Can HIV resist a cure?

Science A surprisingly common genetic mutation that protects against full- blown Aids, offers hope for all HIV sufferers. Michael Hanlon reports

An HIV-positive blood test, it used to be assumed, was tantamount to a death sentence. Inevitably (the thinking went), carriers of the human immunodeficiency virus (HIV) would start to develop the skin lesions, fungal infections, lung problems and tumours that mark the progression of the resultant disease of Aids through a dying body - its immune system damaged, leaving the victim open to infection from any source. Treatments such as the drug AZT would offer hope to some, but, in the end, the future seemed to hold the promise only of crippling illness and a slow death.

But that thinking is rapidly being discarded. It is becoming clear that thousands of people all over the world have some, if not total, resistance to the disease. Prostitutes in Africa, where Aids has reached epidemic proportions, have been exposed to HIV through years of unprotected sex, yet fail to pick up the virus. Others become infected, yet remain healthy for decades. Some people, indeed, may be totally immune either to the effects of HIV, or to infection itself. Now, a team of scientists in the US may have found the answer to the question why some people are apparently able to fight HIV infection - and this new research offers the tantalising possibility of an effective treatment, using widely available drugs, for a disease that is claiming the lives of tens of thousands of people every year around the world.

Last year Bill Paxton, a Glaswegian molecular biologist working in New York, announced the discovery of a mutation, present in about 1 per cent of white Europeans, that appeared to confer a degree of immunity to HIV. The mutation occurs in a matched pair of genes - the segments of DNA that programme cells to manufacture particular proteins. In this case, the proteins are found in the membranes of white blood cells, which make up the core of the body's immune system. It is these cells which are attacked by the virus.

For the immunity to be effective, both copies of the mutated gene, which is known as CCR5, must be present. The result is that the white cells lack the CCR5 protein - which HIV needs in order to attack them. Studies by Belgian scientists have shown that the mutation did not seem to occur in people of African or Japanese origin. About 20 per cent of Caucasians have at least one copy of the gene, and 1 per cent have both - rendering them apparently immune to Aids. One such case is Steve Crohn, a freelance travel editor living in New York, who remains uninfected despite multiple exposure over years.

Because it is found in only one racial group, scientists think that the mutation is recent, perhaps dating back only 4,000 years or so. However, the latest research, published in Science magazine, has uncovered another genetic mutation, this time found in between 15 and 20 per cent of people of all races.

This beneficial genetic mutation offers no protection against picking up HIV, but instead appears to slow down the onset of Aids dramatically. A team working at the US-government-funded National Cancer Institute in Maryland has discovered the mutation, which affects the gene for a chemokine receptor, a structure in the white blood cell membrane that forms the entry point for HIV. This gene is known as CCR2. Chemokine receptors are normally beneficial, helping the body to marshal its forces in the fight against infection. But HIV attacks these defences, using the chemokine receptors to gain a bridgehead into the immune system. It is thought that the change in the cell membrane may interfere in some way with HIV, rendering it less effective. Dr Michael Dean, one of the molecular geneticists working on the project, described the discovery as a real breakthrough.

"We have known for a long time that there are people out there who survive for a long time after infection. There are people who have been infected for about 10 or 20 years who have not developed Aids," he told The Independent. He thinks it likely that a host of genetic factors may be coming into play.

"It seems that the CCR2 gene has no effect on whether or not infection occurs; it comes into effect after infection. There have been well-studied cohorts of prostitutes in the Gambia and other places who have not developed Aids. I think there are probably other genes coming into play here as well, that we don't know about yet."

In the study carried out by the Maryland team, 3,003 HIV-positive patients all over the US and in other countries were studied, and it was found that a large number of the long-term survivors - those who had avoided Aids for 16 years or more after HIV infection - carried the mutant CCR2 gene.

The effect of the CCR2 mutation is all the more surprising because it is caused by such a small change in the cell's DNA. One gene consists of several hundred base pairs (guanine, thymine, adenine, and cytosine) on the DNA strand, arranged in triplets of base pairs called codons. Each codon tells the cell to manufacture a single amino acid - the building blocks of proteins. The CCR2 mutation is caused by a change in a single codon, a tiny fraction of a whole gene, like a single spelling mistake in one chapter of a book. What originally caused it is unknown, but the fact that it occurs in all racial groups shows that it is very old - hundreds of thousands of years old. "It is surprising that this small mutation has such a big effect," said Dr Dean.

The discovery could have profound implications for treating Aids patients. If a disease is susceptible to being beaten off by a simple genetic mutation, then it could be possible to treat a patient using "gene therapy" - introducing into the body cells containing the mutant genes. Michael Dean thinks there may be even simpler ways forward in the immediate future.

"Gene therapy is hard to do, and I think that is a long way off," he said. "However, one thing that is interesting is that the chemokine receptors are involved in a lot of other diseases, such as asthma. Drug companies already have a lot of products on the shelves which may be useful against chemokine receptors, and these drugs could be used in HIV therapy," he added.

These drugs, which have already been safety tested, could, within a year, end up being used in the treatment of Aids patients, according to the Maryland team.

Michael Dean is optimistic that science is finally making significant breakthroughs in the fight against the disease. "We are beginning to figure out why some people are resistant to infection or have a delay in coming down with Aids. If you can figure out why they are doing so, then we may be able to come up with strategies to help the rest of the population"

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