HTB South

Genetic protection against malaria may increase susceptibility to HIV infection in people of African decent

Richard Jefferys, TAG

A new and complex study has identified a possible genetic influence on susceptibility to HIV acquisition that preferentially impacts Africans and people of recent African descent. [1] The paper is available free on the website of the journal Cell Host & Microbe (link below).

The major points are as follows:

  • The Duffy Antigen Receptor for Chemokines (DARC) [2] on red blood cells can bind a slew of different chemokines and also HIV itself (X4-using HIV isolates much more than R5-using isolates).
  • A genetic change (called a single nucleotide polymorphism or SNP) can lead to a lack of DARC receptors on red blood cells. This SNP is very common in Africans and people of recent African descent, because it once protected against a form of malaria caused by the pathogen Plasmodium vivax.
  • In a large cohort of African American individuals from the US military, having the DARC-negative SNP was associated with a significantly increased risk of having HIV infection, even in multivariate analyses controlling for various confounding variables. However, the confidence intervals on the multivariate analyses ppear to approach a relative risk of 1.0 at the low end (in other words, based on the numbers in this study, it is within the bounds of possibility that the SNP has little impact on susceptibility). The result appears to rest on the finding that perhaps ~60% of 814 HIV-negative African Americans lacked the DARC receptor compared to ~70% of 470 HIV-infected African Americans. [3]
  • If the result holds up, the fact the SNP is nearly ubiquitous among African populations could contribute to the higher incidence of HIV infection on that continent (the researchers estimate it might explain ~11%).
  • The absence of the DARC receptor is associated with lower levels of CCL5 (formerly called RANTES), a chemokine with strong anti-HIV activity, providing a possible mechanistic explanation of the finding. A prior study has reported that persistently exposed, uninfected sex workers have ten-fold higher levels of CCL5 in the genital tract compared to both infected individuals and uninfected study participants who had recently started sex work and thus had little prior exposure to HIV. [4] Higher CCL5 production has also been reported in highly exposed but uninfected gay men. [5]
  • Although at first blush it might sound paradoxical, the absence of DARC was also associated with a slight but significant slowing of disease progression in the HIV-infected members of the study cohort. The researchers suggest that this is likely explained by the association between the presence of DARC and higher levels of pro-inflammatory chemokines such as CCL2. Once infection occurs, the authors propose, the presence of DARC may exacerbate immune activation due to this association with elevated levels of pro-inflammatory chemokines (immune activation is the single strongest predictor of the pace of disease progression in people with HIV). While this hypothesis remains speculative, the authors argue it is supported by an association they have reported previously; in that case, a SNP that increases CCL2 levels in European Americans was shown to be linked to reduced susceptibility to acquisition of HIV infection and also faster disease progression in infected individuals. [6] Another non-exclusive possibility raised by the authors is that the absence of DARC slows progression by preventing transfer of DARC-bound HIV particles to CD4 T cells.

In discussing their results, the study authors acknowledge that there is a possibility that the associations they have observed are connected to an unknown factor or factors that are linked to the DARC SNP, and stress that confirmation of these results in other cohorts will be necessary to ensure they are valid. If it does turn out that there is a protective effect mediated by elevated levels of CCL5, this information could potentially assist vaccine development, as it would suggest that using adjuvants that elevate CCL5 levels and/or inducing HIV-specific T cell responses that produce CCL5 could be useful strategies for HIV vaccines.

Source
TAG Basic Science Blog. Expression of the Duffy antigen receptor for chemokines may impact susceptibility to HIV infection. (16 Jul 2008)
http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2008/07/expression-of-t.html

References

1. He W, Neil S, Ahuja SK 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 and Microbe, Vol 4, 52-62, 17 July 2008.
2. http://en.wikipedia.org/wiki/Duffy_antigen_system
3. http://www.cellhostandmicrobe.com/content/article/image?uid=PIIS193131280800190X&imageid=fig2
4. http://www.ncbi.nlm.nih.gov/pubmed/16088822
5. http://www.ncbi.nlm.nih.gov/pubmed/15166527
6. http://www.ncbi.nlm.nih.gov/pubmed/12374865

Free online access
http://www.cellhostandmicrobe.com/content/article/fulltext?uid=PIIS193131280800190X

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