Bone marrow transplant suppresses AIDS in patient

[Shiloh]

Source: http://www.reuters.com/article/healthNews/idUSTRE4AC07O20081113

Bone marrow transplant suppresses AIDS in patient
Wed Nov 12, 2008 9:06pm EST

BERLIN (Reuters) - A bone marrow transplant using stem cells from a donor with natural genetic resistance to the AIDS virus has left an HIV patient free of infection for nearly two years, German researchers.

The patient, an American living in Berlin, was infected with the human immunodeficiency virus that causes AIDS and also had leukemia. The best treatment for the leukemia was a bone marrow transplant, which takes the stem cells from a healthy donor's immune system to replace the patient's cancer-ridden cells.[/B]

Dr. Gero Hutter and Thomas Schneider of the Clinic for Gastroenterology, Infections and Rheumatology of the Berlin Charite hospital said on Wednesday the team sought a bone marrow donor who had a genetic mutation known to help the body resist AIDS infection.

The mutation affects a receptor, a cellular doorway, called CCR5 that the AIDS virus uses to get into the cells it infects.

When they found a donor with the mutation, they used that bone marrow to treat the patient. Not only did the leukemia disappear, but so did the HIV.

"As of today, more than 20 months after the successful transplant, no HIV can be detected in the patient," the clinic said in a statement.

"We performed all tests, not only with blood but also with other reservoirs," Schneider told a news conference.

"But we cannot exclude the possibility that it's still there."

The researchers stressed that this would never become a standard treatment for HIV. Bone marrow stem cell transplants are rigorous and dangerous and require the patient to first have his or her own bone marrow completely destroyed.

Patients risk death from even the most minor infections because they have no immune system until the stem cells can grow and replace their own.

HIV has no cure and is always fatal. Cocktails of drugs can keep the virus suppressed, sometimes to undetectable levels. But research shows the virus never disappears -- it lurks in so-called reservoirs throughout the body.

Hutter's team said they have been unable to find any trace of the virus in their 42-year-old patient, who remains unnamed, but that does not mean it is not there.

"The virus is tricky. It can always return," Hutter said.

The CCR5 mutation is found in about 3 percent of Europeans, the researchers said. They said the study suggests that gene therapy, a highly experimental technology, might someday be used to help treat patients with HIV.

(Reporting by Oliver Denzer; Writing by Maggie Fox in Washington; Editing by Vicki Allen)

 

[Coleman]

Re: Bone marrow transplant suppresses AIDS in patient

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[Sunshine123]

Re: Bone marrow transplant suppresses AIDS in patient

http://online.wsj.com/article//SB122602394113507555.htm

* NOVEMBER 7, 2008

A Doctor, a Mutation and a Potential Cure for AIDS
A Bone Marrow Transplant to Treat a Leukemia Patient Also Gives Him Virus-Resistant Cells; Many Thanks, Sample 61



(See Corrections & Amplifications item below.)

The startling case of an AIDS patient who underwent a bone marrow transplant to treat leukemia is stirring new hope that gene-therapy strategies on the far edges of AIDS research might someday cure the disease.

The patient, a 42-year-old American living in Berlin, is still recovering from his leukemia therapy, but he appears to have won his battle with AIDS. Doctors have not been able to detect the virus in his blood for more than 600 days, despite his having ceased all conventional AIDS medication. Normally when a patient stops taking AIDS drugs, the virus stampedes through the body within weeks, or days.
[Dr. Gero Hutter] Sixten Koerper

Dr. Gero H?tter isn't an AIDS specialist, but he 'functionally cured' a patient, who shows no sign of the disease.

"I was very surprised," said the doctor, Gero H?tter.

The breakthrough appears to be that Dr. H?tter, a soft-spoken hematologist who isn't an AIDS specialist, deliberately replaced the patient's bone marrow cells with those from a donor who has a naturally occurring genetic mutation that renders his cells immune to almost all strains of HIV, the virus that causes AIDS.

The development suggests a potential new therapeutic avenue and comes as the search for a cure has adopted new urgency. Many fear that current AIDS drugs aren't sustainable. Known as antiretrovirals, the medications prevent the virus from replicating but must be taken every day for life and are expensive for poor countries where the disease runs rampant. Last year, AIDS killed two million people; 2.7 million more contracted the virus, so treatment costs will keep ballooning.

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.

Back in 1996, when "cocktails" of antiretroviral drugs were proved effective, some researchers proposed that all cells harboring HIV might eventually die off, leading to eradication of HIV from the body -- in short, a cure. Those hopes foundered on the discovery that HIV, which integrates itself into a patient's own DNA, hides in so-called "sanctuary cells," where it lies dormant yet remains capable of reigniting an infection.

But that same year, researchers discovered that some gay men astonishingly remained uninfected despite engaging in very risky sex with as many as hundreds of partners. These men had inherited a mutation from both their parents that made them virtually immune to HIV.

