HIV: getting to the heart of DARCness

In this issue of Blood, Kulkarni and colleagues continue their exploration of genetic regulation of HIV pathogenesis, and report that the absence of erythrocyte Duffy antigen is associated with a survival advantage in leukopenic, but not nonleukopenic, HIV-infected African Americans.¹ 

Chemokines and their receptors play critical roles in HIV pathogenesis, and genetic variation in the chemokine system has a profound impact on susceptibility to HIV infection and progression to AIDS. Ahuja's group and their collaborators have made key contributions to these genetic studies, and their recent work²  has led to increased attention to the role of the Duffy antigen, or DARC (Duffy antigen receptor for chemokines), in HIV pathogenesis. DARC is a nonsignaling chemokine receptor that, on erythrocytes, regulates the abundance of proinflammatory chemokines in serum.³  It also acts as a docking site for the malarial species Plasmodium vivax, and this is believed to have driven the emergence of the DARC-null state (ie, erythrocytes lacking DARC) common among persons with sub-Saharan African ancestry.⁴  DARC could impact on HIV pathogenesis in a number of ways. First, DARC binds several of the chemokine ligands for CCR5, the critical coreceptor for HIV entry into cells. These chemokines can suppress HIV entry, so their regulation by DARC could modify cellular infection rate. Second, erythrocyte DARC binds HIV where it remains viable for infection of CCR5⁺ T cells.^2,5  Third, the DARC-null state was recently shown, for reasons that remain unclear, to be the principal genetic determinant for the benign ethnic leukopenia (primarily neutropenia) seen in people of African ancestry.⁶  Such differences in white blood cell (WBC) count could clearly impact on disease course.

Ahuja and colleagues previously reported that DARC-null individuals show increased susceptibility to HIV infection, but slower HIV disease progression once infected.²  In this issue of Blood, Kulkarni et al examine associations among WBC count, DARC genotype, and survival in a large natural history cohort of HIV-infected Americans of both European (EA) and African (AA) descent. Leukopenia, defined as an average WBC count during disease of less than 4 × 10⁹ cells per liter, was associated with faster HIV disease progression rates, but notably leukopenic AAs had a slower disease course than leukopenic EAs. As in uninfected AAs, the DARC-null state was associated with low WBC count in HIV⁺ AAs. Significantly, among leukopenic subjects, there was a survival advantage for DARC-null AAs compared with DARC-positive AAs or EAs. By contrast, rates of disease progression in nonleukopenic AAs did not differ by DARC genotype. Although the mechanism(s) underpinning the survival advantage in DARC-null leukopenics remains unclear, several thought-provoking possibilities are aired in the article's discussion. It should be noted, however, that several recent studies failed to find associations, in other cohorts, between DARC genotype and an individual's susceptibility to HIV infection or disease progression.^7-10  Possible explanations for these discrepancies have been discussed previously by Ahuja and colleagues.¹¹  One of these explanations is highlighted in this new report by Kulkarni et al. It suggests that it is the strong interaction between DARC genotype and WBC counts that influences HIV disease course. Further studies are required to determine, for example, whether similar interactions influence HIV susceptibility, and how DARC genotype and WBC counts are mechanistically linked. Nonetheless, the novel functions emerging for DARC in homeostasis and disease mean that we are steadily making progress toward the heart of DARCness, and it is clearly going to be an exciting and illuminating journey.