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January 4, 2013
Researchers Discover How HIV Binds to Dendritic 'Carrier' Immune Cells
Scientists have identified the precise protein on the surface of dendritic immune cells that HIV binds to in order to gain entry, and the discovery could lead to the development of new antiretroviral agents that, for the first time, would attack HIV outside of its life cycle within CD4 cells, ScienceDaily reports. Responsible for prompting immune response in CD4 cells, dendritic cells are also known as carrier cells. In the case of HIV, the virus invades the cell, which then spreads it to CD4s.
Researchers from the AIDS Research Institute IrsiCaixa published a paper in the open access journal PLOS Biology about their discovery of a protein called Siglec-1 that’s on the surface of dendritic cells. Siglec-1 binds to what are known as gangliosides on HIV’s surface and thus help transmit more of the virus to CD4s.
In a lab setting, the researchers combined HIV with varying quantities of Siglec-1 and discovered that higher levels of the protein improved the dendritic cells’ capacity to capture HIV, which then led to greater transmission of the virus into CD4 cells. The scientists also found that inhibiting Siglec-1 prevented dendritic cells from capturing the virus, indicating that such inhibition may be an effective aim for a future drug therapy.
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Scientists Discover How HIV Virus Gains Access to Carrier Immune Cells to Spread Infection
Scientists from the AIDS Research Institute IrsiCaixa have identified how HIV, the virus that causes AIDS, enters the cells of the immune system enabling it to be dispersed throughout an organism. The new study is published December 18 in the open access journal PLOS Biology.
One of the reasons why we do not yet have a cure for HIV infection is that the virus infects cells of the immune system that would normally fight such an infection. The main targets of HIV are white blood cells named CD4 T lymphocytes (so called because they have the protein CD4 in their membrane), and while more than 20 different drugs are available today to help control HIV, all of them act by blocking the cycle that HIV follows to infect these CD4 T lymphocytes. However, these treatments do not fully act on another cell of the immune system, the dendritic cell, which takes up HIV and spreads it to target CD4 T lymphocytes.
Mature dendritic cells are responsible for activating an immune response by CD4 T lymphocytes, but when they carry viruses, their contact with T lymphocytes causes the virus to be passed on, thus increasing viral spread.
The results continue the research led by ICREA researchers at IrsiCaixa, Javier Martínez-Picado, and Nuria Izquierdo-Useros, in collaboration with research groups from Heidelberg University, Germany, and the University of Lausanne, Switzerland. This team published a previous PLOS Biology paper in April 2012, in which they identified molecules, called gangliosides, located on the surface of HIV that are recognized by dendritic cells and are necessary for viral uptake. The new results now identify a molecule on the surface of dendritic cells that recognizes and binds the gangliosides and allows HIV to be taken up by dendritic cells and transmitted to its ultimate target: T lymphocytes.
"We have observed that the protein that acts as a lock for the entrance of HIV could also facilitate the entrance of other viruses," explains Nuria Izquierdo-Useros. "Therefore, our results could also help us understand how other infections might exploit this mechanism of dispersion."
In order to identify the precise molecule located on the membrane of the dendritic cells capable of capturing HIV, the researchers studied one family of proteins that are present on the surface of these cells, called Siglecs. It is known that these proteins bind to the gangliosides on the HIV surface. In the laboratory, they mixed the virus with dendritic cells that displayed different quantities of Siglec-1, and found that a higher quantity of Siglec-1 led to those dendritic cells capturing more HIV, which in turn allowed for enhanced transmission of HIV to CD4 T lymphocytes, a process called trans-infection.
The team then tried inhibiting the Siglec-1 protein. Doing so in the laboratory, they found that the dendritic cells lost their capacity to capture HIV and, importantly, they also lost their ability to transfer HIV to CD4 T lymphocytes. With all these data, the scientists concluded that Siglec-1 is the molecule responsible for HIV entrance into the dendritic cells, and could therefore become a new therapeutic target.
"We had the key and now we have found a lock," explains Javier Martínez-Picado. "Now we are already working on the development of a drug that could block this process to improve the efficacy of the current existing treatments against AIDS."
A Baltimore biotech reported that its experimental HIV vaccine showed promising results in a phase 1 clinical study.
Profectus BioSciences tested its vaccine on 60 adults in Philadelphia, San Francisco, Nashville, Tenn., and Decatur, Ga., who were not infected by the virus that causes AIDS. It was safe at all dose levels and immunogenic — as it was in studies involving macaques.
"The demonstration that our ... vaccine delivery platform is safe and immunogenic in healthy adult volunteers is a milestone that allows Profectus to advance not only its HIV vaccine program, but also vaccines for multiple infectious disease indications," John Eldridge, the 9-year-old company's chief scientific officer, said in a statement. "The response rate observed in this clinical trial is absolutely consistent with our data in non-human primates."
