HIV Induces both a Down‐Regulation of IRAK‐4 that Impairs TLR Signalling and an Up‐regulation of the Antibiotic Peptide Dermcidin in Monocytic Cells

Abstract

HIV‐infected individuals have an increased risk of invasive bacterial infections, even at early clinical stages with relatively normal CD4+ T‐cell counts. The pathogenic mechanisms behind this are not fully understood. However, an increasing number of studies indicate that HIV may impair the innate immunity to bacteria by infecting key cells of the monocyte/macrophage lineage. In this study, the effects of HIV infection on the protein profile of undifferentiated monocyte‐like THP‐1 cells were examined by a mass spectrometric approach based on stable isotope labelling with amino acid in cell culture (SILAC). We identified 651 proteins, of which nine proteins were down‐regulated and 17 proteins were up‐regulated in HIV‐infected THP‐1 cells as compared to uninfected controls. Most remarkably, the IL‐1 receptor associated kinase 4 (IRAK‐4), which is essential for virtually all TLR signalling, was suppressed, whereas the precursor for the antibiotic peptide Dermcidin was up‐regulated in HIV‐infected cells. Upon stimulation of either TLR2 or TLR4, the HIV‐infected THP‐1 cells displayed reduced TNF‐α secretion. The HIV‐induced down‐regulation of IRAK‐4 was reconfirmed in monocyte‐derived macrophage cell cultures. These data suggests that HIV may impair the TLR signalling cascade for pathogen recognition in cells of the monocyte/macrophage lineage and thus, may reduce the ability of the innate immune system to sense invading pathogens and initiate appropriate responses.

MyD88-dependent TLR4 signaling is selectively impaired in alveolar macrophages from asymptomatic HIV+ persons

“…by guest www.bloodjournal.org From present study. 24 Taken together, these observations support the concept that HIV infection is associated with targeted and specific impairment of macrophage innate immune function rather than a global impairment of macrophage function.…”

“…This data suggest that the activity of IRAK in HIV ϩ macrophages is diminished in response to TLR4 activation and is in agreement with a previous report. 24 Recognizing the importance of NF-B in the TLR-mediated signaling pathway, 25 human U937 and U1 macrophages were incubated with lipid A (10 g/mL) up to 120 minutes; nuclear and cytoplasmic extracts were isolated and probed by Western blot with the antibody directed against the NF-B p65 component. Quantitative densitometric analysis showed marked reduction of p65 nuclear translocation in HIV ϩ U1 macrophages compared with U937 macrophages ( Figure 1C).…”

Expresión diferencial en placenta de beta-defensinas humanas y detección de variantes alélicas en el gen DEFB1 de madres positivas para VIH-1

“…In this regard, HBD-3 promoter is known to contain a functional binding site for the activator protein 1 (AP-1) (59); AP-1-convergent signaling pathways [for example those of toll-like receptor (TLR), and particularly TLR-2] are upstream events in the regulation of HBD-3 expression (59). Furthermore, all TLRs are expressed in human placenta (60,61) and it is known that HIV-1 inhibits the normal activation of these receptors leading to a down-regulation of their downstream gene products (62,63). Therefore, the down-regulation of HBDs by HIV-1 probably occurs through the inhibition of normal activation of some receptors and different transcription factor signaling pathways such as AP-1.…”

Antimicrobial Peptides: New Frontiers in the Therapy of Infections

“…et al, 2005). These peptides possess a potent and widespectrum antimicrobial activity against S. aureus, E. coli, Enterococcus faecalis, Listeria monocytogenes, Salmonellae, Pseudomonas and Candida albicans (Hata & Gallo, 2008;Pathak et al, 2009). By means of nuclear magnetic resonance it has been established that DCD-1 has an -helical structure with a helix-hinge-helix motif, which is a common molecular fold among antimicrobial peptides (Jung et al, 2010).…”