Failure of TLR4-Driven NF-<i>κ</i>B Activation to Stimulate Virus Replication in Models of HIV Type 1 Activation

Nordone, Sushila K.; Ignacio, Glicerio; Su, Lishan; Sempowski, Gregory D.; Golenbock, Douglas T.; Li, Liwu; Dean, Gregg A.

doi:10.1089/aid.2007.0033

Cited by 27 publications

(31 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The pattern of IL-10 release was confirmed in clinically relevant human AMs, showing similar levels of lipid A-mediated IL-10 release comparing AMs from healthy persons to AMs from asymptomatic HIV ϩ persons ( Figure 2F). The observed differences in TLR4-mediated TNF␣ and IL-10 release were not related to differences in macrophage expression of essential TLR4 modulator molecule MD2 30 ( Figure 2G) or surface expression of TLR4 coreceptor CD14 ( Figure 2H), consistent with our prior studies showing similar TLR4 surface expression comparing U937 and HIV ϩ U1 macrophages 7,31 and comparing AMs from healthy and HIV ϩ persons. 8 In contrast to impaired TLR4-mediated MyD88-dependent release of TNF␣, collectively these data show that TLR4-mediated IL-10 and RANTES release in human macrophages is predominantly MyD88 independent and suggest that HIV may specifically target the MyD88-dependent TLR4 signaling pathway, while preserving the MyD88-independent TLR4 signaling pathway.…”

Section: Reduced Tlr4-mediated Tnf␣ Release Associated With Impaired supporting

confidence: 90%

“…31,33 TLR4 is unique among the TLR family, supporting both MyD88-dependent and MyD88-independent signaling pathways, 11 whereas TLR3 exhibits MyD88-independent signaling, and all other TLRs exhibit MyD88-dependent signaling. 34 Activation of the MyD88-dependent signaling pathway promotes proinflammatory cytokine release such as TNF␣ and IL-12, 35 whereas activation of the MyD88-indepenent pathway promotes release of IFN-inducible genes such as type-1 IFN, IL-10, and RANTES.…”

Section: Discussionmentioning

confidence: 97%

See 1 more Smart Citation

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

Tachado

Bole

et al. 2010

Blood

View full text Add to dashboard Cite

IntroductionBacterial pneumonia remains a frequent and serious complication in asymptomatic HIV ϩ persons, despite relatively preserved peripheral blood CD4 ϩ T-lymphocyte counts 1 and use of highly active antiretroviral therapy (HAART) with undetectable plasma viral loads. 2 These persons have up to 25-fold greater risk of bacterial pneumonia than their healthy cohorts. 3 However, the mechanism contributing to this increased risk is not well understood. Toll-like receptor 4 (TLR4) represents a critical pattern recognition receptor in the innate immune host cell response to bacterial infection. Functional deficiency or genetic deletion of TLR 4 increases susceptibility to Haemophilus influenza, Streptococcus pneumoniae, and Klebsiella pneumoniae respiratory tract infections in murine models. 4,5 Another indication of its importance is that TLR4 polymorphisms are associated with increased susceptibility to lung infection. 6 Our laboratory has reported impaired TLR4-mediated tumor necrosis factor ␣ (TNF␣) release in alveolar macrophages from asymptomatic HIV ϩ persons at increased clinical risk of bacterial pneumonia. 7 Increased susceptibility may be in part related to reduced alveolar macrophage extracellular signalregulated kinase 1/2 (ERK1/2) mitogen-activated protein (MAP) kinase phosphorylation attributed to elevated MAP kinase phosphatase 1 (MKP-1) activity, 7 and constitutive phosphoinositol-3 kinase (PI3K) activation and heightened PI3K signaling in response to TLR4 activation. 8 These data suggest that the host cell proinflammatory cytokine may be suboptimal in the lungs of HIV ϩ persons and may in part contribute to increased bacterial pneumonia susceptibility and pathogenesis.TLR4 is the most studied of the TLR family of innate receptors. 9 It is a unique member of the TLR family of mammalian receptors in that TLR4 is capable of both adaptor molecule myeloid differentiation factor 88 (MyD88)-dependent and MyD88-independent signaling. 10-12 TLR4-mediated MyD88-dependent recognition of bacterial cell wall occurs at the cell surface, 11,13 does not require receptor internalization, 11 involves interleukin-1 receptorassociated kinase (IRAK) phosphorylation, and activation of TNF receptor-associated factor 6 (TRAF6), nuclear factor-B (NF-B), and MAP kinases (such as ERK1/2, p38, and Jun kinase), with the subsequent release of proinflammatory cytokines such as TNF␣ 14 that may contribute to an effective host defense response to bacteria. In contrast, TLR4-mediated MyD88-independent signaling requires receptor internalization and is mediated through Toll/interleukin-1 receptor (TIR) domain-containing adaptor inducing interferon-␤ (IFN␤; TRIF), 11 involves activation of IFN regulatory factor 3 (IRF3) and STAT1 15 with release of type-1 IFNs, 16 IL-10, 15 RANTES 15 and may be involved in antiviral host defense. 17 Recent work in our laboratory has shown impaired TLR4-mediated signaling response in alveolar macrophages from asymptomatic HIV ϩ persons at high clinical risk of bacterial pneumonia. 7,8 However, whe...

