Thursday, 12 February 2009

CCR5, HIV and West Nile Virus.

When Human Immunodeficiency Virus (HIV) finds its way into the bloodstream, it seeks out cells bearing the two receptors it requires to gain entry. These two receptors are CCR5 and CD4, both principally expressed by immune cells. particularly 'T-helper' Cells. These cells are essentially the directors of the fight against infection, activating and co-ordinating attacks by the many other types of immune cells. In the early weeks of HIV infection, the virus infects and destroys T-helper cells while the immune system fights the infection by also destroying the infected T-helper cells. This immune response successfully damps down the HIV infection but consequently causes a sudden severe drop in T-helper cell numbers. However, the virus is not totally cleared, less than 0.1% of T-helper cells remain infected. The thymus is responsible for producing replacement T-helper cells and will do so for many years, but eventually direct infection of the thymus reduces this ability and the level of T-helper cells begins its final drop. As this happens other infections take advantage of the reduced power of the immune system, and Acquired Immuno-Deficiency Syndrome (AIDS) begins.

Current treatments for HIV infection are very effective but also very expensive. Highly Active Anti Retroviral Therapy (HAART) uses a cocktail of inhibitors to target a range of points in the viral life-cycle and slow the whole replication process down. There are many variations of this line of therapy, all very effective in reducing the total number of virus in the body, but unable to remove the virus completely. This is due in part to the viruses ability to rapidly mutate and also the way the virus integrates its DNA into the host's DNA, where it can remain inactive for extended periods before re-emerging.

This week the New England Journal of Medicine published a report detailing a treatment method which appears to have totally eradicated the virus from a patients body. It is an extreme method that is not suitable for use with everybody and has only a 60% chance of survival, but it highlights the possibilities. A treatment option for leukaemia (cancer of the blood cells) is to use chemotherapy to completely destroy the source of blood cells: The bone marrow. This leaves the patient with no immune system at all, and so a bone marrow transplant from a donor is required to re-establish one.

This is the procedure that Dr. Gero Hutter performed at Charite Universitatsmedizin Berlin in Germany on an American living there. Dr. Hutter's patient had a 10 year HIV infection as well as leukaemia, and so it was decided that the bone marrow donor should be one that has a mutant gene for the CCR5 receptor. Around 2% of the European population have this mutant gene with a sequence that is deleted. This gives them immunity from most strains of HIV as the virus cannot recognise this mutant. The bone marrow transplant was a success, and the patients new immune system lacked the normal CCR5 receptor. More than 2 years after the operation no HIV has been detected in the patients body even without HAART which was essential before.

This is not likely to become a common procedure for people infected with HIV due to the high risk of death, but it does indicate a potential route for gene therapy. If the CCR5 gene can be specifically mutated or replaced with the mutant version, it could have the same effect. There might be a catch though, like all proteins in the human body, it must be there performing a function of some sort, just because the mutant version doesn't cause death or illness doesn't necessarily mean we can do what we like with it and not worry about consequences. Giving people mutant CCR5 may well give them protection from HIV, but it has also been shown that mutant CCR5 may make people more vulnerable to infection by West Nile virus.

West Nile virus is transmitted via mosquitoes, recent outbreaks have been seen in Europe, Asia, The Middle East, Africa and Oceania. In 1999 it became established in the USA, beginning with an outbreak in New York City and subsequently spreading throughout North and Central America and the Caribbean. In the USA thousands of cases are recorded each year and annual deaths have previously numbered in the 100s. Altering the CCR5 genetics of a population may provide relief from the HIV pandemic, but it might make the West Nile virus problem even worse. We cannot know the precise reasons why natural selection has left us with the genes we have, nor do we fully understand the immune system; So it may be wise to tread carefully when using genetics to impart resistance to infectious diseases, in case we inadvertently leave our population vulnerable to a new pandemic with potentially fatal consequences.

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