HIV particles infect the white blood cells of the host. In order to gain access to the cells, the virus particle binds to a receptor molecule known as CD4 found on the surface of certain white blood cells including macrophages and some T-cells. Interaction with other surface proteins (co-receptors) on the cell membrane enables the virus envelope to fuse with the cell membrane, releasing the viral contents into the cell. The virus is then able to replicate within the cell, and new virus particles are released to infect further white blood cells.
There are two main strains of HIV-1: macrophage-trophic and T-trophic strains (Deng et al, 1996). Macrophage-trophic strains are predominant in most infected individuals, they infect macrophages but not mature T-cells, and they gain entry to the cell using the co-receptor C-C chemokine receptor 5 (CKR-5). T-trophic strains infect T-cells primarily, and their entry to the cell is mediated by the co-receptor fusin (Feng et al, 1996).
A study of 25 subjects who remained uninfected with HIV despite numerous high-risk exposures to the virus was carried out by Paxton et al (1996). They found immunological evidence that the subjects had been exposed to HIV virus particles, but the white blood cells usually infected by the virus seemed to be less susceptible to infection than normal. This resistance seemed to be associated with the activity of CKR-5. The white blood cells studied only displayed resistance to infection by macrophage-trophic strains of HIV.
Liu et al (1996) described a genetic deletion of 32 base pairs in the gene coding for the co-receptor CKR-5, which results in a severely truncated version of the co-receptor. Two subjects who appeared resistant to HIV infection were studied, and both had two copies of the defective gene, rendering their white blood cells incapable of manufacturing functioning receptors. This mutation does not appear to have any negative effects and is only detectable by genetic testing.
Individuals who have a single copy of the defective gene do not appear to be resistant to HIV infection, as their cells are still able to express the co-receptor from the second normal copy of the gene. It is believed that individuals with one copy of the defective gene are quite common in some populations, estimations suggest the proportion may be as high as 20%.
Further studies are required to establish the full implications of these findings. For example, some individuals seem to remain asymptomatic following infection of HIV for an unusually long period of time: it is possible they may have a single copy of the mutated gene, or maybe another undiscovered variant of the co-receptor which renders them less susceptible.
Since CKR-5 appears to be dispensable, this discovery may pave the way for new therapeutic approaches targeting the receptor through gene therapy (Feng et al, 2000). Stem cell transplants from individuals with two copies of the mutation have already yielded promising results, although this type of therapy is unlikely to be practical on a large scale without further advances in stem cell research, as availability of donors is likely to be an issue.
Written by Mark Riegel, MD
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