HIV: Is this the breakthrough?

An antibody neutralises the world's most destructive virus - Steve Connor reports on how scientists may at last have the key to defeating Aids

It could be one of the most important discoveries in the 20-year history of research into an Aids vaccine. Scientists have captured an image of the crucial moment when the human immunodeficiency virus can be blocked from gaining entrance to the human cells it ravages. In the words of the American research agency behind the study, the findings could have "profound implications" for the design and development of a future Aids vaccine.

The importance of the study, published in the current issue ofNature, should not be underestimated. "Creating an HIV vaccine is one of the great scientific challenges of our time," says Elias Zerhouni, director of the US National Institutes of Health. "NIH researchers and their colleagues have revealed a gap in HIV's armour and have thereby opened a new avenue to meeting that challenge."

The computer-generated image, created by the NIH scientists, shows what happens when HIV locks on to human cells. The virus relies on a key protein on its surface, and this protein is effectively neutralised by an antibody protein. This neutralising antibody could form the basis of a working vaccine.

The 3-D image was captured when a crystallised form of the two interlocking proteins was bombarded by X-rays. Such an atomic-level image gives crucial insights into how to work towards Aids medicine's Holy Grail: a prophylactic vaccine that prevents HIV infection.

Anyone who knows anything about Aids research knows that the field is littered with false dawns. American politicians promised an effective vaccine within five years of discovering HIV in 1984. British scientists thought that they could develop one within 10 years of being given huge government grants in the early 1990s. And in 1997 President Bill Clinton said he wanted to see an Aids vaccine by 2007 - which, of course, has not happened.

By the mid-1990s, the first clinical trials of antiviral drugs demonstrated their immense potential for keeping HIV-positive people alive, though they don't rid the body of the virus. This month, Merck, the US pharmaceuticals company, started trials in South Africa of a vaccine based on a genetically modified virus, with three HIV genes. Three thousand HIV-negative people will be immunised in the four-year trial.

The focus of the latest study is a protein in the virus's outer surface known as gp120 - the gp refers to glycoprotein and the 120 to its molecular weight. This protein molecule sticks out of the virus much like the detonator spikes that stick out of a naval mine as it floats in the sea. In fact the analogy is quite apposite because HIV uses its gp120 protein effectively to "detonate" itself across the membrane of the human cell to get access to the cellular machinery that it then hijacks.

The gp120 does this by binding to a human protein called CD4 which protrudes from the surface membrane of certain human cells - notably the white blood cells of the immune defences. From the earliest days, scientists reasoned that if they could somehow block this link between gp120 and its target protein, CD4, they could also block HIV infection, and hence prevent the spread of Aids.

It was originally thought that it would be fairly straightforward to construct a vaccine that stimulates the production of human antibodies which could neutralise the gp120 protein. By sticking to the gp120 protein, the antibodies would prevent HIV from binding to its target cell and at the same time stimulate immune cells to destroy the invader.

Scientists soon discovered that HIV has many ways of preventing antibodies from blocking its vital gp120 protein. Its first trick is to change the overall shape of gp120 through genetic mutations to generate countless strains and subtypes of the virus. This rapid mutation rate of gp120 makes it a difficult, chameleon-like target for the body's immune system.

Another trick used by HIV is to load its outer membrane with tough, sugary molecules that prevent antibody proteins from getting too close to the relatively small part of the gp120 protein involved in direct, initial contact with the CD4 molecule. Sugar molecules cover HIV in what amounts to a magic cloak that makes the virus invisible to the immune system.

"The more we learnt about HIV, the more we realised just how many levels of defence the virus has against attacks by the immune system," says Peter Kwong, of the US National Institute of Allergy and Infectious Diseases in Bethesda, Maryland.

In 1998, Dr Kwong and his colleagues published the first 3-D X-ray snapshot of the gp120 protein as it attached itself to the CD4 receptor protein of human cells. Dr Kwong says that the image gave scientists a glimpse of some sites on the virus that could be potential targets for new drugs and vaccines.

But the image also showed another layer of defence that HIV employs to prevent anything interfering with its deathly mission. Dr Kwong's first X-ray images of the gp120 and the CD4 proteins in 1998 showed that as the two proteins merge to form an interlocking complex, the 3-D shape of gp120 changes in what amounts to a viral feint caused by "conformational masking". By doing this, HIV shields itself still further from attack by the immune system.

The latest pictures in Nature this week show the detailed engagement between gp120 and CD4. They reveal the first contact between the two proteins - a crucial phase that could be the Achilles' heel of HIV - before the more generalised contact over a wider area which stabilises the merger. "The first contact is like a cautious handshake, which then becomes a hearty bear hug," explains Gary Nabel, a member of the research team at the national institute.

By studying the atomic details of this "first handshake", scientists hope to be able to study the precise part of the gp120 molecule that acts like the key that opens the CD4 lock, and so which could be the bull's-eye of the vaccine target. Scientists call this the "epitope" and it is the element they will work on to produce a vaccine that will hopefully produce neutralising antibodies against all strains of HIV.

The specific human antibody they used is called b12. It was discovered during studies of people who appear to have lived for years with HIV without developing Aids. "One of our primary goals is to develop HIV vaccines that can stimulate broadly neutralising antibodies," says Dr Nabel. "The structure of this gp120 epitope, and its susceptibility to attack by a broadly neutralising antibody, shows us a critical area of vulnerability on the virus that we may be able to target with vaccines."

Anthony Fauci, director of the National Institute for Allergy and Infectious Diseases, says that Dr Kwong's study provides a long-sought picture of the precise interaction between the gp120 surface protein of HIV and a neutralising antibody. "This finding could help in the development of an HIV vaccine capable of eliciting a robust antibody response," Dr Fauci says.

If so, then the Holy Grail of Aids medicine may have been finally found, with millions of lives saved with the help of an effective HIV vaccine.

Resistance movement: viruses that have yet to be conquered

HEPATITIS C

Spread by blood-to-blood contact, this liver-damaging virus currently infects around 200 million people. It is unlikely that one vaccine will ever protect against all strains.

PANDEMIC INFLUENZA

The vaccine for HN15 (bird flu, above) is updated as the virus mutates. Scientists expect a flu pandemic, but do not know which strain will attack. A vaccine will take six months to develop.

RESPIRATORY SYNCYTIAL VIRUS (RSV)

Thisvirus, the most common cause of respiratory infections, can be life-threatening to babies. A vaccine is high-priority, but nothing is available yet.

CYTOMEGALOVIRUS (CMV)

Every year around 300 babies in the UK are born handicapped as a result of CMV. Itspreads in bodily fluids, and most adults are unwittingly infected at some point. No vaccine exists.

GENITAL HERPES

Carriers of genital herpes appear to be more susceptible to infection from HIV. A vaccine for genital herpes could help prevent the spread of HIV.

Kate Ravilious

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