show abstract

Section: Reduced Tlr4-mediated Tnf␣ Release Associated With Impaired supporting

confidence: 90%

Section: Discussionmentioning

confidence: 97%

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

Tachado

Bole

et al. 2010

Blood

View full text Add to dashboard Cite

show abstract

“…6). An increase of TLR2, TLR4, and TNF-a in the H9 HTLV-IIIcc cells, a chronically infected cell line (data not shown), was observed, as also reported in U1 cells, 49 arguing that during chronic HIV-1 infection, proinflammatory cytokine release is increased.…”

supporting

confidence: 77%

“…These observations agree with the findings that HIV-1 infection itself leads to up-regulation of TLRs. 26 However, other authors have reported that TLRs signaling could be attenuated in HIV-1-infected cells, 48,49 although this was observed in a chronically HIV-1-infected cell line, that may contain some metabolic alterations affecting intracellular pathways. Likewise, it has been reported that HIV-1 and its products can also modulate TLR expression and functions.…”

Section: Discussionmentioning

confidence: 97%

HIV Type 1 Infection Up-Regulates TLR2 and TLR4 Expression and Function in Vivo and in Vitro

Hernández

Stevenson

Latz

et al. 2012

AIDS Research and Human Retroviruses

View full text Add to dashboard Cite

Toll-like receptors (TLRs) play a critical role in innate immunity against pathogens. Their stimulation induces the activation of NF-jB, an important inducer of HIV-1 replication. In recent years, an increasing number of studies using several cells types from HIV-infected patients indicate that TLRs play a key role in regulating the expression of proinflammatory cytokines and viral pathogenesis. In the present study, the effect of HIV-1 stimulation of monocyte-derived macrophage (MDM) and peripheral blood mononuclear cell (PBMC) subpopulations from healthy donors on the expression and functions of TLR2 and TLR4 was examined. In addition, and to complete the in vitro study, the expression pattern of TLR2 and TLR4 in 49 HIV-1-infected patients, classified according to viral load and the use of HAART, was determined and compared with 25 healthy subjects. An increase of TLR expression and production of proinflammatory cytokines were observed in MDMs and PBMCs infected with HIV-1 in vitro and in response to TLR stimulation, compared to the mock. In addition, an association between TLR expression and up-regulation of CD80 in plasmacytoid dendritic cells (pDCs) was observed. The ex vivo analysis indicated increased expression of TLR2 and TLR4 in myeloid dendritic cells (mDCs), but only of TLR2 in monocytes obtained from HIV-1-infected patients, compared to healthy subjects. Remarkably, the expression was higher in cells from patients who do not use HAART. In monocytes, there was a positive correlation between both TLRs and viral load, but not CD4 + T cell numbers. Together, our in vitro and ex vivo results suggest that TLR expression and function can be up-regulated in response to HIV-1 infection and could affect the inflammatory response. We propose that modulation of TLRs represents a mechanism to promote HIV-1 replication or AIDS progression in HIV-1-infected patients.

show abstract

“…TLR2 and TLR4 expressions are up-regulated after HIV infection. At the same time, high expression of TLR2 can promote HIV viral multiplication, but TLR4 expression has no such effect [19]. Therefore, TLR4 does not have any effects on HIV patients with TB, but TLR2 may play a key role in these patients.…”

Section: Cd4mentioning

confidence: 99%

Expressions of toll-like receptors 2 and 4, and relative cellular factors in HIV patients with tuberculosis infection

Chen¹,

Li²,

Wang³

et al. 2017

Trop. J. Pharm Res

View full text Add to dashboard Cite

Purpose: To investigate the expressions of toll-like receptor 2 (TLR2), toll-like receptor 4 (TLR4), tumor necrosis factor alpha (TNF-α), IFN-γ (IFN-gamma), interleukin 2 (IL-2), interleukin 6 (IL-6) and interleukin 10 (IL-10) in human immunodeficiency virus (HIV) patients with tuberculosis (TB) infection. Methods: Two groups of HIV patients (68 in each group) were used for this study. These were HIV with TB (HIV/TB) group and HIV without TB group. A third group (68 healthy people) served as control. Quantitative polymerase chain reaction (qPCR) was adopted to measure TLR-2 and TLR-4 expressions in peripheral blood mononuclear cells (PBMC), while the serum levels of TNF-α, IFN-γ, IL-2, IL-6 and IL-10 were determined by ELISA. Results: The △Ct values of TLR-2 and TLR-4 in HIV/TB and HIV groups were significantly lower than those in the control group (p < 0.05). Compared to control group, the serum levels of TNF-α, IL-6 and IL-10 significantly increased, while IFN-γ and IL-2 in HIV/TB and HIV groups significantly decreased (p < 0.05). However, IFN-γ and IL-2 decreased significantly in HIV/TB group (p < 0.05). Expression of TLR2correlated positively with serum levels of

show abstract

Failure of TLR4-Driven NF-κB Activation to Stimulate Virus Replication in Models of HIV Type 1 Activation

Cited by 27 publications

References 43 publications

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

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

HIV Type 1 Infection Up-Regulates TLR2 and TLR4 Expression and Function in Vivo and in Vitro

Expressions of toll-like receptors 2 and 4, and relative cellular factors in HIV patients with tuberculosis infection

Contact Info

Product

Resources

About