IL-4 increases Simian immunodeficiency virus replication despite enhanced SIV immune responses in infected rhesus macaques

Boyer, Jean; Nath, Brett; Schumann, Kristen; Curley, Eugene; Manson, Kelledy; Kim, J; Weiner, David B.

doi:10.1016/s0020-7519(01)00355-1

Cited by 12 publications

(5 citation statements)

References 32 publications

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“…Since Type I IFNs can restrict both HIV infection of DCs and DC's ability to infect in trans CD4 T cells [68], IL-4 suppression of the IFN response of DCs to lentiviruses may affect both pivotal steps in HIV pathogenesis. Our results can provide a molecular explanation for the results of Boyer et al who have found that IL-4 increases in vivo Simian immunodeficiency virus loads in infected rhesus macaques, despite enhanced antibody responses [26]. These findings can be due to the inability of DCs, and possibly other cell types, to respond to the recognition of the virus by TLR7-9.…”

Section: Discussionsupporting

confidence: 70%

“…Schistosoma ) [23], [24], [25]. The co-infection of Human immunodeficiency virus (HIV) and helminth parasites, such as Schistosoma spp, is dramatically frequent in sub-Saharan Africa and it adversely impacts the ability of the immune system to control HIV progression [26], [27]. It has been shown that IL-4, a prototype Th2 cytokine, increases Simian immunodeficiency virus load in infected rhesus macaques, despite enhanced antibody responses [26].…”

Section: Introductionmentioning

confidence: 99%

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IL-4 Suppresses the Responses to TLR7 and TLR9 Stimulation and Increases the Permissiveness to Retroviral Infection of Murine Conventional Dendritic Cells

Sriram

Chain

et al. 2014

PLoS ONE

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Th2-inducing pathological conditions such as parasitic diseases increase susceptibility to viral infections through yet unclear mechanisms. We have previously reported that IL-4, a pivotal Th2 cytokine, suppresses the response of murine bone-marrow-derived conventional dendritic cells (cDCs) and splenic DCs to Type I interferons (IFNs). Here, we analyzed cDC responses to TLR7 and TLR9 ligands, R848 and CpGs, respectively. We found that IL-4 suppressed the gene expression of IFNβ and IFN-responsive genes (IRGs) upon TLR7 and TLR9 stimulation. IL-4 also inhibited IFN-dependent MHC Class I expression and amplification of IFN signaling pathways triggered upon TLR stimulation, as indicated by the suppression of IRF7 and STAT2. Moreover, IL-4 suppressed TLR7- and TLR9-induced cDC production of pro-inflammatory cytokines such as TNFα, IL-12p70 and IL-6 by inhibiting IFN-dependent and NFκB-dependent responses. IL-4 similarly suppressed TLR responses in splenic DCs. IL-4 inhibition of IRGs and pro-inflammatory cytokine production upon TLR7 and TLR9 stimulation was STAT6-dependent, since DCs from STAT6-KO mice were resistant to the IL-4 suppression. Analysis of SOCS molecules (SOCS1, −2 and −3) showed that IL-4 induces SOCS1 and SOCS2 in a STAT6 dependent manner and suggest that IL-4 suppression could be mediated by SOCS molecules, in particular SOCS2. IL-4 also decreased the IFN response and increased permissiveness to viral infection of cDCs exposed to a HIV-based lentivirus. Our results indicate that IL-4 modulates and counteracts pro-inflammatory stimulation induced by TLR7 and TLR9 and it may negatively affect responses against viruses and intracellular parasites.

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Section: Discussionsupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

IL-4 Suppresses the Responses to TLR7 and TLR9 Stimulation and Increases the Permissiveness to Retroviral Infection of Murine Conventional Dendritic Cells

Sriram

Chain

et al. 2014

PLoS ONE

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“…In this study, Boyer et al [68] examined macaques infected with SIVmac239 and treated with 9-2-(phosphonomethoxy)propyl-adenine (PMPA) to control viral load in a therapeutic vaccine model. The macaques were subsequently vaccinated with SIV antigen expressing DNA constructs with one group being given IL-4 plasmid construct while another group was not given IL-4.…”

