HIV-1 gp120 Induces TLR2- and TLR4-Mediated Innate Immune Activation in Human Female Genital Epithelium

Nazli, Aisha; Kafka, Jessica K.; Ferreira, Victor H; Anipindi, Varun C.; Mueller, Kristen; Osborne, B.; Dizzell, Sara; Chauvin, Sarah; Mian, M. Firoz; Ouellet, Michel; Tremblay, Michel J.; Mossman, Karen; Ashkar, Ali A.; Kovacs, Colin; Bowdish, Dawn M. E.; Snider, Denis P.; Kaul, Rupert; Kaushic, Charu

doi:10.4049/jimmunol.1301482

Cited by 126 publications

(130 citation statements)

References 61 publications

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“…In the case of HIV-1, our group has shown that the Tat protein, in addition to gp120 (52) and Vpr (15), by activating the TLR4 pathway, leads to the production of proinflammatory cytokines, including TNF-␣, IL-1␤, IL-6, IL-8, and type 1 IFN-␣1, and to stimulation of immunosuppressive factors, including IL-10, PD-L1, and IDO, by dendritic cells (22)(23)(24), thus supporting the implication of the HIV-1 Tat protein as a potential pathogenic factor. The product of the tat gene is a protein of 14 to 16 kDa, composed of 86 to 101 amino acids, which is expressed during the early phase of the HIV-1 cycle.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Tat Protein Activates both the MyD88 and TRIF Pathways To Induce Tumor Necrosis Factor Alpha and Interleukin-10 in Human Monocytes

Planès

Haij

Leghmari

et al. 2016

J Virol

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In this study, we show that the HIV-1 Tat protein interacts with rapid kinetics to engage the Toll-like receptor 4 (TLR4) pathway, leading to the production of proinflammatory and anti-inflammatory cytokines. The pretreatment of human monocytes with Tat protein for 10 to 30 min suffices to irreversibly engage the activation of the TLR4 pathway, leading to the production of tumor necrosis factor alpha (TNF-␣) and interleukin-10 (IL-10), two cytokines strongly implicated in the chronic activation and dysregulation of the immune system during HIV-1 infection. Therefore, this study analyzed whether the HIV-1 Tat protein is able to activate these two pathways separately or simultaneously. Using three complementary approaches, including mice deficient in the MyD88, TIRAP/MAL, or TRIF adaptor, biochemical analysis, and the use of specific small interfering RNAs (siRNAs), we demonstrated (i) that Tat was able to activate both the MyD88 and TRIF pathways, (ii) the capacity of Tat to induce TIRAP/MAL degradation, (iii) the crucial role of the MyD88 pathway in the production of Tat-induced TNF-␣ and IL-10, (iv) a reduction but not abrogation of IL-10 and TNF-␣ by Tat-stimulated macrophages from mice deficient in TIRAP/MAL, and (v) the crucial role of the TRIF pathway in Tat-induced IL-10 production. Further, we showed that downstream of the MyD88 and TRIF pathways, the Tat protein activated the protein kinase C (PKC) ␤II isoform, the mitogen-activated protein (MAP) kinases p38 and extracellular signal-regulated kinase 1/2 (ERK1/2), and NF-B in a TLR4-dependent manner. Collectively, our data show that by recruiting the TLR4 pathway with rapid kinetics, the HIV-1 Tat protein leads to the engagement of both the MyD88 and TRIF pathways and to the activation of PKC, MAP kinase, and NF-B signaling to induce the production of TNF-␣ and IL-10. IMPORTANCEIn this study, we demonstrate that by recruiting the TLR4 pathway with rapid kinetics, the HIV-1 Tat protein leads to the engagement of both the MyD88 and TRIF pathways and to the activation of PKC-␤II, MAP kinase, and NF-B signaling to induce the production of TNF-␣ and IL-10, two cytokines strongly implicated in the chronic activation and dysregulation of the immune system during HIV-1 infection. Thus, it may be interesting to target Tat as a pathogenic factor early after HIV-1 infection. This could be achieved either by vaccination approaches including Tat as an immunogen in potential candidate vaccines or by developing molecules capable of neutralizing the effect of the Tat protein.

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Section: Discussionmentioning

confidence: 99%

HIV-1 Tat Protein Activates both the MyD88 and TRIF Pathways To Induce Tumor Necrosis Factor Alpha and Interleukin-10 in Human Monocytes

Planès

Haij

Leghmari

et al. 2016

J Virol

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“…A role for specific glycosylation would be in line with other viral glycoproteins that can activate DC, including the fusion protein of respiratory syncytial virus and HIV-derived gp120 as previously described (26,27).…”

Section: Discussionmentioning

confidence: 99%

Hepatitis B Virus Surface Antigen Activates Myeloid Dendritic Cells via a Soluble CD14-Dependent Mechanism

