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CHEMOKINE RECEPTORS ACT AS CO-RECEPTORS FOR HIV
The entry of HIV into T cells requires binding of virus to both the CD4 protein and one of several chemokine receptors, which act as co-receptors. The chemokine receptors are membrane proteins with seven trans-membrane segments. They bind chemokines , a group of approximately 50 small messenger peptides that activate the white blood cells of the immune system and attract them to the site of infections. The most important chemokine receptors for HIV entry are CCR5 and to a lesser extent CXCR4.
Mutations in CCR5 are largely responsible for the small proportion of the population who are naturally resistant to infection by the AIDS virus. The CCR5 ∆32 allele has a deletion of 32 base pairs and results in nonfunctional CCR5 protein. Individuals homozygous for CCR5 ∆32 are vastly less susceptible to infection by HIV (though not totally resistant). In addition, if the individual is infected, the disease progresses much more slowly. About 2% of Europeans are homozygous for CCR5 ∆32 and 14% are heterozygous. Heterozygotes appear to be mildly protected and show slower progression, in accord with the lower levels of CCR5 protein on the surfaces of their T cells. The origin of the CCR5 ∆32 allele has been traced back to around 700 years ago in northwest Europe, at about thetime of the Black Death. Conceivably, the defects in CCR5 wereselected by providing resistance against the bubonic plague. Variations in susceptibility to AIDS also result from alterations in the DNA sequence of the promoter for the CCR5 gene. Presumably these cause variations in the level of CCR5 protein expressed.
Preexisting receptors that direct the uptake of important molecules into animal cells are often the targets for viruses.
It is quite possible for the same host cell protein to be used as a receptor by unrelated infectious agents, including both viruses and bacteria. Thus, the myxoma poxvirus, which causes immune deficiency in rabbits, also uses the CCR5 and CXCR4 chemokine receptors. Which receptors are used by smallpox or other poxviruses is still unknown. Other pathogens, including the malaria parasite, also target chemokine receptors, although not CCR5 and CXCR4. Scientists are presently trying to identify the functions of the various receptors on immune cells in the hope of understanding how viruses exploit them for their own use.
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