HIV This Week

Duffy antigen receptor for chemokines (DARC) expressed on red blood cells influences plasma levels of HIV-1-suppressive and proinflammatory chemokines such as CCL5/RANTES. DARC is also the red blood cell receptor for Plasmodium vivax. Africans with DARC _46C/C genotype, which confers a DARC negative phenotype, are resistant to vivax malaria. Here, Weijing and co-authors show that HIV-1 attaches to red blood cells via DARC, effecting trans-infection of target cells. In African Americans, DARC _46C/C is associated with 40% increase in the odds of acquiring HIV-1. If extrapolated to Africans, approximately 11% of the HIV-1 burden in Africa may be linked to this genotype. After infection occurs, however, DARC-negative red blood cell status is associated with slower disease progression. Furthermore, the disease-accelerating effect of a previously described CCL5 polymorphism is evident only in DARC-expressing and not in DARC-negative HIV-infected individuals. Thus, DARC influences HIV susceptibility by mediating trans-infection of HIV-1 and by affecting both chemokine-HIV interactions and chemokine-driven inflammation.

Editors´note: A genetic trait found in 60 per cent of African-Americans and 90% of Africans increases the risk of HIV infection but decreases the rate of disease progression once infected.  The precise mechanisms by which lack of the Duffy antigen receptor for chemokines (DARC) can have this paradoxical effect are now the subject of much theorizing. Although an estimated 11% of the HIV epidemic in sub-Saharan Africa may be accounted for by people being DARC-negative, this does not change our basic understanding of the structural and behavioural determinants that lead people to being exposed to HIV in the first place.

Waters L, Mandalia S, Randell P, Wildfire A, Gazzard B, Moyle G. The impact of HIV tropism on decreases in CD4 cell count, clinical progression, and subsequent response to a first antiretroviral therapy regimen. Clin Infect Dis. 2008;46(10):1617-23.

Human immunodeficiency virus (HIV) uses 2 distinct chemokine receptors, CCR5 (R5) or CXCR4 (X4), during entry. Viruses may be R5 tropic, X4 tropic, or dual/mixed tropic. R5-tropic virus predominates at high CD4 cell counts, with the number of X4-tropic strains increasing as CD4 cell count decreases. Waters and colleagues investigated the relationship between tropism and decreases in CD4 cell count before antiretroviral therapy initiation, the frequency of clinical events, and responses to antiretroviral therapy in a cohort of treatment-naive patients. Four hundred two treatment-naive patients underwent tropism determination; 326 harboured R5-tropic virus, and 76 harboured X4- or dual/mixed-tropic virus. After adjustment for baseline characteristics, the rate of decrease in CD4 cell count was significantly greater in patients infected with X4- or dual/mixed-tropic virus at 12 months (P=.026). Two hundred twenty-nine individuals infected with R5-tropic virus and 60 individuals infected with X4- or dual/mixed-tropic virus commenced antiretroviral therapy between tropism testing and the time of data analysis. Time to viral suppression and the proportion of patients achieving viral suppression were similar at 6, 12, and 24 months. CD4 cell count increases were similar. Clinical events were significantly more common in the group infected with X4- or dual/mixed-tropic virus. Multivariate analysis demonstrated a relative risk of experiencing a clinical event of 2.56 (95% confidence interval, 1.37-4.76; P=.003) among patients infected with X4- or dual/mixed-tropic virus.  The authors conclude that the presence of dual/mixed- or X4-tropic virus has a deleterious effect on CD4 cell count decrease and risk of clinical disease. Response to standard antiretroviral therapy is not affected by viral tropism.

Editors’ note: Tropism is a word derived from the Greek meaning to turn. Most tropism is towards the source of the stimulus. In the case of HIV, when viral gp120 binds to CD4 cells, a chemokine receptor site on the cell becomes exposed. R5-tropic viruses will then use the CCR5 chemokine receptor on the cell surface, X4-tropic viruses will use the CXCR4 receptor and yet other viruses are dual tropic, using either receptor. It is unclear why X4-tropic strains increase as CD4 cell counts decrease but they are associated with increased clinical progression. At some point in the future, tropism testing may help determine when to start antiretroviral treatment.