Scientists Have Found A Way To Make Cells Resistant To HIV

TSRI Senior Staff Scientist Jia Xie was first author of the new study. (Photo by Madeline McCurry-Schmidt.)

In a remarkable step forward in the potential treatment of HIV, scientists in California have successfully created a cell population that is resistant to the disease.

The new approach, described as a form of “cellular vaccination” aims to offer long-term protection for patients by tethering HIV-fighting antibodies to their immune cells.

Jia Xie, senior staff scientist, said: “The ultimate goal will be the control of HIV in patients with AIDS without the need for other medications,” as even with antiretroviral drug treatments, people with HIV still suffer much higher incidences of cancer and other deadly diseases.

Here, cells protected from rhinovirus by membrane-tethered, receptor-blocking antibodies survive well and form colonies. Credit: Jia Xie, Lerner Lab

Joseph Alvarnas who was involved in the study, said: “HIV is treatable but not curable – this remains a disease that causes a lot of suffering. That makes the case for why these technologies are so important.”

The new technique is superior to therapies where antibodies float freely in the bloodstream at a relatively low concentration, as the antibodies hang on to the cell’s surface blocking HIV from accessing a crucial receptor and spreading infection.

Known as the ‘neighbour effect’ the team showed that resistant cells could quickly replace diseased cells, potentially curing a person of HIV through gradual displacement.

Xie said: “You don’t need to have so many molecules on one cell to be effective.”

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.

To infect a person, all strains of HIV need to bind with a cell surface receptor called CD4, so the team at the Scripps Research Institute and City of Hope research centre near Los Angeles, tested antibodies that could potentially protect this receptor on the very immune cells normally killed by HIV.

The antibodies recognized the CD4 binding site, blocking HIV from getting to the receptor.

The next step in this research is to try engineering antibodies to protect a different receptor on the cell surface, according to Xie.

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Such as new techniques to find peptide chains that are capable of preventing HIV from invading cells!

Christodoulos Floudas, study leader and chemical and biological engineering professor at Princeton University, along with Meghan Bellows-Peterson, a Princeton engineering doctoral student, and Robert Siliciano, professor of medicine at Johns Hopkins University School of Medicine and a 1974 Princeton graduate, are developing a technique that will allow them to discover new drugs for a myriad of diseases by mathematically calculating the effectiveness of certain physical properties of biological molecules as medications.

This new method combines the optimization theory, which is a field of mathematics that aims to calculate the best option among a certain number of choices, with computational biology, which incorporates statistics, mathematics and computer science. The result is a technique that is capable of predicting which physical properties of biological molecules can be used to create medicines used to fight different diseases.

“The power of this is that it’s a general method,” said Floudas. “It has proven successful in finding potential peptides to fight HIV, but it should also be effective in searching for drugs for other diseases.”

Searching for peptides, which are chains of biologically active amino acids that build proteins, was the challenge when attempting to find a medication that can stop HIV from infecting cells. Finding new peptides could lead to new medications to treat HIV, replacing traditional drugs like Fuzeon (enfuvirtide), which has not been proven fully effective and costs US$20,000 per year.

Researchers believe Fuzeon attaches to the HIV virus, and disables the structure used to break through the membrane of human cells. But the actual process for entering cells is still unknown at this point.

“The Princeton researchers have a very sophisticated way of selecting peptides that will fit a particular binding site on an HIV virus,” said Siliciano. “It narrows the possibilities, and may reduce the amount of time and resources it takes to find new drugs.”

The Princeton researchers used data on the proteins that create the structure on the HIV virus, and mathematically calculated what type of drug might be most effective against it. To do this, the team utilized a formula based on statistical thermodynamics to see what kind of peptide would bind to the HIV virus’ structure for penetration and inhibit it more efficiently than Fuzeon. What they ended up with was five shorter peptides (12 amino acids long, instead of Fuzeon’s 36-amino-acid-long peptide) that shift to a lower energy state after clinging to the HIV virus, allowing them to bind to the virus easily and more effectively. Four out of five of these peptides proved to be effective against HIV and were also nontoxic to cells.

“One could never test all the possible peptides to see if they are effective against HIV,” said Floudas. “But this model was able to sort through millions of possibilities and identify just a few that show promise.”

The next step is to change the shape of the peptide candidates to see if this alters their effectiveness against HIV. Researchers will also modify the technique so it can be applied to other types of diseases.

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