production of Interferon is regulated by a protein located on the infected cell’s surface called BST2,” explains Mariana Bego, PhD, first author of the study and research associate in Dr. Cohen’s laboratory. “BST2 has the ability to bind to and activate a receptor called ILT7, found on the surface of pDCs, which, in turns, sends a signal that suppresses the production of Interferon and halts its defensive functions. Interestingly, BST2 is also responsible for restricting HIV production by trapping the virus at the cell surface before it can exit infected cells and disseminate. However, HIV uses the viral protein Vpu to counteract BST2 antiviral activity.”

“With this study, we uncovered a unique mechanism whereby HIV exploits the regulatory process between BST2 and ILT7 to limit the body’s antiviral response, which allows the virus to spread and leads to persistent infection,” adds Dr. Bego. “We found that HIV, through Vpu, takes advantage of the role played by BST2 by maintaining its ability to activate ILT7 and limit the production of Interferon, all the while counteracting its direct antiviral activity on HIV production.”

“The hope for a definitive cure and an effective vaccine has been frustrated by HIV’s endless propensity to subvert the host’s defenses and persist in small populations of long-lasting reservoirs despite antiretroviral therapy,” describes Dr. Cohen, who also leads CanCURE, a team of leading Canadian researchers working towards an HIV cure. “Our findings can provide tools to enhance antiviral responses during the early stages of infection. By blocking Vpu’s action, we could prevent early viral expansion and dissemination, while also allowing pDCs to trigger effective antiviral responses. We believe that such interventions during primary infection have the potential to limit the establishment and complexity of viral reservoirs, a condition that seems required to achieve a sustained HIV remission.”

“The discovery by Drs. Bego and Cohen, which explains how the virus can’t be held down or wiped out during early periods of infection, will bring us closer to ending HIV/AIDS,” says Robert Reinhard, CanCURE Community Liaison. “By filling an important gap in knowledge, this new study will advance research for an HIV cure.”

About the study
The research project was funded by the Canadian Institutes of Health Research (CIHR), the Canadian HIV Cure Enterprise (CanCURE) through a partnership between CIHR, the Canadian Foundation for AIDS Research (CANFAR) and the International AIDS Society (IAS), as well as by a pilot project from the FRQS AIDS and Infectious Disease Network. The study’s authors also include Édouard Côté and Johanne Mercier from the IRCM, as well as Nick Aschman and Winfried Weissenhorn from the Université Grenoble Alpes in France. For more information on the study, please refer to the article published online by PLoS Pathogens

Findings from this study presented by Dr. Cohen on July 21 at the Vancouver Convention Centre as part of the 8th IAS Conference on HIV Pathogenesis, Treatment and Prevention.

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2015: Lung Cancer Research Outside the USA

Female Lung Cancer Deaths to Surpass Breast Cancer in Europe

In January 2015, a study by researchers from Switzerland and Italy revealed that lung cancer deaths among women in Europe would overtake those from breast cancer in 2015.[1] Lung cancer is the most common type of cancer, accounting for 13% of all cancer deaths worldwide. That represents a death toll of 1.6 million people, over 80% of who are tobacco users.[2]  While European men have been more afflicted by the disease due to higher smoking rates, the rates among men have been on the decline in the recent past. Meanwhile, the rates among women have been on an upward trend. This year, the prevalence of lung cancer among women in Europe is expected to rise by 9% over 2009 levels to reach 14.24 per 100,000 of population. Meanwhile, the death rate from breast cancer over the same period will fall by 10.2% to 14.22 deaths per 100,000 of population.[3]

The rise is attributed to the delayed effect of the surge in smoking among European women during the period after the 2nd World War and extending to the late 1960s.[4] The UK is one of the main drivers of this trend. Of all the countries surveyed independently, the UK had the highest level of lung cancer deaths, 21 per 100,000 of population.[5] Professor Carlo La Vecchia of the University of Milan, who is also the lead researcher attributed this to the fact that, “…British women started smoking during the second world war, while in most other EU countries women started after 1968.”

Research Shows Personalized Treatments are Underutilized

An international survey conducted between December and January 2015 revealed that the rates of patients receiving personalized treatment for advanced non-small cell lung cancer (NSCLC) remains low despite a large proportion of them (81%) having been tested for EGFR mutations. The results of the study were released in April in Ingelheim Germany, the seat of the Boehringer Ingelheim Pharmaceutical group which is the main sponsor of the study. The results were collected from 562 oncologists from 10 developed countries across Asia, Europe and North America. In Europe, 30% of advanced NSCLC patients were put on first-line treatment before their test results were ready, displaying a huge disparity with Asia (12%). The average global rates were 25%. The main reasons cited by oncologists for non-testing were insufficient tissue, poor patient fitness and protracted process of acquiring results once samples had been taken. Additionally 51% of all oncologists involved in the study stated that their treatment decisions were not dependent on EGFR mutation subtype of their patients. EGFR mutations are present in 40% of East Asian and 10-15% of white NSCLC patients.[6] ESMO clinical practice guidelines[7] recommend the use of EFGR mutation testing results to guide treatment decisions according to each patient’s specific cancer type as this has been shown to improve survival rates at least with the Del 19 mutation[8], the most common type of mutation.[9]

Sources:
[1] http://annonc.oxfordjournals.org/content/early/2015/01/24/annonc.mdv001.full
[2] http://www.cancerresearchuk.org/about-cancer/causes-of-cancer/smoking-and-cancer/smoking-facts-and-evidence#smoking_facts0
[3] http://annonc.oxfordjournals.org/content/early/2015/01/24/annonc.mdv001.full
[4] http://www.theguardian.com/society/2014/oct/07/smoking-falls-lowest-level-uk-recording-started-1940s
[5] http://annonc.oxfordjournals.org/content/early/2015/01/24/annonc.mdv001.full
[6] https://www.boehringer-ingelheim.com/news/news_releases/press_releases/2015/17_april_2015_oncology.html

[7] http://annonc.oxfordjournals.org/content/early/2014/08/11/annonc.mdu199.full.pdf+html
[8] Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials
    Yang, James Chih-Hsin et al., The Lancet Oncology , Volume 16 , Issue 2 , 141 – 151
[9] http://link.springer.com/article/10.1007/s00330-015-3697-0/fulltext.html

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