The mutation prevents a molecule called CCR5 from appearing on the surface of cells. CCR5 acts as a kind of door for the virus. Since most HIV strains must bind to CCR5 to enter cells, the mutation bars the virus from entering. A new AIDS drug, Selzentry, made by Pfizer Inc., doesn't attack HIV itself but works by blocking CCR5.

About 1% of Europeans, and even more in northern Europe, inherit the CCR5 mutation from both parents. People of African, Asian and South American descent almost never carry it.

Dr. H?tter, 39, remembered this research when his American leukemia patient failed first-line chemotherapy in 2006. He was treating the patient at Berlin's Charit? Medical University, the same institution where German physician Robert Koch performed some of his groundbreaking research on infectious diseases in the 19th century. Dr. H?tter scoured research on CCR5 and consulted with his superiors.

Finally, he recommended standard second-line treatment: a bone marrow transplant -- but from a donor who had inherited the CCR5 mutation from both parents. Bone marrow is where immune-system cells are generated, so transplanting mutant bone-marrow cells would render the patient immune to HIV into perpetuity, at least in theory.

There were a total of 80 compatible blood donors living in Germany. Luckily, on the 61st sample he tested, Dr. H?tter's colleague Daniel Nowak found one with the mutation from both parents.

To prepare for the transplant, Dr. H?tter first administered a standard regimen of powerful drugs and radiation to kill the patient's own bone marrow cells and many immune-system cells. This procedure, lethal to many cells that harbor HIV, may have helped the treatment succeed.

The transplant specialists ordered the patient to stop taking his AIDS drugs when they transfused the donor cells, because they feared the powerful drugs might undermine the cells' ability to survive in their new host. They planned to resume the drugs once HIV re-emerged in the blood.

But it never did. Nearly two years later, standard tests haven't detected virus in his blood, or in the brain and rectal tissues where it often hides.

The case was presented to scientists earlier this year at the Conference on Retroviruses and Opportunistic Infections. In September, the nonprofit Foundation for AIDS Research, or amFAR, convened a small scientific meeting on the case. Most researchers there believed some HIV still lurks in the patient but that it can't ignite a raging infection, most likely because its target cells are invulnerable mutants. The scientists agreed that the patient is "functionally cured."

Caveats are legion. If enough time passes, the extraordinarily protean HIV might evolve to overcome the mutant cells' invulnerability. Blocking CCR5 might have side effects: A study suggests that people with the mutation are more likely to die from West Nile virus. Most worrisome: The transplant treatment itself, given only to late-stage cancer patients, kills up to 30% of patients. While scientists are drawing up research protocols to try this approach on other leukemia and lymphoma patients, they know it will never be widely used to treat AIDS because of the mortality risk.

There is a potentially safer alternative: Re-engineering a patient's own cells through gene therapy. Due to some disastrous failures, gene therapy now "has a bad name," says Dr. Baltimore. In 1999, an 18-year-old patient died in a gene therapy trial. Even one of gene therapy's greatest successes -- curing children of the inherited "bubble boy" disease -- came at the high price of causing some patients to develop leukemia.
[Chart]

Gene therapy also faces daunting technical challenges. For example, the therapeutic genes are carried to cells by re-engineered viruses, and they must be made perfectly safe. Also, most gene therapy currently works by removing cells, genetically modifying them out of the body, then transfusing them back in -- a complicated procedure that would prove too expensive for the developing world. Dr. Baltimore and others are working on therapeutic viruses they could inject into a patient as easily as a flu vaccine. But, he says, "we're a long way from that."

Expecting that gene therapy will eventually play a major role in medicine, several research groups are testing different approaches for AIDS. At City of Hope cancer center in Duarte, Calif., John Rossi and colleagues actually use HIV itself, genetically engineered to be harmless, to deliver to patients' white blood cells three genes: one that inactivates CCR5 and two others that disable HIV. He has already completed the procedure on four patients and may perform it on another.

One big hurdle: doctors can't yet genetically modify all target cells. In theory, HIV would kill off the susceptible ones and, a victim of its own grim success, be left only with the genetically engineered cells that it can't infect. But so far that's just theory. All Dr. Rossi's patients remain on standard AIDS drugs, so it isn't yet known what would happen if they stopped taking them.

In 1989, Dr. Rossi had a case eerily similar to the one in Berlin. A 41-year-old patient with AIDS and lymphoma underwent radiation and drug therapy to ablate his bone marrow and received new cells from a donor. It is not known if those cells had the protective CCR5 mutation, because its relation to HIV hadn't been discovered yet. But after the transplant, HIV disappeared from the patient's blood. The patient died of his cancer 47 days after the procedure. Autopsy tests from eight organs and the tumor revealed no HIV.

Write to Mark Schoofs at mark.schoofs@wsj.com
Corrections & Amplifications

The Foundation for AIDS Research, which uses the acronym amFAR, is the name of the nonprofit group cited in this article. The name of the group was in