25 July 2008
The prevalence of a specific infectious disease typically varies in different populations; much of this variation may result from differing social and economic factors, but genetic factors that influence susceptibility and resistance to the infectious agent can also play a significant role, and are of obvious relevance to public health. For example, it has been known for a long time that cellular receptors play a role in viral entry, and that mutations in such receptors can confer increased resistance to infection by HIV-1. HIV-1 enters a type of white blood cell via interactions with the CCR5 surface receptor; around 1% of Caucasians are homozygous for a specific deletion in the CCR5 gene, which confers a significant degree of resistance to HIV-1 infection.
New research has implicated the red blood cell (RBC) surface Duffy antigen receptor for chemokines (DARC) in susceptibility to HIV-1 (see BBC news). DARC is the RBC receptor for Plasmodium vivax, one of the four most common species that causes human malaria. Individuals who lack a functional DARC (with a DARC −46C/C genotype) including over 90% of West Africans, are resistant to infection by P. vivax; it is thought that the very high population prevalence of this genotype in areas where P. vivax malaria is endemic is the result of a selective evolutionary advantage.
A paper published in Cell Host and Microbe from researchers at University College London and the University of Texas has reported that DARC is also a receptor for HIV-1 attachment and entry to RBCs, which influences blood plasma levels of chemokines (molecular mediators of the immune response) that suppress HIV-1 and promote inflammatory responses. The researchers also report that the DARC-negative genotype is associated with 40% increase in risk of HIV-1 infection among African Americans [He W et al. (2008) Cell Host Microbe. 4(1):52-62], allowing for the influence of different environmental factors, and propose that, based on the prevalence of this genotype in sub-Saharan African populations, it could account for 11% of all HIV-1 cases. However, the DARC-negative genotype is also associated with slower disease progression. The authors conclude that DARC influences HIV/AIDS susceptibility by mediating infection of red blood cells by HIV-1 and immune responses to the virus.
Comment: The processes by which HIV-1 is able to infect different types of human cell and to evade human immune responses are many and complex, and this research merely adds one more piece of evidence to the body of knowledge in this area; it does not represent a breakthrough that could lead to an effective vaccine or curative therapeutic. The epidemiological work should be repeated in native African populations to determine a more accurate assessment of the impact of the DARC-negative genotype on infection rates and disease progression. However, the paper marks the “first genetic risk factor for HIV found only in people of African descent, and sheds light on the differences in genetic makeup that play a crucial role in susceptibility to HIV and AIDS” (see press release), helping to explain at least some of the observed variation in prevalence rates between different populations.