Montfoort

Bosch

et al. 2016

J Virol

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Hepatitis B virus (HBV) infection can cause chronic liver disease, which is associated with increased risk of liver cirrhosis, liver failure, and liver cancer. Clearance of HBV infection requires effective HBV-specific immunity; however, the immunological mechanisms that determine the development of effective HBV-specific immunity are poorly understood. Dendritic cells (DC) play a pivotal role in the regulation of antiviral immunity. Here, we investigated the interaction between HBV surface antigen (HBsAg), the main envelope glycoprotein of HBV, and BDCA1؉ myeloid dendritic cells (mDC). Exposure of peripheral bloodderived BDCA1؉ mDC to HBsAg resulted in strong DC maturation, cytokine production, and enhanced capacity to activate antigen-specific cytotoxic T cells (CTLs). By using neutralizing antibodies, crucial roles for CD14 and Toll-like receptor 4 (TLR4) in HBsAg-mediated BDCA1 ؉ mDC maturation were identified. Concordantly, HBsAg-mediated DC maturation required fetal calf serum (FCS) or human plasma, naturally containing soluble CD14 (sCD14). Intriguingly, HBsAg-induced DC maturation was significantly reduced in umbilical cord blood plasma, which contained less sCD14 than adult plasma, indicating that sCD14 is an important host factor for recognition of HBsAg by DC and subsequent DC activation. A direct interaction between sCD14 and HBsAg was demonstrated by using enzyme-linked immunosorbent assay (ELISA). Moreover, sCD14-HBsAg complexes were detected both in vitro and in sera of HBV-infected patients. The abundance of sCD14-HBsAg complexes varied between chronic HBV disease stages and correlated with activation of BDCA1 ؉ mDC in vivo. We conclude that HBsAg activates BDCA1 ؉ DC via an sCD14-dependent mechanism. These findings provide important novel insights into the initiation of HBV-specific immunity and facilitate development of effective immunotherapeutic interventions for HBV. Hepatitis B virus (HBV) is a double-stranded DNA (dsDNA) virus that is transmitted via blood and specifically infects hepatocytes. It can cause chronic liver disease and progressive liver injury leading to increased risk of liver cirrhosis, liver failure, and liver cancer (1). The current estimated prevalence of HBV infection is 248 million individuals globally (2). Although the initiation of an effective antiviral immune response is paramount for resolving HBV infection (3), the early steps in the recognition of the virus by immune cells and the functional consequences of this interaction remain to be resolved.A pivotal role for dendritic cells (DC) is anticipated, because these cells play a central role in the orchestration of antiviral immunity due to the expression of a wide variety of different pathogen recognition receptors (PRR) and their unique capacity to initiate virus-specific cytotoxic T cell (CTL) responses (4, 5). Among the different DC subsets, BDCA1 ϩ myeloid DC (mDC) are of particular interest for HBV-specific immunity, since hepatitis B surface antigen (HBsAg)-positive mDC were detected in liver (6) an...

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“…11,12 Recent studies have shown that HIV disrupted the epithelial TJ in an intestinal cell line and primary endometrium epithelial cells. 10,35 However, no studies have determined the direct effect of HIV on the epithelium in human ectocervical or colon tissues.…”

Section: Discussionmentioning

confidence: 99%

HIV Exposure to the Epithelia in Ectocervical and Colon Tissues Induces Inflammatory Cytokines Without Tight Junction Disruption

Sankapal

Gupta

Ratner

et al. 2016

AIDS Research and Human Retroviruses

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Epithelial cells in human cervical and colonic mucosa do not express HIV receptor. However, HIV transmission occurs across the unbreached epithelia by an unknown mechanism. In this study, the effect of HIV exposure on tight junction (TJ) and cytokine production in ectocervical and colon mucosal epithelia in tissue biopsies was investigated in an organ culture model. After HIV exposure, the distribution patterns and quantities of epithelial TJ and adherens proteins were evaluated by immunofluorescence staining followed by confocal microscopy. Cytokine mRNA in the mucosal epithelia was also evaluated by real-time reverse transcription-polymerase chain reaction (RT-PCR). HIV transmission was evaluated by measuring p24 production in culture supernatant. Our results showed there were no significant changes in the distribution and quantities of epithelial TJ/adherens junction (AJ) proteins after exposure to HIV. However, higher levels of CXCL10 and CXCL11 mRNA expression were detected in HIV-exposed ectocervical epithelia. In case of colon mucosa, higher levels of CXCL10 and IL-6 mRNA expression were detected in HIV-exposed colon mucosa. Our study suggests that HIV induces cytokine production in epithelial cells, which may facilitate HIV transmission by recruiting HIV target cells in the submucosal region. Furthermore, HIV transmission may not occur through epithelial TJ/AJ disruption.

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HIV-1 gp120 Induces TLR2- and TLR4-Mediated Innate Immune Activation in Human Female Genital Epithelium

Cited by 126 publications

References 61 publications

HIV-1 Tat Protein Activates both the MyD88 and TRIF Pathways To Induce Tumor Necrosis Factor Alpha and Interleukin-10 in Human Monocytes

HIV-1 Tat Protein Activates both the MyD88 and TRIF Pathways To Induce Tumor Necrosis Factor Alpha and Interleukin-10 in Human Monocytes

Hepatitis B Virus Surface Antigen Activates Myeloid Dendritic Cells via a Soluble CD14-Dependent Mechanism

HIV Exposure to the Epithelia in Ectocervical and Colon Tissues Induces Inflammatory Cytokines Without Tight Junction Disruption

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