Molecular Piracy Turns Protein Into Traitor

New Chemokine Holds Hope For HIV Treatment

An act of molecular piracy may put Glaxo Wellcome scientists on the track of drugs that would prevent HIV from entering human cells. Human herpes virus 8 (HHV-8) appears to have stolen a gene from the human host which codes for a chemokine. The virus then transformed it into a potent and broad-spectrum blocker of our chemokine system. Recent research has shown that two of the chemokine receptors blocked by the new molecule, CCR5 and CXCR4, are co-receptors essential for HIV infection of human cells.

This is the first naturally occurring chemokine antagonist. In humans, chemokines, also called chemoattractant cytokines, regulate the movement of white blood cells. However, in this case, the virus has modified the original human chemokine so that it binds to the chemokine receptor but does not stimulate the normal response. Instead, the resulting viral chemokine, vMIP-II, acts as an antagonist blocking the normal action of the receptor. Even more surprisingly, vMIP-II is able to block two distinct types of chemokine receptors, so called CC and CXC receptors. This is the first known molecule able to bind to both types of receptor.

The biological process the virus used to develop vMIP-II is not unlike the chemical process used by Glaxo Wellcome scientists to find new drugs. After lifting a human gene for a chemokine receptor agonist, the virus used genetics to perform a type of biological 'combinatorial chemistry'. This process can be used to produce a family of similar molecules. The virus then tested the related molecules against our own immunological defence mechanisms, making modifications until it found a molecule with the desired properties. In this particular case, the virus was hunting for a molecule that would prevent an inflammatory immune response that might clear the virus.

"The hope is that by understanding how the virus made this antagonist, we will learn lessons which will help us in the design of our own drugs. The virus has given us a substantial lesson in the rules of drug design", said Dr Tim Wells of the Glaxo Wellcome Geneva Institute of Biomedical Research.

vMIP-II is the only known molecule to block all main co-receptors used by HIV to gain entry to cells (CCR5, CCR3, CXCR4 and US28). Full details of the research, carried out in a three way collaboration with the Geneva Glaxo Wellcome group and teams led by Dr Thue Schwartz in Copenhagen and Dr Paul Clapham in London, are reported in the September 12th issue of Science.

The research adds to the growing evidence that chemokine antagonists may lead to novel approaches to HIV therapy either to prevent initial infection or to slow down disease progression in an already infected patient. Importantly, this research shows for the first time that it is possible to block both types of chemokine receptor used by HIV with one molecule. "vMIP-II will help us understand the structural differences between these two types of receptors and may lead to the discovery of a small molecule that would block both receptors," said Dr Wells. HIV uses CCR5 as a co-receptor to gain entry to macrophages during the initial infection and asymptomatic phase of the disease. Later on, HIV mutates allowing it to gain entry to T cells through CXCR4.

Biologically, the virus appears to have optimised vMIP-II to block leukocyte recruitment to the site of Kaposi's sarcoma. HHV-8 is most probably using the novel chemokine to shut off the inflammatory response that would normally be associated with a tumour. This means it may also be a useful tool in diseases such as rheumatoid arthritis or asthma where the human immune system is abnormally activated or even as a means of understanding transplant rejection. It may also lead to useful anti-inflammatory agents for asthma and rheumatoid arthritis.

Dr Tim Wells, Geneva Biomedical Research Institute,
Glaxo Wellcome Research and Development SA, 14 chemin des Aulx,
1228 Plan-les-Ouates, Geneva, Switzerland,
Tel: +4122 7069 804/824,
Fax: +41 22 794 6965,
e-mail tncw5312@ggr.co.uk

Philip Connolly,
Group Public Affairs,
Glaxo Wellcome plc,
Glaxo Wellcome House, Berkeley Avenue,
Greenford, Middx, UB6 0NN.
Tel: +44 181 966 8185,
Fax: +44 181 966 8827,
e-mail pgc2355@ggr.co.uk

. Emma Weitkamp,
Hayhurst Conington Cripps, Fry's Yard,
39-40 Bridge Street,
Godalming, Surrey, GU7 1HP.
Tel: +44 1483 414182,
Fax: +44 1483 414157,
e-mail emma@hcc.co.uk