Sunday, August 3, 2008

Duffy Antigen Receptor for Chemokines Mediates trans-Infection of HIV-1 from Red Blood Cells to Target Cells and Affects HIV-AIDS Susceptibility

ResearchBlogging.orgSo there's a genetic variation common in Africans, which both confers malaria resistance and facilitates HIV infection. I am totally not an expert in this area, but this is really important research, so I struggled through it in order to write it up. HIV/AIDS prevalence is disproportionately high in Africa, and we need to know why to try to figure out what to do about it. (For some prevalence data see here and here and especially the CIA world factbook rank order page here.) I've left out almost all technical detail from the paper here, to try to get the main outline as clear as I could. Among the other accessible accounts of the research out on the tubes is this piece in The Economist. (Shout to Michael over at Ionian Enchantment for sending me the paper in the first place.)

First some background. Among the factors affecting HIV prevalence are:

(1) Individual susceptibility to infection, and (especially in the case of HIV) to trans-infection of some cells by others within an infected individual. Leaving aside contingencies like other infections, age and more, this susceptibility can vary between individuals for genetic reasons - and there can be different ways, and combinations of ways, that a given individual can be more or less susceptible to infection by one or more strain of HIV.

(2) The rate of progression from being HIV-positive to developing AIDS. People who are HIV+ for longer before being debilitated by AIDS are, other things being equal, going to have more chances to infect others. Here too individual biological differences could be important.

(3) Individual biological differences might be patterned across the human population. We should expect this in cases where there are stable environmental considerations, and there are various examples including lactose tolerance, and sickle-cell anemia. The sickle cell trait affects haemoglobin properties in ways conferring malaria resistance, but when an individual inherits the gene from both parents she or he suffers from a form of anemia. (For more see here and here.)

This paper gives a variety of pieces of evidence relating to all three:

(1) It describes some of the evidence relating to a genetic difference between individuals that increases susceptibility to trans-infection by HIV-1.

(2) It describes some of the evidence that the same genetic difference also decreases the rate of progression to AIDS. (The authors are not able to explain this phenomenon, although there is clearly an association.)

(3) It shows that the genetic difference, which is associated with resistance to vivax malaria, is relatively more common in African Americans, and Africans. The key is a molecule called the Duffy antigen, which is the receptor molecule that malaria vivax uses to enter host cells, and is at least a part of the sickle cell trait. The absence of the antigen makes a difference to the course of HIV infection, by preventing some inflammatory activity that would otherwise slow the rate of trans-infection.

This is bad. Everything else being equal, some Africans, as a by-product of an adaptation conferring advantages against malaria are relatively more vulnerable to HIV infection, and relatively more dangerous epidemiologically, through having more time to pass on the infection. The authors of this study estimate that their findings might explain around 11 percent of the HIV burden in Africa.

The details of the research mostly concern providing evidence for the main claims, by means of genetic analysis of cohorts of people for whom data on disease progression is also available, laboratory studies of trans-infection in cell cultures, and plenty of specific detail regarding the molecular processes at work. Much of the specifics relate to red blood cells, which is where the malarial resistance is manifest, and where the properties conferring malarial resistance are also responsible for accelerated trans-infection by HIV-1.

The authors do not have direct African data, but make use of a substantial number of US servicemen in the Wilford Hall Medical Center cohort, including significant numbers of African Americans, who agreed to participate in a long term health study. Additional genetic and other work in Africa will help clarify matters.

HE, W., NEIL, S., KULKARNI, H., WRIGHT, E., AGAN, B., MARCONI, V., DOLAN, M., WEISS, R., AHUJA, S. (2008). Duffy Antigen Receptor for Chemokines Mediates trans-Infection of HIV-1 from Red Blood Cells to Target Cells and Affects HIV-AIDS Susceptibility. Cell Host & Microbe, 4(1), 52-62. DOI: 10.1016/j.chom.2008.06.002

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