Monday, December 13, 2010

Possible HIV cure?

Doctors who carried out a stem cell transplant on an HIV-infected man with leukaemia in 2007 say they now believe the man to have been cured of HIV infection as a result of the treatment, which introduced stem cells which happened to be resistant to HIV infection.

The man received bone marrow from a donor who had natural resistance to HIV infection; this was due to a genetic profile which led to the CCR5 co-receptor being absent from his cells. The most common variety of HIV uses CCR5 as its ‘docking station’, attaching to it in order to enter and infect CD4 cells, and people with this mutation are almost completely protected against infection.

Doctors chose stem cells from an individual who had an unusual genetic profile: a mutation inherited from both parents that resulted in CD4 cells that lacked the CCR5 receptor. This mutation, called CCR5 delta 32 homozygosity, is present in less than 1% of Caucasians in northern and western Europe, and is associated with a reduced risk of becoming infected with HIV.

This is because all new infecting viruses need to use the CCR5 receptor on CD4 cells when infecting an immune system cell of the CD4 type.

Before the stem cell transplant the patient received chemotherapy treatment that destroyed most immune cells and total body irradiation, and also received immunosuppressive drugs to prevent rejection of the stem cells. One of the challenges for any approach to curing HIV infection is long-lived immune system cells, which need to be cleared before a patient can be cured.

The repopulation of CD4 cells was accompanied by the complete disappearance of host CD4 cells, and after two years the patient had the CD4 count of a healthy adult of the same age.

In the case of the Berlin patient CCR5-bearing macrophages could not be detected after 38 months, suggesting that chemotherapy had destroyed these longer-lived cells, and that they had also been replaced by donor cells.


The `Berlin patient`, Timothy Ray Brown, a US citizen who lives in Berlin, was interviewed this week by German news magazine Stern.

His course of treatment for leukaemia was gruelling and lengthy. Brown suffered two relapses and underwent two stem cell transplants, as well as a serious neurological disorder that flared up when he seemed to be on the road to recovery.

The neurological problem led to temporary blindness and memory problems. Brown is still undergoing physiotherapy to help restore his coordination and gait, as well as speech therapy.

Friends have noticed a personality change too: he is much more blunt, possibly a disinhibition that is related to the neurological problems.

On being asked if it would have been better to live with HIV than to have beaten it in this way he says “Perhaps. Perhaps it would have been better, but I don’t ask those sorts of questions anymore.”

If a cure has been achieved in this patient, it points the way towards attempts to develop a cure for HIV infection through genetically engineered stem cells.

Scientists were sufficiently intrigued by the Berlin patient that they met in Berlin in 2009 to discuss how they could coordinate efforts to identify CCR5-delta32 homozygous donors and expand the supply of stem cells from these donors, for example through sampling blood cells from the umbilical cord of babies born to mothers who are homozygous for CCR5-delta32, in order to eventually facilitate stem-cell therapy.


More CCR5 info.

People with two copies of the CCR5 delta32 gene (inherited from both parents) are virtually immune to HIV infection. This occurs in about 1% of Caucasian people.

One copy of CCR5-delta32 seems to give some protection against infection, and makes the disease less severe if infection occurs. This is more common, it is found in up to 20% of Caucasians.

Should everyone be tested for this mutation? Not necessarily. It would be dangerous to assume you are completely safe from infection if you have the CCR5-delta32 mutation.

It's not an airtight guarantee of never getting AIDS. Some unusual types of HIV can use other proteins for entering cells. Rarely, there have been people who have two mutant CCR5 genes who have died from AIDS.

Also, CCR5 is not the whole story of immunity to HIV infection. Some resistant people have been found who have two perfectly normal copies of CCR5. So other genes also contribute to slowing down HIV infection, and scientists are busy trying to identify them.

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