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UCLA researchers use stem cells to kill HIV
by David Hutton  |  Email the author


LOS ANGELESóResearchers at the University of California, Los Angeles (UCLA) AIDS Institute say they have found a way to engineer human blood stem cells into "killer" cells that can target and kill HIV-infected cells, which potentially could be used against other chronic viral diseases.
Lead investigator Scott G. Kitchen says the study, published Dec. 7 in the-peer reviewed online journal PLoS ONE, provides proof-of-principle that human stem cells can be engineered into the equivalent of a genetic vaccine.  
Kitchen says existing CD8 cells that help fight help infection can already destroy HIV-infected cells, but there are not enough of the "killer" cells to clear the virus from the body.  
Kitchen is an assistant professor of medicine in the division of hematology and oncology at the David Geffen School of Medicine at UCLA and a member of the UCLA AIDS Institute.
"These studies lay the foundation for further therapeutic development that involves restoring damaged or defective immune responses toward a variety of viruses that cause chronic disease, or even different types of tumors," Kitchen says.  
According to the researchers, there is a desperate need for effective therapies to fight chronic viral infections.
"The immune response is normally fastidious at controlling the majority of viral infections and a therapeutic strategy aimed at reestablishing immune control represents a potentially powerful approach towards treating persistent viral infections," they wrote.  
The team examined the potential of genetically programming human hematopoietic stem cells to generate mature CD8+ cytotoxic T lymphocytes that express a molecularly cloned, "transgenic" human anti-HIV T cell receptor (TCR).  
Kitchen points out that the human immune system is incapable of clearing an infection with HIV largely due to the fact that the virus directly targets the immune system itself.  
"We wanted to investigate the feasibility of being able to reconstitute the ravaged immune system in HIV infected individuals in a manner to "program" cells to target and clear HIV infected cells," he says. "In this proof-of-principle approach, we took T cells from an HIV infected individual and identified a molecule (the T cell receptor) on these cells that specifically allows a particular T cell to recognize and kill HIV infected cells."    
While cells that have this molecule on them can kill HIV infected cells in that individual, Kitchen notes that they do not exist in great enough quantities or are dysfunctional in clearing the virus from the body.   
"To study this and eventually attempt to fix this defect, we cloned this T cell receptor and genetically engineered human blood stem cells," he says. "These genetically modified stem cells were then placed into human thymus tissue previously implanted in mice. " These mice serve as a surrogate host that allows the study of human tissue in a living organism.    

The researchers found that the stem cells developed into mature human T cells in the thymus tissue, becoming cells that can specifically target cells that contain HIV proteins.  
"Our results further indicate that the T cell receptor that is specific to HIV needs to be  'matched' in an individual in a manner similar to matching human tissues that are used in transplantation," Kitchen says. "Thus, these results suggest that blood stem cells can be manipulated and  'tailored' to produce T cells that can target infected cells."
Anti-HIV TCR transduction of human hematopoietic stem cells directed the maturation of a large population of polyfunctional, HIV-specific CD8+ cells capable of recognizing and killing viral antigen-presenting cells.  
According to Kitchen, these cells, while able to destroy HIV-infected cells, do not exist in enough quantities to clear the virus from the body. So the researchers cloned the receptor and genetically engineered human blood stem cells, then placed the stem cells into human thymus tissue that had been implanted in mice, allowing them to study the reaction in a living organism.
The research wasn't without its hurdles and according to Kitchen the biggest challenge involved the identification and molecular cloning of a single HIV-specific T cell receptor.   
"This hurdle was overcome in a manner that advanced the technology so that it will allow the rapid identification and cloning of additional T cell receptors to different proteins belonging to HIV and other viruses that cause chronic infection in humans," he says. "Further, the development of this system that allows the examination of virus specific T cell development in human tissue in vivo was a significant challenge."

Kitchen notes that researchers believe that this system will allow them to further investigate the therapeutic potential of this approach in humans and will provide insight into mechanisms of virus-specific T cell development and function.
According to Kitchen, the approach could also be used to target any virus that results in chronic infection and disease in humans, such as hepatitis B and C, herpes viruses (HSV1, HSV2, Epstein-Barr Virus, VZV, etc.), human papilloma viruses as well as different types of cancers or tumors.  
"We're very excited of the possibility of expanding this," adds Kitchen. "We're much closer to understanding aspects to repair damage to the immune system."  
The next step is to test this strategy in a more advanced model to determine if it would work in the human body, says co-author Jerome A. Zack, UCLA professor of medicine in the division of hematology and oncology and associate director of the UCLA AIDS Institute.  
The researchers also hope to expand the range of viruses against which this approach could be used.  
But the results of the study suggest that this strategy could be an effective weapon in the fight against AIDS and other viral diseases.  
"This approach could be used to combat a variety of chronic viral diseases," says Zack, who is also a professor of microbiology, immunology and molecular genetics. "It's like a genetic vaccine."  
The research also could provide new approaches to develop new drug candidates to combat HIV.  
"This system could be utilized to examine ways that enhance or modulate the ability of T cells to interact with HIV and virally infected cells and ways that allow the rapid characterization of technologies that enhance stem cell and T cell development," notes Kitchen. "The use of this mouse/human chimeric system allows a great deal of manipulation to occur that further allows the rapid and close assessment of these human cellular processes."  
Kitchen also points out that these studies set the stage for the identification and characterization of other T cell receptors that target different viruses or tumor cells. 
"The ultimate goal of these studies is the further understanding of the human immune response and the development of therapeutic approaches that allow the individual "tailoring" of immune responses in individuals requiring treatment," he says. "These studies suggest that in individuals requiring treatment, we could engineer their immune systems to specifically fight off infection or cancers."  
In addition to Kitchen and Zack, investigators included Michael Bennett, Zoran Galic, Joanne Kim, Qing Xu, Alan Young, Alexis Lieberman, Hwee Ng and Otto Yang, all of UCLA, and Aviva Joseph and Harris Goldstein of the Albert Einstein College of Medicine in New York.  
The California Institute for Regenerative Medicine (CIRM) and the UCLA Center for AIDS Research funded this study.  
The UCLA AIDS Institute, established in 1992, is a multidisciplinary think tank drawing on the skills of top-flight researchers in the worldwide fight against HIV and AIDS, the first cases of which were reported in 1981 by UCLA physicians. Institute members include researchers in virology and immunology, genetics, cancer, neurology, ophthalmology, epidemiology, social science, public health, nursing, and disease prevention. Their findings have led to advances in treating HIV, as well as other diseases, such as hepatitis B and C, influenza and cancer.
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