[Interrelationship between human cytomegalovirus infection and chemokine]

Abstract

Human cytomegalovirus (HCMV) infection is frequently associated with AIDS patients and immunocompromised recipients of organ transplants. The progression of HCMV infection is related to a complex interrelation of virus replication with the host immune system, including soluble and cellular factors. A chemokine, interleukin-8 (IL-8), is essentially involved in neutrophil-mediated tissue injury. Moreover, several chemokine receptors are co-receptor for HIV entry. Hence, we investigated the effects of IL-8 on HCMV replication in human embryonic fibroblasts, MRC-5 cells. IL-8 augmented both infectious virus production and replication of HCMV, with concomitant increases in the levels of both the HCMV pp71 genome and the synthesis of the HCMV late antigen. The enhancing effect of IL-8 was observed at concentration from 0.1 ng to 10 ng of IL-8/ml, showing a dose-response relationship similar to that observed in the neutrophil chemotactic activity of IL-8. IL-8 did not enhance the growth of MRC-5 cells, indicating that IL-8 enhanced HCMV replication and virus production without affecting the proliferation of host cells. We also found that HCMV selectively induced transcripts of CXCR-1 in fibroblasts by RT-PCR, but significant numbers of binding sites could not be detected on HCMV infected cells by using 125I-labeled IL-8. Thus, IL-8 may enhance HCMV replication in fibroblasts through interaction with small number of CXCR-1. Furthermore, HCMV infection induced IL-8 gene transcription in a human monocytic cell line, THP-1, leading to IL-8 secretion. It is unlikely that HCMV infection enhanced IL-8 production indirectly by inducing the production of some soluble factors, because virus-free filtrated HCMV or UV-irradiated HCMV infected supernatants failed to induce IL-8 production. The functional analysis of the IL-8 gene revealed that both AP-1 and NF-kB factor-binding element were involved in conferring the responsiveness to HCMV. Moreover, electrophoretic mobility shift assay demonstrated that the formation of AP-1 and NF-kB complex was observed upon HCMV infection. These results suggest that IL-8 produced upon HCMV infection, may aggravate HCMV infection by enhancing its replication. Thus, IL-8 and CXCR-1 might be a novel target for intervention therapy for opportunistic HCMV infection.