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Genes involved in evolutionary fight with HIV discovered

News

9 December 2004

Researchers from Oxford, South Africa and Harvard have discovered exactly which human genes are principally involved in the evolutionary arms race with HIV, leading to a greater understanding of how some people can survive symptom free for years whilst others proceed rapidly to AIDS and death.

HIV infection in most people is a killer. However, in a small proportion of infected people, the virus is successfully controlled by the immune system. There is an evolutionary arms race occurring, in which HIV is mutating to avoid the immune defences mounted by the infected person, and, at the same time, the virus is driving evolution of human immune genes, because those genetic variations that are less successful at fighting the virus will have a lesser chance of survival. Normally we would expect this process of virus adapting to humans and humans adapting to virus to take thousands of years, but a study funded in part by the Wellcome Trust and published today in Nature suggests that in the case of HIV it is happening much more rapidly. Not only are human immune responses to HIV causing rapid changes in the virus, HIV is also causing rapid evolutionary changes in humans. Researchers from the Universities of Oxford, KwaZuluNatal in South Africa, and Harvard, set out to understand precisely how this evolutionary battle is being fought in order to pave the way for vaccine design.

Human leucocyte antigen (HLA) class I molecules play an essential role in the immune system’s fight against infection. Found on the surface of all nucleus-containing cells in the body, they identify to the immune system which cells are infected with HIV and should be destroyed. They do this by presenting tiny fragments of the virus on the surface of the infected cell, signalling to the body’s cytotoxic T lympohocytes, or “killer” T cells, that they should be destroyed.

There are three types of HLA molecule, termed A, B and C, which help the immune system to see virus-infected cells. Previous studies have shown that HLA-B genes are evolving more rapidly than HLA-A or HLA-C, for reasons that have been unclear. To investigate whether significant biological differences exist between HLA-B and the other HLA class I molecules, the team examined the role of HLA-B in control of HIV infection in Durban, South Africa. South Africa is afflicted by more HIV infections than any other country worldwide. In the antenatal clinics in Durban involved in the study, the proportion of mothers attending these clinics who are infected by HIV has risen from less than 1 per cent in 1990 to around 50 per cent today.

The data collected in South Africa showed that above all other types, HLA-B molecules are doing the best job of identifying HIV infected cells to the body’s “killer” T cells. Correspondingly, it is these immune responses against which HIV is adapting the fastest. The researchers found that the success of the immune response in controlling HIV infection, and therefore the speed of progression to AIDS, is primarily determined by the particular HLA-B genes that each individual possesses.

Dr Philip Goulder, a paediatrician and research scientist working within the Peter Medawar Building for Pathogen Research at the University of Oxford, and at Massachusetts General Hospital, was principal investigator on the study. He said: ‘We have known for some time that HLA-B molecules are evolving more rapidly than other types, but it has been unclear why this is happening. These data suggest an explanation for the more rapid evolution of HLA-B in response to other infectious diseases, not only HIV. This is an exciting time for infectious disease research because we are witnessing the evolutionary fight between the human immune system and the HIV virus happening right now, rather than over a period of thousands of years.

‘This study identifies the genetic battleground where the struggle between HIV and the human immune response occurs. The findings will help in understanding precisely how the immune system can succeed or fail against HIV, a prerequisite for a rational approach towards design of an HIV vaccine.’

Dr Mark Walport, Director of the Wellcome Trust, said: ‘Developing a vaccine to prevent transmission of HIV from person to person is a very high priority for the international scientific community. This study adds a key piece to the jigsaw that needs to be completed in order to develop a successful vaccine.’

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Notes to Editors:

  • The results of this study are published in the 9 December 2004 edition of Nature. See www.nature.com.
  • The Peter Medawar Building for Pathogen Research at the University of Oxford houses an interdisciplinary research consortium which exploits technical advances and theoretical developments for the study of important pathogens. The unifying theme is the investigation of pathogen diversity through molecular characterisation and theoretical analysis. The combination of groups studying malaria, meningitis, hepatitis and AIDS, with a strong bioinformatics group which exploits population genetic theory, produces unique insights into the emergence, evolution and spread of infectious diseases.
  • The study was supported by the Wellcome Trust, the Elizabeth Glaser Pediatric AIDS Foundation, the National Institutes of Health and the Doris Duke Charitable Foundation.
  • The Wellcome Trust is an independent research funding charity established in 1936 under the will of the tropical medicine pioneer Sir Henry Wellcome. The Trust’s mission is to foster and promote research with the aim of improving human and animal health and it currently spends over £400 million per annum.
  • The study a collaboration between researchers from the Peter Medawar Building for Pathogen Research, University of Oxford; the Doris Duke Medical Research Institute, University of KwaZuluNatal, South Africa; the Centre for Clinical Immunology and Boimedical Statistics, Royal Perth Hospital and Murdoch University, Australia; the Department of Microbiology, University of Washington, Seattle; the Partners AIDS Research Center, Massachusetts General Hospital and Harvard Medical School; the Anthony Nolan Research Institute, Royal Free Hospital, London; the Santa Fe Institute, New Mexico; and the Howard Hughes Medical Institute, Maryland.