A Doc, a Mutation and a Potential Cure for AIDS

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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

By MARK SCHOOFS

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 Hütter 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 Hütter.

The breakthrough appears to be that Dr. Hütter, 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,

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. Hütter, 39, remembered this research when his American leukemia

patient failed first-line chemotherapy in 2006. He was treating the

patient at Berlin's Charité Medical University, the same institution

where German physician Koch performed some of his

groundbreaking research on infectious diseases in the 19th century.

Dr. Hütter 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. Hütter's colleague

Nowak found one with the mutation from both parents.

To prepare for the transplant, Dr. Hütter 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., 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.

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 incorrectly given as the American Foundation for AIDS Research.

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