Genetic Resistance to the Human Immunodeficiency Virus
The mutation that apparently confers significantly increased resistance to HIV occurs in the gene that codes for CCR5, a chemokine receptor found in the plasma membrane of certain cell types.
In order to infect a cell, HIV uses its envelope glycoprotein to bind the CD4 receptor found on several cell lineages of the immune system. This then changes the conformation of the envelope, allowing the virus to bind a coreceptor -- the main ones being CCR5 or CXCR4. Coreceptor binding induces the process of fusion, allowing viral RNA to enter and infect a cell. This mutation in the CCR5-coding gene alters the conformation of the final protein product, affecting its ability to bind chemokines.The import of the CCR5 mutation is that initial stages of infection with HIV, including infection via mother to child transmission, have been observed to involve cells that express CCR5. (With HIV-1 subtype B, which is common in the United States and Europe, for example, coreceptor switching to CXCR4 occurs later in the course of disease progression.) Apparently, the HIV virion is also unable to recognize this mutated CCR5, thus preventing the first stage of infection.
The association with the Black Death and bubonic plague is not yet solid. There are, however, reasons why it was singled out:
1. The extraordinarily high frequency of the mutation in European populations and those of European descent in the United States is quite striking. CCR5 normally functions by acting as a receptor for chemokines, signalling intracellularly to modulate the state and activity of the cell. With such a crucial role in the maintainence of normal immune function, it would require a very strong selective pressure to make the mutation provide enhanced fitness, thereby ensuring the continued presence of the mutation in a given population.
2. Population-level genetic analyses indicated that this mutation and its spread may be relatively recent. Certainly, it occurred after the separation of Asiatic, African and European races, as this mutation is not generally found in non-Europeans (this does not mean to say that the mutation may not have arisen spontaneously on various occasions, only to die out due to the decreased fitness that it confers).
3. Aside from the high selective pressure, the frequency indicates that there may have been a bottle-neck in the recent past. Genetic analyses suggested that the most recent impact of this pressure occurred around 700 years ago. This estimate coincides with the Black Death which rampaged through Europe in the mid 14th century. This disease, which resulted in the death of about a third of Europe's population, is hypothesized to have exerted powerful selective pressure on the relatively rare number of people carrying the mutation, subsequently allowing for the increased transmission of this mutated gene to the next generation.
HIV-1 Versus HIV-2
There are two types of HIV, denoted as 1 and 2. HIV-1 is the most widespread and most extensively studied. HIV-2 is more closely related to the simian immunodeficiency virus, or SIV, and is quite rare, being more or less confined to West Africa. Studies done on a cohort of female sex workers have suggested significantly slower progression to AIDS. It is also possible that prior infection with the less pathogenic HIV-2 maybe prevent superinfection with a HIV-1 strain.