UCLA-engineered stem cells seek out and kill HIV in living organisms

HIV virus

By Enrique Rivero April 12, 2012

Expanding on previous research providing proof-of-principle that human stem cells can be genetically engineered into HIV-fighting cells, a team of UCLA researchers have now demonstrated that these cells can actually attack HIV-infected cells in a living organism.

The study, published April 12 in the journal PLoS Pathogens, demonstrates for the first time that engineering stem cells to form immune cells that target HIV is effective in suppressing the virus in living tissues in an animal model, said 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.

"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," he said.

In the previous research, the scientists took CD8 cytotoxic T lymphocytes — the "killer" T cells that help fight infection — from an HIV-infected individual and identified the molecule known as the T cell receptor, which guides the T cell in recognizing and killing HIV-infected cells. However, these T cells, while able to destroy HIV-infected cells, do not exist in great enough quantities to clear the virus from the body. So 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, allowing them to study the reaction in a living organism.

The engineered stem cells developed into a large population of mature, multi-functional HIV-specific CD8 cells that could specifically target cells containing HIV proteins. The researchers also discovered 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 this current study, the researchers similarly engineered human blood stem cells and found that they can form mature T cells that can attack HIV in tissues where the virus resides and replicates. They did so by using a surrogate model, the humanized mouse, in which HIV infection closely resembles the disease and its progression in humans.

In a series of tests on the mice's peripheral blood, plasma and organs conducted two weeks and six weeks after introducing the engineered cells, the researchers found that the number of CD4 "helper" T cells — which become depleted as a result of HIV infection — increased, while levels of HIV in the blood decreased. CD4 cells are white blood cells that are an important component of the immune system, helping to fight off infections. These results indicated that the engineered cells were capable of developing and migrating to the organs to fight infection there.

The researchers did note a potential weakness with the 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 mutate in the mice than in human hosts. So the use of multiple, engineered T cell receptors may be one way to adjust for the higher potential for HIV mutation in humans.

"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," Kitchen said.

The researchers will now begin making T cell receptors that target different parts of HIV and that could be used in more genetically matched individuals, he said.

Other study authors are Bernard R. Levin, Gregory Bristol, Valerie Rezek, Sohn Kim, Christian Aguilera-Sandoval, Arumugam Balamurugan, Otto O. Yang and Jerome A. Zack, all of UCLA.

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) funded this study.

The UCLA AIDS Institute, established in 1992, is a multidisciplinary think tank drawing on the skills of top-flight researchers in the worldwide fight against HIV and AIDS, the first cases of which were reported in 1981 by UCLA physicians. Institute members include researchers in virology and immunology, genetics, cancer, neurology, ophthalmology, epidemiology, social sciences, public health, nursing and disease prevention. Their findings have led to advances in treating HIV, as well as other diseases, such as hepatitis B and C, influenza and cancer.

For more news, visit the UCLA Newsroom and follow us on Twitter.

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Gilead Bets on Hepatitis C Data to Back Pharmasset Deal

An automated machine works on purification of potential hepatitis C virus drug candidate at the Gilead Sciences Inc. lab in Foster City, California. Photographer: David Paul Morris/Bloomberg

Bloomberg News

By Ryan Flinn on April 12, 2012

Gilead Sciences Inc. (GILD) (GILD), after paying $10.8 billion for the developer of an experimental hepatitis C drug, will soon give investors a better sense of whether its largest-deal ever is going to pay off.

Beginning next week, Gilead will release data from dozens of patients who have tried the medicine, providing the most complete evidence yet about its prospects for treating 170 million people who are infected with the virus globally. Trial results reported in 10 people in February spurred wild swings in the company’s stock price.

Gilead, the world’s largest maker of HIV drugs, has fallen 10 percent in the past four years, and is facing the loss of half of its revenue from patent expirations on AIDS medicines beginning in 2018. Despite that, 26 analysts (GILD) advise buying the shares, and seven suggest holding them.

“They will be there as one of the key players to treat a very large unmet medical need in hepatitis C, and one of the first players,” said Joshua Schimmer, a Leerink Swann & Co. analyst. “You can make a very strong case that Gilead shares are worth owning through the volatility.”

The purchase of Pharmasset Inc., announced Nov. 21, was designed to add a heavyweight product to diversify Gilead in an area -- infectious disease -- where the Foster City, California-based biotechnology company has expertise and an established sale force.

The company became a leader in AIDS treatments by finding the right combinations of drugs to help change the disease from a quick killer into one that’s manageable. Researchers say hepatitis C also may be attacked with drug cocktails. It’s a matter of finding “the right recipe,” said Mani Subramanian, a Gilead vice president of clinical research.

Liver Meeting

Investors are looking to results to be reported beginning at next week’s European Association for the Study of Liver meeting in Barcelona to define what role Gilead’s hepatitis C drug, known as 7977, will play in a developing market for new medicines that is expected to reach $20 billion.

In data reported on Feb. 2, four weeks of Gilead’s medicine seemed to eradicate the virus in 10 patients who hadn’t responded to prior rounds of therapy, boosting the company’sstock market value (GILD). On Feb. 17, when some patients relapsed, Gilead shares fell the most in 11 years.

“You have to be kind of astounded by it,” Leerink Swann’s Schimmer said in a telephone interview.

One key study weighs the performance of Gilead’s 7977 in tandem with an experimental product from Bristol-Myers Squibb Co. (BMY) (BMY) when used by all types of patients. Others will report on 7977’s effectiveness in those who have never been treated.