Section: Hiv/sivmentioning

confidence: 99%

DNA vaccines: developing new strategies to enhance immune responses

2008

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We have focused our research on understanding the basic biology of and developing novel therapeutic and prophylactic DNA vaccines. We have among others three distinct primary areas of interest which include: 1. Enhancing in vivo delivery and transfection of DNA vaccine vectors 2. Improving DNA vaccine construct immunogenicity 3. Using molecular adjuvants to modulate and skew immune responses. Key to the immunogenicity of DNA vaccines is the presentation of expressed antigen to antigen-presenting cells. To improve expression and presentation of antigen, we have investigated various immunization methods with current focus on a combination of intramuscular injection and electroporation. To improve our vaccine constructs, we also employed methods such as RNA/codon optimization and antigen consensus to enhance expression and cellular/humoral cross-reactivity, respectively. Our lab also researches the potential of various molecular adjuvants to skew Th1/Th2 responses, enhance cellular/humoral responses, and improve protection in various animal models. Through improving our understanding of basic immunology as it is related to DNA vaccine technology, our goal is to develop the technology to the point of utility for human and animal health.

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“…Specifically, it is thought that IL-4-mediated Th2 responses contribute to the onset of AIDS [34]. In a murine model for AIDS, a murine leukemia retrovirus mixture induced increased production of IL-4 by thymocytes [35,36] and IL-4 may also contribute to increased viral replication, as observed in SIV infection [37].…”

Section: Introductionmentioning

confidence: 99%

Interleukin‐4 downregulates CD127 expression and activity on human thymocytes and mature CD8⁺ T cells

et al. 2010

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Signaling via the IL-7 receptor complex (IL-7Ra/CD127 and IL-2Rc/CD132) is required for T-cell development and survival. Decreased CD127 expression has been associated with persistent viral infections (e.g. HIV, HCV) and cancer. Many IL-2Rc-sharing (c C ) cytokines decrease CD127 expression on CD4 1 and CD8 1 T cells in mice (IL-2, IL-4, IL-7, IL-15) and in humans (IL-2, IL-7), suggesting a common function. IL-4 is of particular interest as it is upregulated in HIV infection and in thyroid and colon cancers. The role of IL-4 in regulating CD127 expression and IL-7 activity in human thymocytes and mature CD8 1 T cells is unknown and was therefore investigated. IL-4 decreased CD127 expression on all thymocyte subsets tested and only on naïve (CD45RA 1 ) CD8 1 T cells, without altering membrane-bound CD127 mRNA expression. Pre-treatment of thymocytes or CD8 1 T cells with IL-4 inhibited IL-7-mediated phosphorylation of STAT5 and decreased proliferation of CD8 1 T cells. By downregulating CD127 expression and signaling on developing thymocytes and CD8 1 T cells, IL-4 is a potential contributor to impaired CD8 1 T-cell function in some anti-viral and anti-tumor responses. These findings are of particular consequence to diseases such as HIV, HCV, RSV, measles and cancer, in which CD127 expression is decreased, IL-7 activity is impaired and IL-4 concentrations are elevated.

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IL-4 increases Simian immunodeficiency virus replication despite enhanced SIV immune responses in infected rhesus macaques

Cited by 12 publications

References 32 publications

IL-4 Suppresses the Responses to TLR7 and TLR9 Stimulation and Increases the Permissiveness to Retroviral Infection of Murine Conventional Dendritic Cells

IL-4 Suppresses the Responses to TLR7 and TLR9 Stimulation and Increases the Permissiveness to Retroviral Infection of Murine Conventional Dendritic Cells

DNA vaccines: developing new strategies to enhance immune responses

Interleukin‐4 downregulates CD127 expression and activity on human thymocytes and mature CD8⁺ T cells

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IL-4 increases Simian immunodeficiency virus replication despite enhanced SIV immune responses in infected rhesus macaques

Cited by 12 publications

References 32 publications

IL-4 Suppresses the Responses to TLR7 and TLR9 Stimulation and Increases the Permissiveness to Retroviral Infection of Murine Conventional Dendritic Cells

IL-4 Suppresses the Responses to TLR7 and TLR9 Stimulation and Increases the Permissiveness to Retroviral Infection of Murine Conventional Dendritic Cells

DNA vaccines: developing new strategies to enhance immune responses

Interleukin‐4 downregulates CD127 expression and activity on human thymocytes and mature CD8+ T cells

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Interleukin‐4 downregulates CD127 expression and activity on human thymocytes and mature CD8⁺ T cells