Defective Neutrophil Degranulation Induced by Interleukin-8 and Complement 5a and Down-Regulation of Associated Receptors in Children Vertically Infected with Human Immunodeficiency Virus Type 1

Abstract

The polymorphonuclear neutrophils (PMNs) of patients infected with human immunodeficiency virus type 1 (HIV-1) show impaired microbicidal responses. The present study assessed the functional integrity of PMN degranulation responses and the expression of specific receptors that mediate these responses in a group of children vertically infected with HIV-1. PMN degranulation in response to interleukin-8 (IL-8) and complement 5a (C5a) was measured in a group of HIV-1-infected children with mild and severe clinical disease and in an uninfected control group. In addition, the expression of CXCR1, CXCR2, and CD88 on whole-blood PMNs was quantified by flow cytometry. Although CXCR1 expression was found to be largely unaltered in the HIV-1-infected children relative to that in the control children, the intensity of CXCR2 expression was significantly reduced in those with severe disease. Furthermore, there was a significant reduction in the percentage of cells expressing CD88 and in the intensity of CD88 fluorescence in the HIV-1-infected children compared to that in control children, with CD88 fluorescence intensity more significantly reduced in the presence of severe disease. PMNs from a large proportion of the HIV-1-infected children either showed reciprocal degranulation responses or were unresponsive to IL-8 and C5a, whereas the PMNs from the uninfected children showed positive responses. Inefficient agonist-induced degranulation may contribute to the increased susceptibility of HIV-1-infected children to secondary microbial infections. Furthermore, reduced expression of CXCR2 and CD88 may be suggestive of defects in other functions of PMNs from HIV-1-infected children.

Granulocyte macrophage colony stimulating factor

“…2C). This is in agreement with other studies that demonstrated decreased expression of other chemotactic and phagocytic receptors on the neutrophils of HIV patients (61,64). Second, acute application of GM-CSF did not have any beneficial effect (Fig.…”

“…5A). This is consistent with other studies that demonstrated that HIV infection inhibits, rather then promotes, neutrophil degranulation (60,61). In vivo GM-CSF treatment had no effect on the granule content of blood neutrophils from uninfected animals ( Fig.…”

Reduced frequency of wheezing respiratory illness in infants with perinatal human immunodeficiency virus‐type 1 infection: A model for immunologic and inflammatory mechanisms of airway obstruction?

“…An increased production of neutrophil chemoattractant IL-8 has been found in children with bronchiolitis (26). Thus, a defective neutrophil degranulation induced by IL-8 has been reported in HIV-1 infected children (27) and this finding may contribute to a less frequent finding of wheezing respiratory disease. In vitro exposure of monocytes to HIV-1 reduces their ability to produce eicosanoids, and ex vivo alveolar macrophages of HIV-1 infected patients highlight impaired expression of 5-lypoxygenase protein as well as a reduced production of proinflammatory leukotrienes and other 5-lipoxygenase metabolites of arachidonic acid (28).…”

Regulation of rainbow trout (Oncorhynchus mykiss) interleukin-8 receptor (IL-8R) gene transcription in response to viral hemorrhagic septicemia virus (VHSV), DNA vaccination and chemokines

“…For example, human cytomegalovirus inhibits the migration of immature dendritic cells by down-regulating the presence of CCR1 and CCR5 on the cell surface, while the levels of expression are unaffected [34]. However, the levels of expression of CXCR2 but not of CXCR1 are down-modulated in children infected with human deficiency virus type 1 [35]. Recently, a new mechanism through which viruses inhibit the migratory capacity of dendritic cells without affecting the …”

“…This down-regulation is no longer observed in response to Poly I:C, a dsRNA which in fact mimics the replication of the virus, and some up-regulation of IL-8R was even observed in this case, suggesting a viral interference in the regulation of IL-8R transcription. The mechanism through which VHSV is capable of down-regulating IL-8R gene expression is still unknown, but the down-regulation of chemokine receptors by viruses is a common pathogenic effect [34,35]. However, the chemokine presence in the cell surface may be regulated by two different mechanisms: altered gene expression or desensitization caused by phosphorylation-dependent internalization of the receptor upon ligand binding [36,37].…”