Gene that protects against malaria may increase HIV risk in Africans

Keith Alcorn
Published: 21 July 2008

A gene variant that became common in people of African ancestry because it protected against malaria appears to increase the risk of HIV infection by around 40% and may contribute to the higher HIV burden in sub-Saharan Africa, according to a study published on July 17th in the journal Cell Host and Microbe.

The genetic variation occurs in a gene that encodes a protein found mainly on the surface of red blood cells. The genetic variant confers protection against the malaria parasite Plasmodium vivax. It became more common over time in Africans because it protected against malaria, but is not present outside people of African ancestry.

The protein, called Duffy Antigen Receptor for Chemokines (DARC), is expressed on the surface of red blood cells, and tethers HIV to the surface of the cell. HIV is then presented to lymphocytes and infects them.

But in people with the genetic variant DARC -46C/C, the gene does not instruct the production of the protein, and so it does not appear on the surface of red blood cells. At first sight this would suggest that these people would be protected against HIV, but the opposite appears to be the case because, say the researchers, people with DARC also have high levels of the chemokine CCL5 (immune system messengers) that suppresses HIV before it can infect cells.

People without DARC, on the other hand, have low levels of these suppressive chemokines, which seems to create an environment in which HIV infection is easier.

But once infection occurs, the tables are turned. Looking at a cohort of 1284 African-Americans receiving medical care through an air force base in Texas who have been followed for up to 22 years, the researchers found that although the DARC -46C/C variant was associated with a higher risk of HIV infection, it was also also associated with slower disease progression.

The presence of DARC on cells may exacerbate the effects of HIVinfection by increasing the presence of a wide range of pro-inflammatory cytokines, which increase HIV replication and immune activation to a far greater extent than the HIV suppressive chemokine CCL5.

Also, once the virus reaches higher levels, it is more likely to displace chemokines bound to DARC on red cells, further exacerbating inflammation. And during established infection, HIV bound to DARC on red cells is poised for delivery to CD4+ T cells, the researchers said.

"The parts of a car that get it into gear are separate from those that get it moving once in gear," said Professor Sunil K. Ahuja, from The University of Texas Health Science Center at San Antonio. "A similar analogy applies to HIV; the factors that influence its transmission are not necessarily the same as those that influence disease progression."

The DARC -46C/C gene variant is almost universal among Africans, and the authors say it may have contributed towards the spread of HIV in sub-Saharan Africa. However the gene variant, which became widespread because it protected against malaria, does not protect against malaria spread by the predominant vector worldwide today, Plasmodium falciparum.

"The results underscore that genetic variants that influence transmission and disease progression can differ in their frequency among different populations, with possible impacts on the heterogeneity of HIV disease burden,” say the authors, “not just at the level of individuals but also populations."

Reference

He et al.: 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, 52–62, July 17, 2008. DOI 10.1016/j.chom.2008.06.002

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