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On The Brink of A Cure: HIV Resistant Cells

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Scientists have discovered how to make cells resistant to the HIV virus, an important breakthrough that could be a vital step for an eventual HIV cure, according to a new study published in the journal Proceedings of the National Academy of Sciences.

Researchers at the Scripps Research Institute (TSRI) in California have found a way to tether HIV-fighting antibodies to immune cells, which in turn creates a cell population that is resistant to the virus. These resistant cells then can replace diseased cells, which can potentially cure the disease in a person living with HIV.

To infect T-cells, HIV needs to bind to CD4 receptors, which are found on the surface of T-cells. Scientists genetically engineered the DNA of T-cells so that they produce an antibody that travels to the surface of a T-cell and attaches at the site of the CD4 receptor. Therefore, that receptor is now blocked by the antibody and prevents HIV molecules from entering.

"This protection would be long term," said Jia Xie, senior staff scientist at TSRI and first author of the study.

While these results have so far only been in experiments under particular lab conditions, researchers plan to collaborate with investigators at City of Hope's Center for Gene Therapy to evaluate this new therapy in efficacy and safety tests, and then hopefully begin to test the therapy in patients.

"City of Hope currently has active clinical trials of gene therapy for AIDS using blood stem cell transplantation, and this experience will be applied to the task of bringing this discovery to the clinic," said John A. Zaia, M.D., director of the Center for Gene Therapy in the Hematological Malignancy and Stem Cell Transplantation Institute at City of Hope. "The ultimate goal will be the control of HIV in patients with AIDS without the need for other medications."

To deliver the therapy to patients, scientists will inject these engineered cells into patients. As these cells are resistant to HIV they will outlive the patient's regular T-cells. Eventually after multiple injections, the hope is that all of a patient's T-cells will be the engineered ones, effectively curing the patient of HIV.

"By collaborating with physicians and scientists at City of Hope who have expertise in transplantation in HIV patients, we should hopefully be able to begin this therapy in people," said co-author Richard Lerner.

The new technique developed in the study offers a significant advantage over current therapies that involve antibodies, according to the authors. In the current therapies, antibodies float freely in the bloodstream, but at relatively low concentrations. In the new study, antibodies bind directly on a cell's surface, which allow them to block HIV from accessing a crucial cell receptor and thus spreading the infection.

The study utilizes a technique that the authors have deemed the "neighbor effect." An antibody glued to the cell is much more effective than having many antibodies floating throughout the bloodstream.

"You don't need to have so many molecules on one cell to be effective," said Xie.

Before testing their system against HIV, the scientists used rhinovirus, a virus responsible for many strands against the common cold, as a model. They used a vector called lentivirus to deliver a new gene to cells, which instructed cells to synthesize antibodies that bind with the human cell receptor (ICAM-1) that rhinovirus needs. With the antibodies monopolizing that site, the virus cannot enter the cell to spread infection.

"This is really a form of cellular vaccination," said Lerner.

In essence, the researchers had forced the cells to compete in Darwinian "survival-of-the-fittest" selection in a lab dish. Cells without antibody protection died off, leaving protected cells to survive and multiply, passing on the protective gene to new cells.

After the technique succeeded in protecting the cells against rhinovirus, the researchers then applied the same technique against HIV. To infect a person, all strains of HIV need to bind with a cell surface receptor called CD4. The scientists tested antibodies that could potentially protect this receptor on the very immune cells normally killed by HIV.

After introducing cells to the virus, the researchers ended up with an HIV-resistant population. The antibodies recognized the CD4 binding site, blocking HIV from getting to the receptor.

"HIV is treatable but not curable and it remains a disease that causes a lot of suffering. That makes the case for why these technologies are so important," Xie said.

The scientists further confirmed that these tethered antibodies blocked HIV more effectively than free-floating, soluble antibodies in similar experiments. The authors believe that this therapy could help patients, who despite treatment with antiretroviral drugs, still suffer from higher rates of diseases, such as cancers.


 

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