Background. The Duffy-null trait and ethnic netropenia are both highly prevalent in Africa. The influence of pre-seroconversion levels of peripheral blood cell counts (PBCs) on the risk of acquiring human immunodeficiency virus (HIV)-1 infection among Africans is unknown. Methods. The triangular relationship among pre-seroconversion PBC counts, host genotypes, and risk of HIV acquisition was determined in a prospective cohort of black South African high-risk female sex workers. Twenty-seven women had seroconversion during follow-up, and 115 remained HIV negative for 2 years, despite engaging in high-risk activity. Results. Pre-seroconversion neutrophil counts in women who subsequently had seroconversion were significantly lower, whereas platelet counts were higher, compared with those who remained HIV negative. Comprising 27% of the cohort, subjects with pre-seroconversion neutrophil counts of <2500 cells/mm3 had a ∼3-fold greater risk of acquiring HIV infection. In a genome-wide association analyses, an African-specific polymorphism (rs2814778) in the promoter of Duffy Antigen Receptor for Chemokines (DARC -46T > C) was significantly associated with neutrophil counts (P = 7.9 × 10-11). DARC -46C/C results in loss of DARC expression on erthyrocytes (Duffy-null) and resistance to Plasmodium vivax malaria, and in our cohort, only subjects with this genotype had pre-seroconversion neutrophil counts of <2500 cells/mm3. The risk of acquiring HIV infection was ∼3-fold greater in those with the trait of Duffy-null-associated low neutrophil counts, compared with all other study participants. Conclusions. Pre-seroconversion neutrophil and platelet counts influence risk of HIV infection. The trait of Duffy-null-associated low neutrophil counts influences HIV susceptibility. Because of the high prevalence of this trait among persons of African ancestry, it may contribute to the dynamics of the HIV epidemic in Africa.
Bibliographical noteFunding Information:
Financial support. The CAPRISA 002 study was supported by the National Institute of Allergy and Infectious Disease, National Institutes of Health (NIH; grant U19 AI 51794). V.R. was a recipient of a CAPRISA training fellowship and a Fogarty AITRP fellowship (TWO-0023) and a KwaZulu-Natal Research Institute for TB and HIV (K-RITH) travel award. T.N. is supported by the Hasso Plattner Foundation and holds the South African DST/NRF Research Chair in Systems Biology of HIV/AIDS. This work was supported by the VA HIV/AIDS Center of the South Texas Veterans Health Care System, an NIH award (R37046326), the Doris Duke Distinguished Clinical Scientist Award to S.K.A. S.K.A. is also supported by a VA MERIT award and the Burroughs Wellcome Clinical Scientist Award in Translational Research.