The vaccine is based on the recombinant vesicular stomatitis virus vector. The RNA virus, which can infect both insects and mammals, is used in laboratories as a gene delivery vector without the potential for integration, which makes it safer for vaccine applications, according to company information. The recombinant version used in the trial can replicate in human cells, but has been weakened so it won't cause illness.
The National Institute of Allergy and Infectious Disease is supporting Profectus' vaccine development with a $22.5 million contract.
In other Maryland bioscience industry news:
Sucampo Pharmaceuticals has gotten the regulatory go-ahead to remove the warnings and precautions for pregnant and nursing women from the labels of its constipation drug, Amitiza.
The Bethesda company's product already received marketing approval from the Food and Drug Administration for treating chronic idiopathic constipation in adults and irritable bowel syndrome with constipation in women 18 and older.
“We believe these changes will enable physicians and women of child-bearing age who are suffering from [constipation] to better evaluate the risk-benefit profile of Amitiza," CEO Ryuji Ueno said in a statement.
Sucampo also reported that the FDA postponed the goal date for its review of the company's application to market the drug for treating opioid-induced constipation in patients with chronic, non-cancer pain. Because new submitted information was deemed a major amendment to the application, that date has been pushed back three months, to late April. The FDA did not seek any new clinical trials or studies.
An experimental nanoparticle vaccine for respiratory syncytial virus developed by Novavax was safe and effective in a preclinical trial on animals. Results from the study were published online in the journal Plos One.
The data demonstrated the candidate's potential "to elicit the level and type of immunity required to protect humans as measured by virus neutralization activity," Gale Smith, vice president of vaccine development with the Rockville biotech, said in a statement.
Severe respiratory syncytial virus infections are the leading cause of infant hospitalization in the U.S., and globally there are 64 million cases and 160,000 deaths annually, according to Novavax. The infection also is especially dangerous among older populations, and there is no approved prophylactic vaccine.
"We have completed a phase 1 trial and recently initiated two separate dose-ranging clinical trials of the ... nanoparticle vaccine candidate in the elderly (phase 1) and in women of child-bearing age (phase 2)," Gregory Glenn, chief scientific officer, said in the statement. "These preclinical observations are consistent with the promising safety and immunogenicity seen in our clinical trials reported to date and suggest that this vaccine should continue to be developed."
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Cytomedix, with funding from the National Heart, Lung and Blood Institute, will conduct a phase 2 clinical study of its treatment for an ailment called intermittent claudication. It’s caused by peripheral arterial disease, which results in reduced flow of blood and oxygen to leg muscles. About 8 million to 10 million Americans have the disease, with many of them having intermittent claudifcation, which causes lower-leg pain when the patient is moving, according to company information.
The study will involve 80 patients, with some receiving a placebo and others receiving injections of stem cells isolated from their bone marrow using the Gaithersburg biotech’s Bright Cell technology. Enrollment is expected to begin in the first quarter of next year.
“Our February acquisition of Aldagen and the Bright Cell technology has positioned us well to play a leading role in investigating promising clinical paths in regenerative medicine where there exists significant unmet medical need,” CEO Martin P. Rosendale said in a statement. “Intermittent claudication is a serious consequence of arteriosclerosis which, if left untreated, will likely progress to pain at rest and possibly open wounds.”
Supernus Pharmaceuticals, which went public this year and later won FDA approval for its anti-epilepsy treatment, announced the pricing of its public offering of six million shares: $8 a share.
The Rockville company also is developing drugs to treat impulsive aggression in people with attention deficit hyperactivity disorder.
Rexahn Pharmaceuticals closed on its previously announced public offering, grossing $6.6 million, including a partial exercise of the over-allotment option by the underwriter.
The Rockville biotech focuses on developing treatments for cancer and central nervous system disorders.
EntreMed, another Rockville biotech that develops cancer treatments, announced the publication of preclinical results of its compound for multiple sclerosis.
The report on 2-methoxyestradiol was published online in this week's Early Edition of Proceedings of the National Academy of Sciences. The study was conducted at the Campbell Family Institute for Breast Cancer Research at Princess Margaret Hospital in Toronto.
"In this study, we demonstrated that 2ME2 ... significantly inhibits lymphocyte activation and proliferation and dramatically suppresses development of experimental MS," Tak W. Mak, director of the institute and leader of the study, said in a statement.
The compound "represents another important asset for our company with its strong [intellectual property] position and sound safety profile," EntreMed CEO Ken Ren said in the statement. "For the next step, we intend to further advance 2ME2 development as part of our global drug development plan and strategy to leverage resources both in the U.S. and China. We are currently exploring multiple strategies for the development of 2ME2 including possible partnership opportunities. We believe that the development of 2ME2 for autoimmune diseases fits well with our plan to build a robust product pipeline and to add value for our long term shareholders."