IM approaches remain an unproven concept in HIV therapy. In a study publishing July 13, 2007 in PLoS Computational Biology, clinical responses to antiretroviral drug therapy are simulated for the first time, and the model is then applied to IM therapy. Marcel Curlin, Shyamala Iyer, and John Mittler, from the University of Washington, find that IM is expected to be successful beyond three years and that six to ten months of induction therapy should achieve durable suppression of HIV and maximize the possibility of eradicating viruses resistant to the maintenance regime. They also find the counter-intuitive result that for induction regimens of limited duration the optimal time to initiate induction therapy may be several days or weeks after the start of regular (maintenance) therapy.
These results are important not simply because they show how this particular, albeit important, therapy strategy may be optimized, but because they illustrate the more general potential for mathematical models to influence therapy decisions. "Our experience has been that clinicians and policy makers are often hesitant to consider, sometimes even hostile towards, mathematical modeling approaches. Instead, they rely on intuition or await the results of expensive, long-term clinical trials", says Mittler. By presenting a detailed model that makes concrete quantitative predictions and gives some interesting, counter-intuitive qualitative results, this paper may help to change attitudes concerning the value of dynamical modeling approaches.
Please click here. (link will go live on July 13th)
"Optimal timing and duration of induction therapy for HIV-1 Infection"
Curlin ME, Iyer S, Mittler JE (2007).
PLoS Comput Biol 3(7): e133. doi:10.1371/journal.pcbi.0030133
Click here to see article online
About PLoS Computational Biology
PLoS Computational Biology (http://www.ploscompbiol.org) features works of exceptional significance that further our understanding of living systems at all scales through the application of computational methods. All works published in PLoS Computational Biology are open access. Everything is immediately available subject only to the condition that the original authorship and source are properly attributed. Copyright is retained by the authors. The Public Library of Science uses the Creative Commons Attribution License.
About the Public Library of Science
The Public Library of Science (PLoS) is a non-profit organization of scientists and physicians committed to making the world's scientific and medical literature a freely available public resource.
http://www.plos.org. |
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Major Breakthrough In Understanding How HIV Interferes With Infected Cell Division
Dr. Eric A. Cohen, a researcher at the IRCM (Institut de recherches cliniques de Montreal), and his team will publish on Friday, July 13, in PLoS Pathogens a discovery that could lead to the development of a new class of drugs to combat HIV.
Human immunodeficiency virus type 1 (HIV-1) causes AIDS by depleting essential immune cells called CD4+T lymphocytes in infected individuals, resulting in a compromised immune system. At the center of this process is the HIV protein, viral protein R (Vpr), which stops infected CD4+T cells from dividing and as a consequence compromises their immune function. In addition, by arresting cell division, Vpr helps HIV to harness the infected cell's resources to enhance viral replication. The way Vpr exerts this effect is by interacting with cellular proteins that control cell division.
Dr. Cohen and his team have identified a novel cellular protein complex targeted by HIV-1 Vpr to stop infected cell division. This protein complex, designated DDB1-CUL4-VprBP, is involved in a process called ubiquitination. Ubiquitination is a mechanism by which a small protein called ubiquitin is conjugated to cellular proteins in order to modulate their biological activity or induce their degradation. The researchers demonstrated that association of Vpr with this ubiquitinating complex, also called an E3 ubiquitin ligase complex, is essential for the defect in cell division induced by Vpr. Further characterization of this protein complex as well as the elucidation of the mechanism by which it affects cell division may open new avenues for therapeutic intervention against HIV.
Dr. Éric A. Cohen is the Director of the Human Retrovirology Research Unit at IRCM. He holds the Canada Research Chair in Human Retrovirology. His work is supported by grants from the Canadian Institutes of Health Research (CIHR) and the Fonds de la Recherche en Santé du Québec (FRSQ) AIDS and Infectious Diseases Network . Dr. Cohen is also professor in the Department of Microbiology and Immunology at the Université de Montréal.
Established in 1967, the IRCM (http://www.ircm.qc.ca) is recognized as one of the country's top-performing health research centres. It has a mandate to understand the causes and mechanisms of diseases in order to find diagnostic tools and means of prevention and treatment; to train a new generation of high-level scientists; and to contribute to Québec's socio-economic development by facilitating the commercial development of new discoveries. The IRCM has 37 research units and a staff of more than 450.
Link go live on July 12.
"HIV-1 Vpr-mediated G2 arrest involves the DDB1-CUL4AVPRBP E3 ubiquitin ligase."
Belzile JP, Duisit G, Rougeau N, Mercier J, Finzi A, et al. (2007)
PLoS Pathog 3(7): e85. doi:10.1371/journal.ppat.0030085
Click here to see article.
About PLoS Pathogens
PLoS Pathogens publishes outstanding original articles that significantly advance the understanding of pathogens and how they interact with their host organisms. All works published in PLoS Pathogens are open access. Everything is immediately available subject only to the condition that the original authorship and source are properly attributed. Copyright is retained by the authors. The Public Library of Science uses the Creative Commons Attribution License.
About the Public Library of Science
The Public Library of Science (PLoS) is a non-profit organization of scientists and physicians committed to making the world's scientific and medical literature a freely available public resource. For more information, visit http://www.plos.org
Novel AIDS Vaccine Strategy Partnered By Japan's DNAVEC And IAVI
The New York-based International AIDS Vaccine Initiative (IAVI) and DNAVEC Corporation have announced a collaboration to jointly develop an AIDS vaccine using DNAVEC's Sendai virus (SeV) vector technology. The candidate will be designed to be administered intra-nasally to stimulate immune responses in both the blood and mucosal tissues, the initial point of entry for HIV.
