T Cells from Engineered Stem Cells Clear HIV from Infected Mice

A research team at UCLA has published a proof-of-principal study that demonstrates that human stem cells can be genetically engineered to create HIV-fighting cells. Their study was published on April 12, 2012 in the open journal PLoS Pathogens. This paper shows for the first time that engineering stem cells to form immune cells that specifically target HIV is effective in suppressing the virus in living tissues in an animal model. Lead investigator Scott G. Kitchen, 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 said: “We believe that this study lays the groundwork for the potential use of this type of approach in combating HIV infection in infected individuals, in hopes of eradicating the virus from the body.”

In previous research, this research group took a special group of immune cells known as CD8 cytotoxic T lymphocytes from an HIV-infected individual. CD8-positive T cells specifically attack virus-infected cells and destroy them so that they do not anymore virus. After they collected CD8 T cells from HIV-infected individuals, they grew them in culture. Next they established that these cells could attack and destroy HIV-infected cells in culture. The next step was to determine if these same cells could attack HIV-infected cells in a living organism.

When CD8 cells engage an infected cell, they use a molecule on their surfaces called the “T cell Receptor” (TCR). The TCR is an unusual protein that is encoded by a gene complex that consists of many copies of different versions of various regions of the TCR. During the development of the T cell one gene from each of these copies is chosen and spliced together with one copy from each of the other regions. The result is a TCR molecule that is unique to the T cell that makes it. These TCRs are able to bind to foreign substances and when they do, the T cell becomes activated. In the case of CD8 cytotoxic T cells, the binding of foreign substances on the surfaces of cells tell the cells that something dangerous is afoot inside the cell. Therefore, it secretes toxic chemicals that kill the cell.

In previous research carried out by the UCLA team, they isolated CD8 cytotoxic T lymphocytes from an HIV-infected individual and identified the genes from the TCR. Since the TCR guides the T cell in recognizing and killing HIV-infected cells, they reasoned that by making more of the T cells that recognize HIV-infected cells they could potentially provide HIV-infected animals with a way to clear the virus from the cell. The problem in HIV-infected individuals is that CD8 cells that are specific for HIV-infected cells do not exist in great enough quantities to clear the virus from the body.

To solve this problem, the researchers cloned the receptor and used this to genetically engineer human blood stem cells. They then placed the engineered stem cells into human thymus tissue that had been implanted in mice. Now the engineered T cells were observed interacting in a living organism. The engineered stem cells developed into a large population of mature, multi-functional HIV-specific CD8 cells that were able to specifically target HIV-infected cells with HIV proteins on their surfaces. Interestingly, the research group found that HIV-specific T cell receptors have to be matched to an individual in much the same way an organ is matched to a transplant patient.

In the current study, the UCLA group similarly engineered human blood stem cells and discovered that they can form mature T cells that can attack HIV in tissues where the virus resides and replicates. To show this they used the humanized mouse. This animal is a rodent with a human immune system. In these animals, HIV infection closely resembles the disease and its progression in humans.

Two-six weeks after introducing their engineered blood stem cells into the peripheral blood of the mouse, they found that the number of CD4 “helper” T cells — which become depleted as a result of HIV infection — increased and levels of HIV in the blood decreased. CD4 cells or T-helper cells are white blood cells that play a vital role in the immune system. These results indicated that the engineered cells were capable of developing and migrating to the organs to fight infection there.

There is, however, a potential weakness with this study: Human immune cells reconstituted at a lower level in the humanized mice than they would in humans, and as a result, the mice’s immune systems were mostly, though not completely, reconstructed. Because of this, HIV may be slower to accumulate mutations in the mice than in human hosts. Thus the use of multiple, engineered T cell receptors may be one way to adjust for the higher potential for HIV mutation in humans.

Kitchen sounded this optimistic note: “We believe that this is the 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.”