Stem cells genetically engineered to carry a molecule (derived from an HIV-infected person) that recognizes the virus could provide a new way to bolster the immune system against the disease, according to new research published this week in PLoS ONE. When implanted into mice, the stem cells developed into mature immune cells that could target cells with HIV specific proteins. Researchers are using a similar approach to prime the human immune system against cancer.

"We have demonstrated in this proof-of-principle study that this type of approach can be used to engineer the human immune system, particularly the T-cell response, to specifically target HIV-infected cells," says 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, in a press release. "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."

According to the release:

Taking CD8 cytotoxic T lymphocytes--the "killer" T cells that help fight infection--from an HIV-infected individual, the researchers identified the molecule known as the T-cell receptor, which guides the T cell in recognizing and killing HIV-infected cells. 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 engineered stem cells developed into a large population of mature, multifunctional HIV-specific CD8 cells that could specifically target cells containing HIV proteins. The researchers also found that HIV-specific T-cell receptors have to be matched to an individual in much the same way that an organ is matched to a transplant patient.

Researchers hope the technology will have broader applications."This approach could be used to combat a variety of chronic viral diseases," says co-author Jerome A. Zack, a UCLA professor of medicine in the division of hematology and oncology and associate director of the UCLA AIDS Institute, in the same release. "It's like a genetic vaccine."

For the first time, researchers filmed the transfer of HIV from infected to uninfected T cells through structures called virological synapses. The study, conducted by researchers at Mount Sinai School of Medicine, in New York, NY, and the Center for Biophotonics Science and Technology, University of California, Davis, could lead to new methods to block the transmission of HIV. The study published in the March 27 edition of Science.

Researchers captured the video, shown below, by creating a molecular clone of infectious HIV that contains green fluorescent protein. They then used quantitative, high-speed 3-D video microscopy to record both viral particle formation and transmission of the virus between T cells.

From the press release:

The resulting images and videos show that, once an infected cell adheres to a healthy cell, the HIV proteins--which appear bright green in the study--migrate within minutes to the contact site. At that point, large packets of virus are simultaneously released by the infected cell and internalized by the recipient cell. This efficient mode of transfer is a distinct pathway from the cell-free infection that has been the focus of most prior HIV studies, and reveals another mechanism by which the virus evades immune responses that can neutralize free virus particles within the body.

"We found that the transfer of HIV is highly coordinated between T cells, and that the transfer is rapid and massive," said [Benjamin] Chen, [assistant professor of medicine, infectious diseases, Mount Sinai School of Medicine]."Future efforts to block HIV transmission may be designed to specifically exploit and block this cell-to-cell mode of infection."

A rotating three-dimensional view of an HIV-infected T cell (green) forming virological synapses with three healthy CD4+ cells (red). The viral structural protein, shown in green, accumulates in button-shaped structures at the contact sites.

This movie shows high-speed imaging of HIV transfer across a virological synapse. The video begins with a still view of two T cells with transmitted light and an outline of a spot where a synaptic button has formed between them. The movie then shows the movement of fluorescent viral protein into the synaptic button, followed by the transfer of material from the button into the target cells. Note that the movie focuses on the movement of the viral protein without indicating the outlines of the recipient cell.

The video shows a cell that has engaged in a synapse becoming infected days later. Infection was captured by continuous long-term imaging over three days. The HIV green fluorescence image is presented on the left while an overlay of green fluorescence and bright field image is shown on the right. Images were acquired every 10 minutes over 67 hours.

Video credit: © Science/AAAS

A carefully selected bone-marrow transplant for a leukemia patient appears to have stopped the patient's HIV infection: he shows no signs of the virus in his blood nearly two years after the procedure. While it's difficult to draw any conclusions from a single case, the outcome gives hope for new avenues for AIDS treatment.

Some people are genetically resistant to HIV infection, even when they engage in frequent high-risk behavior--a fact that hematologist Gero Hütter wanted to take advantage of when faced with a 42-year-old patient with both leukemia and HIV. The patient needed a bone-marrow transplant, so Hütter searched compatible blood donors for a specific genetic mutation known to protect against most strains of HIV. Doctors then irradiated the patient's immune system and transfused the donor cells.

The transplant surgeons halted his HIV drugs to give the new cells time to take root. They planned to resume the drugs once HIV was found in the patient's blood. But according to an article in the Wall Street Journal, the virus never came back.

Nearly two years later, standard tests haven't detected virus in his blood, or in the brain and rectal tissues where it often hides . . . Normally when a patient stops taking AIDS drugs, the virus stampedes through the body within weeks, or days.

The treatment is unlikely to be broadly applicable: only about two-thirds of cancer patients survive the procedure. But scientists may be able to mimic the effect by reengineering patients' own cells. Doctors are already testing gene-therapy treatments that target the gene that renders some people immune to the virus.

According to the WSJ,

While cautioning that the Berlin case could be a fluke, David Baltimore, who won a Nobel prize for his research on tumor viruses, deemed it "a very good sign" and a virtual "proof of principle" for gene-therapy approaches. Dr. Baltimore and his colleague, University of California at Los Angeles researcher Irvin Chen, have developed a gene therapy strategy against HIV that works in a similar way to the Berlin case. Drs. Baltimore and Chen have formed a private company to develop the therapy.