This direction in AIDS vaccine development is crucial: Today, most candidates in clinical trials -- numbering close to 30 -- are based on a cell-mediated approach, targeting only one arm of the human immune system. Promising vectors that trigger mucosal immunity at the primary site of infection and replication could serve as a first line of defense in fending off the virus. These properties may be necessary for an efficacious vaccine.
Sendai, which serves as a basis of the vector, is a RNA virus that does not cause disease in humans, is capable of efficiently delivering genes expressing HIV proteins to the immune system, and of replicating safely in the upper airway. DNAVEC and the Japanese National Institute for Infectious Diseases (NIID) have demonstrated that monkeys can be protected against SIV, a virus that causes a disease in some non-human primates that is much like AIDS, if vaccinated intra-nasally using a recombinant SeV vaccine candidate.
"One of IAVI's scientific priorities is to develop vaccines by using new and improved viral vectors that can control HIV infection," said Seth Berkley, CEO and President of IAVI. "The preliminary data from DNAVEC and the Japanese NIID in monkeys makes SeV a promising candidate, and we are delighted to be working with our first Japanese industrial partner on the project." Since its inception in 1996, IAVI has tested six candidate vaccines and raised nearly a half billion dollars in new funding for AIDS vaccine research and development.
IAVI and DNAVEC will each contribute scientific and technical expertise to develop the SeV vector-based AIDS vaccine, with a goal of advancing the candidate to human clinical trials within the next three years. The agreement includes pre-clinical testing for immunogenicity and safety, process development for manufacturing, and a Phase I clinical trial for the candidate. The partners will evaluate further development after the results of early testing. DNAVEC will receive royalties from any vaccine licensed for use in developed countries, while both partners have agreed to make any successful vaccine available as quickly as possible to countries hardest hit by the epidemic. IAVI also will provide financial support for the project.
"This agreement brings together IAVI's proven product development expertise and experience conducting clinical trials in North America, Europe, Africa and India with DNAVEC's promising and unique vector technology," said Mamoru Hasegawa, President and CEO of DNAVEC. "We are very hopeful the partnership will bring us closer to a safe and effective AIDS vaccine, which would be a great contribution to human welfare."
Currently, there are close to 40 million people infected with HIV, most of them in developing countries, with the number of new infections worldwide topping 12,000 per day. Although the international community has made significant strides in expanding AIDS treatment and care, HIV/AIDS is outpacing the global response. For every person who begins antiretroviral treatment for AIDS, estimates suggest six more become newly infected with HIV.
"We simply must do a better job of marshalling the scientific talent and resources from every corner of the globe to design effective and long-term approaches to HIV prevention,"concluded Berkley. "Japanese biotechnology companies such as DNAVEC, with a proven capability in developing innovative vaccine concepts, will play a large role in the global search for a vaccine to end AIDS."
To date, DNAVEC has worked with the University of Tokyo and the Beijing University of Technology to develop the Sendai vector as a viable technology for HIV/AIDS vaccines.
About IAVI
The International AIDS Vaccine Initiative (IAVI) is a global not-for-profit organization whose mission is to ensure the development of safe, effective, accessible, preventive HIV vaccines for use throughout the world. Founded in 1996 and operational in 24 countries, IAVI and its network of collaborators research and develop vaccine candidates. IAVI's financial and in-kind supporters include the Alfred P. Sloan Foundation, the Bill & Melinda Gates Foundation, the Foundation for the National Institutes of Health, The John D. Evans Foundation, The New York Community Trust, the James B. Pendleton Charitable Trust, The Rockefeller Foundation, The Starr Foundation, The William and Flora Hewlett Foundation; the Governments of Canada, Denmark, Ireland, The Netherlands, Norway, Sweden, the United Kingdom, and the United States, the Basque Autonomous Government as well as the European Union; multilateral organizations such as The World Bank; corporate donors including BD (Becton, Dickinson & Co.), Continental Airlines, Google Inc., Henry Schein, Inc., Merck & Co., Inc. and Pfizer Inc; leading AIDS charities such as Broadway Cares/Equity Fights AIDS and Until There's A Cure Foundation; other private donors such as The Haas Trusts; and many generous individuals from around the world. For more information, see http://www.iavi.org/.
About DNAVEC Corporation
DNAVEC Corporation is a venture company originally incubated as a Japanese national project supported by the Japanese Ministry of Health and Welfare. During its nine-year project period, DNAVEC Research Inc., the predecessor of DNAVEC Corporation, successfully developed innovative vectors including the Sendai virus vector system, which are expected to become an indispensable device for gene therapy. The company has obtained a number of international patents on these vectors and their use after initial testing predicted a high efficacy and safety profile. DNAVEC is currently promoting multiple joint research and development programs with national and global research institutes and pharmaceutical companies. Gene therapy research conducted by the Kyushu University Hospital for severe ischemic limbs using the Sendai virus vector received regulatory approval from the Ministry of Health and Welfare and was initiated in 2006. The Sendai virus vector is Japan's first viral vector to be tapped for gene therapy. The vector bearing FGF-2, a therapeutic for severe ischemic limbs has been licensed to a major Chinese pharmaceutical company for use in China and is pending Chinese FDA (SFDA) approval. For more information, see http://www.dnavec-corp.com/.
Source: Katie Moore
International AIDS Vaccine Initiative
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