Engineered cells suppress HIV in living tissue

For the first time, US scientists have shown that HIV-fighting cells engineered from human stem cells can suppress the virus in living human tissue in mice. The team, from UCLA in Los Angeles, California, had already shown in principle that it was possible to create cells that seek out and destroy HIV, but this is the first time they have shown this can be done in a living organism. Writing in the 12 April issue of the online open access journal PLoS Pathogens, the researchers suggest their findings show it may be possible to use human stem cells to create tailored cells that target and eradicate viruses like HIV, and thereby \"engineer the human immune response to combat viral infections\". However, there is still a lot of work to do before what happens in mice can be replicated in humans. The lead investigator on the study was Scott G. Kitchen, assistant professor of medicine in the division of hematology and oncology at the David Geffen School of Medicine at UCLA. Kitchen is also a member of the UCLA AIDS Institute. There is a desperate need for new approaches to eradicate HIV, a virus that actively subverts the powerful response that the immune system mounts against it. One particular way the virus subverts the host immune system is by foiling cellular cytotoxic T lymphocyte (CTL) responses. CTLs, or \"killer\" T cells, are a type of white blood cell that triggers death of cells infected with viruses and other pathogens. To do this, they have to carry a particular molecule, a receptor, that helps them find and eliminate the target pathogen. One goal that researchers like Kitchen and his team are pursuing, is to find a way to contain HIV, then restore and boost the CTL response sufficiently to eradicate the virus in the body. In a previous piece of work, they took CTLs from an HIV-infected person and identified they had an HIV-targeting T-cell receptor. But while they showed the CTLs carrying the HIV-targeting T-cell receptor were able to eliminate HIV-infected cells, the numbers were not sufficient to be able to clear HIV from the body. So, to overcome this, the researchers embarked on this current study, where they cloned the HIV-targeting T-cell receptor and used it to genetically engineer human blood-forming stem cells (hematopoietic stem cells, HSCs) destined to mature into working CTLs that kill HIV-infected cells. Then they put the genetically engineered stem stells into human thymus tissue that had been implanted into lab mice. The researchers saw that the stem cells matured into a large population of multi-functional HIV-specific T-cells capabale of targeting cells containing HIV proteins. To check the T-cells were actually behaving in the way intended, they ran a series of tests on the mice\'s peripheral blood, plasma and organs. The tests were done two and six weeks after implanting the engineered cells. They found that levels of CD4 \"helper\" T cells went up, and levels of HIV in the blood, went down. Normally, following an HIV infection, there is a drop in CD4, a group of white blood cells that also help fight off infections. The researchers conclude this showed the engineered cells were capable of growing and migrating to the organs and fighting off HIV there. Kitchen told the media: \"We believe that this study lays the groundwork for the potential use of this type of an approach in combating HIV infection in infected individuals, in hopes of eradicating the virus from the body.\" However, he and his team point to an important limitation of their study: human immune cells reconstituted at a lower level in humanized mice than in humans, allowing the mice\'s immune systems to be almost completed restored. Because of this, it could be that HIV mutates more slowly in mice than in humans. So perhaps when this type of approach is tested in humans, several T cell receptors should be used, to mount a stronger attack on what might be a higher pace of HIV mutation in humans. Kitchen said they see their work as a \"first step in developing a more aggressive approach in correcting the defects in the human T-cell responses that allow HIV to persist in infected people\". The team is already working on making T-cell receptors that target different parts of the HIV that could be used in more genetically matched individuals. (In this study, Kitchen and colleagues also found that HIV-specific T-cell receptors have to be matched to an individual; rather like organs are matched to transplant recipients). Funds from the National Institutes of Health, the California HIV/AIDS Research Program, the California Institute for Regenerative Medicine, the UC Multicampus Research Program and Initiatives from the California Center for Antiviral Drug Discovery, and the UCLA Center for AIDS Research (CFAR) helped pay for the study.