Bristol-Myers Compound

Bristol-Myers’s compound, BMS-790052, hinders a protein called NS5A that creates a scaffolding around the virus, securing it so it can replicate, Gilead’s Subramanian said. His company’s drug integrates itself into the virus’s replicating process, preventing it from churning out copies.

The new hepatitis C drugs also promise to work more quickly and be safer than the current standard of care that combines an antiviral called ribavirin with interferon, an injectable immune-boosting protein, studies have shown.

“We’re very excited about this Bristol-Myers study,”Subramanian said in an interview at the company’s headquarters.“We’ll know whether you even need ribavirin if you have a NS5A in the mix.”

Proving the worth of Bristol-Myers’s product in combination with 7977 could also help Gilead down the line when GS-5885, its own NS5A inhibitor, is put before the U.S. Food and Drug Administration for approval. The product is now in the second of three phases of trials generally required for clearance.

Ribavirin Combination

Gilead is expected to report at the Barcelona conference how 7977 works in combination with ribavirin after 12 weeks of therapy in those who haven’t had other treatments before, so-called naïve patients. This will help establish which patients can be cured, or not, without interferon.

If Gilead’s hepatitis C drug is approved, at the end of 2013 at the earliest, it may add $3 billion to $4 billion in revenue by 2018, said Michael Yee, an analyst with RBC Capital Markets in San Francisco. That would help replace sales from Atripla, the most widely used HIV medicine, and Truvada, a component of Atripla, he said. The medicines generated $6.1 billion in 2011 sales, or 73 percent of Gilead’s revenue.

“The company did have very steady revenue and earnings growth, but they’re looking to accelerate that,” Yee said.“The growth potential of the company has significantly changed, with higher risk and higher reward.”

No Death Knell

The finding last month that some patients have relapsed shouldn’t be looked at as a death knell for the developing product, Gilead’s Subramanian said.

The data “means one of two things,” he said in an interview. “Do you need longer duration, or more drugs?”

Geoff Porges, an analyst with Sanford C. Bernstein & Co. in New York with a market perform rating on Gilead, isn’t so sure.

The failure of 7977 to cure people who had previously been treated “shocked the world,” and means Gilead won’t dominate the field as some had expected, he wrote in a note to clients.“It changes the treatment landscape,” he wrote, and“highlights the vulnerability of Gilead’s stock to any stumbles.”

Subramanian remains philosophical about the hepatitis c therapies: “It’s like cooking,” he said. “At some point we’ll figure out the right recipe.”

To contact the reporter on this story: Ryan Flinn in San Francisco at rflinn@bloomberg.net 

To contact the editor responsible for this story: Reg Gale at rgale5@bloomberg.net

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iPod video used to encourage organ donation

Apple's iPod Nanos are displayed at Apple's music-themed September media event in San Francisco, California September 1, 2010. Credit: Reuters/Robert Galbraith/Files

Thu Apr 12, 2012 8:57am IST

REUTERS - An organ donation video people can watch on an iPod while they wait at the Department of Motor Vehicles may encourage more to become donors, according to a study.

The findings, reported in the Annals of Internal Medicine, point to one potential fix for a well-known problem: that the need for donor organs far exceeds the supply, a gap that in the United States is especially large among minorities.

Of the people who saw the video, 84 percent consented to be a donor, versus 72 percent of those who didn't watch it. The effect was larger among African Americans, with 76 percent of those who watched it agreeing to become donors against 54 percent of those who didn't.

"One reason is that the need for donor organs is so great," said J. Daryl Thornton of Case Western Reserve University School of Medicine in Cleveland, Ohio, the lead researcher.

African Americans are three times more likely than whites to develop kidney disease, and they account for one-third of the waiting list for donor kidneys.

Surveys have pointed to some reasons why not enough people consent to be donors. Many are unaware of the great need for donor organs, while others mistrust the medical establishment and think they won't get life-saving measures if doctors know they are a donor.

Others think their religion disapproves of organ donation, though most have no rules against it.

There have been some efforts, such as billboards and radio spots, to educate people about organ donation, but they haven't met with much success, Thornton told Reuters Health.

"Video has the ability to capture people on so many different levels," he said, noting that he and his colleagues thought showing a video at the Department of Motor Vehicles (DMV), before people are asked to become donors, might work.

Driver's licenses in many U.S. states carry notification of whether the bearer wants to be an organ donor, and people go to the DMV to apply for their license or renew it.

Thornton's team produced a five-minute video featuring an ethnically-diverse group of "real" people - organ donors and recipients, family members of recipients and family of people who died waiting for an organ.

They talked about what organ donation meant to them, hitting on common obstacles to people's willingness to become donors, such as mistrust of doctors and religious views.

The video was tested at 12 Cleveland, Ohio-area DMVs, with two days at each location. Half of each day was designated as the "intervention" period, where license-seekers watched the video on an iPod, and during the other half nobody saw it.

Overall, 443 people saw the video and 84 percent agreed to become organ donors. That compared with 72 percent of the 509 people who did not see the video.

About 20 percent of all study participants were African American. The video raised their consent rate by 22 percentage points, versus 11 percentage points among white viewers.

Thornton's team also found that people's attitudes shifted after seeing the video. They felt more knowledgeable about organ donation and had fewer conflicts about it than their counterparts who had not seen the video.

"We just have to present the information in a way that's accessible to people," Thornton said, noting that video is great because it's inexpensive and in theory, DMVs anywhere could run the video - and not necessarily on an iPod.

A big question is still whether any increase in organ-donor consent will ultimately lead to a bigger organ supply.

"A lot of things happen between consent and donation," Thornton said. SOURCE: bit.ly/HilobF

(Reporting from New York by Amy Norton at Reuters Health; editing by Elaine Lies)

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