The Duffy-null state is associated with a survival advantage in leukopenic HIV-infected persons of African ancestry

Abstract

Persons of African ancestry, on average, have lower white blood cell (WBC) counts than those of European descent (ethnic leukopenia), but whether this impacts negatively on HIV-1 disease course remains unknown. Here, in a large natural history cohort of HIV-infected subjects, we show that, although leukopenia (< 4000 WBC/mm 3 during infection) was associated with an accelerated HIV disease course, this effect was more prominent in leukopenic subjects of European than African ancestry. The Africanspecific ؊46C/C genotype of Duffy Antigen Receptor for Chemokines (DARC) confers the malaria-resisting, Duffy-null phenotype, and we found that the recently described association of this genotype with ethnic leukopenia extends to HIV-infected African Americans (AAs). The association of Duffy-null status with HIV disease course differed according to WBC but not CD4 ؉ T-cell counts, such that leukopenic but not nonleukopenic HIV ؉ AAs with DARC ؊46C/C had a survival advantage compared with all Duffypositive subjects. This survival advantage became increasingly pronounced in those with progressively lower WBC counts. These data highlight that the interaction between DARC genotype and the cellular milieu defined by WBC counts may influence HIV disease course, and this may provide a partial explanation of why ethnic leukopenia remains benign in HIVinfected AAs, despite immunodeficiency.

Neutrophil, lymphocyte and platelet counts, and risk of prostate cancer outcomes in white and black men: results from the SEARCH database

“…Consistent with prior studies, we found that black men had more lymphocytes and fewer neutrophils [15–18]. Beyond mere differences in numbers of inflammatory cells, some studies suggest there may be race differences in how inflammation manifests [9–11].…”

A recombinant dromedary antibody fragment (VHH or nanobody) directed against human Duffy antigen receptor for chemokines

“…Similar to what has been observed with P.vivax infection, it will be interesting to investigate the possibility that CA52 might preclude binding of HIV to DARC-positive red blood cells [39], keeping in mind that, presently, experimental data on binding of HIV to red cells and the relationship of this binding with HIV infection and AIDS progression seems to be complex and controversial [39][40][41][42][43][44][45].…”

“…Mechanisms which might explain the role of DARC are far from clear in many cases, but there is a growing consensus that chemokine binding is probably central to the pleiotropic effects of DARC [36][37][38]. Lastly, it should be mentioned that DARC might be involved in HIV binding to red cells, HIV contamination, and AIDS progression, but the ongoing studies have led to somewhat conflicting results [39][40][41][42][43][44][45].…”

The biochemistry and biology of the atypical chemokine receptors

“…This mechanism potentially explains how HIV infected Duffy "negatives" may exhibit a slower progression to AIDS despite their higher infection rates [46]. These differences in HIV progression between Duffy negative and positive individuals were more significant between the leukopenic patient cohorts [149], but could not be observed in several other studies using different cohorts.…”