Duffy Antigen Receptor for Chemokines Mediates trans-Infection of HIV-1 from Red Blood Cells to Target Cells and Affects HIV-AIDS Susceptibility

He, Weijing; Neil, Stuart J. D.; Kulkarni, Hemant; Wright, Edward; Agan, Brian K.; Marconi, Vincent C.; Dolan, Matthew J.; Weiss, Robin A.; Ahuja, Sunil K.

doi:10.1016/j.chom.2008.06.002

Cited by 165 publications

(206 citation statements)

References 49 publications

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“…In our study cohort, the HIV ϩ AAs had a slight survival advantage compared with HIV ϩ EAs. 10 This finding was consistent with the survival advantage observed in the HIV-infected AAs in a much larger segment of the same cohort of HIV ϩ subjects, of which the group that we studied was a subset. 12 In view of the epidemiologic observation that ethnic leukopenia is "benign" in otherwise healthy AAs, a parsimonious explanation for the survival advantage observed in the overall group of HIVinfected AAs compared with EAs was that it may be the result of a subset of leukopenic AAs who had a benign disease course compared with their leukopenic HIV ϩ EA counterparts.…”

Section: Introductionsupporting

confidence: 79%

“…1,2,9 To address this, we determined whether leukopenia impacts on the HIV disease course of subjects in a natural history cohort. [10][11][12][13] The large representation of both European Americans (EAs) and African Americans (AAs) in the study population allowed us to examine whether the impact of leukopenia on disease course differed according to race. This possibility is of particular interest because persons of African ancestry, on average, have significantly lower WBC counts, secondary to lower neutrophil cell counts, than persons of European descent.…”

Section: Introductionmentioning

confidence: 99%

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

Kulkarni

Marconi

et al. 2009

Blood

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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.

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Section: Introductionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

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

Kulkarni

Marconi

et al. 2009

Blood

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“…CXCL7 recruits PMNs in particular that release large quantities of platelet-activating factor (PAF). RANTES is a potent pro-inflammatory chemokine and inhibitor of HIV replication in vitro and is known to bind the Duffy antigen receptor for chemokines (DARC), coincidentally required for invasion of erythrocytes by P. vivax [16].…”

Section: Discussionmentioning

confidence: 99%

“…The Duffy antigen receptor for chemokines (DARC), which is needed for invasion of erythrocytes by P. vivax, is characterized by its ability to bind a wide array of proinflammatory chemokines (especially RANTES, which is highly effective in suppressing HIV-1 replication) [16]. Whether these platelet-derived chemokines have a similar role in malaria, perhaps by blocking access of P. vivax merozoites to DARC, is unknown.…”

Section: To Die Upon a Platelet's Kissmentioning

confidence: 99%

“…Platelet-derived microparticles account for 90% of the plasma microparticles from healthy individuals and recent proteomic analysis has shown them to contain chemokines CXCL4, CXCL7 and RANTES (CCL5) [15]. It is not known whether these secreted factors directly affect intracellular developing parasites or whether they indirectly recruit other mechanisms of killing, perhaps via pro-inflammatory mediators including cytokines.The Duffy antigen receptor for chemokines (DARC), which is needed for invasion of erythrocytes by P. vivax, is characterized by its ability to bind a wide array of proinflammatory chemokines (especially RANTES, which is highly effective in suppressing HIV-1 replication) [16]. Whether these platelet-derived chemokines have a similar role in malaria, perhaps by blocking access of P. vivax merozoites to DARC, is unknown.…”

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confidence: 99%

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Platelet power: sticky problems for sticky parasites?

Pleass

2009

Trends in Parasitology

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Platelets might have a crucial role in the pathogenesis of both human and rodent malarias by assisting in the sequestration of infected erythrocytes within the cerebral vasculature. However, recent elegant work by McMorran et al. suggests that they are also involved in innate protection during the early stages of infection. Here, we discuss the implications of their important findings in the context of immunity to malaria. Platelet: friend or foe?The platelet, traditionally known for its role in blood clotting, is also known for its putative involvement in malaria pathology [1,2]. However, a recent study using C57BL6 mice genetically deficient in the megakaryocyte growth and differentiation factor C-mpl (encoded by the Mpl gene), and resulting in mice with 90% fewer platelets, showed that these animals were significantly more susceptible to death when infected with Plasmodium chabaudi [3]. Furthermore, the authors went on to show that purified human platelets killed Plasmodium falciparum parasites within red blood cells when added to in vitro cultures and that various platelet antagonists, including aspirin, reversed this antiparasitic activity both in vitro and in vivo. This result raises concerns over the use of aspirin as an antipyretic in patients with malaria. Using specific receptor antagonists, the authors demonstrated that killing and control of parasite growth in P. falciparum cultures was dependent on platelet activation via P2Y1, an ADP-dependent metabotrophic puronergic receptor (Figure 1).These results in animals seem counterintuitive, in that platelets are believed to be involved in pathological disease states that hasten death, such as cerebral malaria [1,2]. For example, mice with significantly compromised platelet function (CXCL4 or CXCR3 deficient) have been shown to survive longer than their wild-type counterparts [4]. By contrast, platelet depletion by anti-CD41 monoclonal antibody injection early, but not late, in the course of disease is known to protect C57BL6 mice from Plasmodium berghei ANKA-induced severe experimental cerebral malaria (ECM) by altering levels of pathogenic cytokines [5]. Unfortunately, the study by McMorran et al. used P. chabaudi, a rodent malaria thatalthough capable of sequestering to a number of organs -is not known to develop ECM. It should also be noted that non-sequestering Plasmodium species also give rise to ECM in some inbred mouse strains, Plasmodium yoelii 17XL in BALB/c mice being a good example Europe PMC Funders Group A cornucopia of receptorsThe first of these questions is easier to explain for P. falciparum than for Plasmodium vivax or the murine malarias. Platelet-mediated clumping is common in P. falciparum field isolates, is distinctive from other adhesive phenotypes and involves the host receptors CD36[7] and gC1qR/HABP1/p32 [8]. Whether these are the only platelet receptors involved is debatable and worth exploring. Although GPIIb/IIIa (CD41/CD61) and GPIb/IX (CD42a/ CD42b)-deficient platelets still clump to infected erythrocytes [7], the...

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Duffy Blood Group System

Daniels

2013

Human Blood Groups

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Duffy Antigen Receptor for Chemokines Mediates trans-Infection of HIV-1 from Red Blood Cells to Target Cells and Affects HIV-AIDS Susceptibility

Cited by 165 publications

References 49 publications

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

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

Platelet power: sticky problems for sticky parasites?

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