Toll-like receptor 3 adjuvant in combination with virus-like particles elicit a humoral response against HIV

Poteet, Ethan; Lewis, Phoebe; Chen, Changyi; Ho, Sam; Do, Thai; Chiang, SuMing; LaBranche, Celia C.; Montefiori, David C.; Fujii, Gary; Yao, Qizhi

doi:10.1016/j.vaccine.2016.10.036

Cited by 21 publications

(17 citation statements)

References 34 publications

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“…Yet, the nature of TFH-favoring innate immune stimuli has remained largely unknown. Several studies have addressed the impact of TLR activation on the development of TFH cells and germinal center formation in mice 63,64,65,66,67,68,69 . For instance, it has been reported that monocyte-derived dendritic cells (Mo-DC) are important stimulators of TFH cell responses in mice, especially when activated via TLR9 70 .…”

Section: Discussionmentioning

confidence: 99%

Recognition of microbial viability via TLR8 drives TFH cell differentiation and vaccine responses

et al. 2018

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Live attenuated vaccines are generally highly efficacious and often superior to inactivated vaccines, yet the underlying mechanisms of this remain largely unclear. Here we identify recognition of microbial viability as a potent stimulus for follicular helper T cell (T cell) differentiation and vaccine responses. Antigen-presenting cells (APCs) distinguished viable bacteria from dead bacteria through Toll-like receptor 8 (TLR8)-dependent detection of bacterial RNA. In contrast to dead bacteria and other TLR ligands, live bacteria, bacterial RNA and synthetic TLR8 agonists induced a specific cytokine profile in human and porcine APCs, thereby promoting T cell differentiation. In domestic pigs, immunization with a live bacterial vaccine induced robust T cell and antibody responses, but immunization with its heat-killed counterpart did not. Finally, a hypermorphic TLR8 polymorphism was associated with protective immunity elicited by vaccination with bacillus Calmette-Guérin (BCG) in a human cohort. We have thus identified TLR8 as an important driver of T cell differentiation and a promising target for T cell-skewing vaccine adjuvants.

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Section: Discussionmentioning

confidence: 99%

Recognition of microbial viability via TLR8 drives TFH cell differentiation and vaccine responses

et al. 2018

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“…In the vaccination experiments, we observed that ncRNA VLPs induced longer-lasting humoral responses. We believe ncRNA VLPs are able to more efficiently activate follicular helper T cells, leading to better memory induction, as has already been shown with a TLR3 ligand encapsidated in HIV-derived VLPs (53). This question is under investigation in our laboratory.…”

Section: Discussionmentioning

confidence: 70%

Retrovirus-Based Virus-Like Particle Immunogenicity and Its Modulation by Toll-Like Receptor Activation

Pitoiset

Vazquez

Levacher

et al. 2017

J Virol

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Retrovirus-derived virus-like particles (VLPs) are particularly interesting vaccine platforms, as they trigger efficient humoral and cellular immune responses and can be used to display heterologous antigens. In this study, we characterized the intrinsic immunogenicity of VLPs and investigated their possible adjuvantization by incorporation of Toll-like receptor (TLR) ligands. We designed a noncoding single-stranded RNA (ncRNA) that could be encapsidated by VLPs and induce TLR7/8 signaling. We found that VLPs efficiently induce dendritic cell activation, which can be improved by ncRNA encapsidation (VLPs). Transcriptome studies of dendritic cells harvested from the spleens of immunized mice identified antigen presentation and immune activation as the main gene expression signatures induced by VLPs, while TLR signaling and Th1 signatures characterize VLPs. and compared with standard VLPs, VLPs promoted Th1 responses and improved CD8 T cell proliferation in a MyD88-dependent manner. In an HIV vaccine mouse model, HIV-pseudotyped VLPs elicited stronger antigen-specific cellular and humoral responses than VLPs. Altogether, our findings provide molecular evidence for a strong vaccine potential of retrovirus-derived VLPs that can be further improved by harnessing TLR-mediated immune activation. We previously reported that DNA vaccines encoding antigens displayed in/on retroviral VLPs are more efficient than standard DNA vaccines at inducing cellular and humoral immune responses. We aimed to decipher the mechanisms and investigated the VLPs' immunogenicity independently of DNA vaccination. We show that VLPs have the ability to activate antigen-presenting cells directly, thus confirming their intrinsic immunostimulatory properties and their potential to be used as an antigenic platform. Notably, this immunogenicity can be further improved and/or oriented by the incorporation into VLPs of ncRNA, which provides further TLR-mediated activation and Th1-type CD4 and CD8 T cell response orientation. Our results highlight the versatility of retrovirus-derived VLP design and the value of using ncRNA as an intrinsic vaccine adjuvant.

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“…Resiquimod, a TLR7/8 agonist also known as R848, has been shown to restrict HIV1 infection of monocytes in a post-entry/pre-reverse transcription SAMHD1independent manner [97]. Together with other molecules, this TLR agonist might serve as adjunct for vaccine strategies in order to elicit antiviral immune defenses against HIV [98,99]. Also, the efficacy of MGN1703/lefitolimod to activate NK cells and reverse HIV latency is being investigated in a phase 1/2 study in HIV1 ART-treated patients (Table 2).…”

Section: Tlr Agonists To Optimize the Induction Of Ifnmentioning

confidence: 99%

Interferon-associated therapies toward HIV control: The back and forth

Noël

Jacquelin

Huot

et al. 2018

Cytokine & Growth Factor Reviews

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Human immunodeficiency virus (HIV) induces a persistent and incurable infection. However, the combined antiretroviral treatment (cART) has markedly changed the evolution of the infection and transformed a deadly disease into a manageable chronic infection. Withdrawal of cART generally leads though to resumption of the viral replication. The eradication of the virus from its cellular and anatomical reservoirs remains a goal-to-achieve for a cure. In this context, developing novel therapies contributing to this aim are an important field of research. Type I IFN has antiviral activity, which, before the presence of efficient anti-HIV drugs, has led to the testing of IFN-based therapeutic strategies during the early years of the pandemic. A historical overview of the results and its limitations that were put into light are reviewed here. In addition, several lessons could be drawn. For instance, the efficacy of the IFN-I depends on the timing of its administration and the context. Thus, the persistence of an endogenous IFN-signature, such as that generally observed in viremic patients, seems to be associated with a lower efficacy of IFN. Based on the lessons from previous trials, and in the context of cART and research for a cure, type I Interferon has regained interest and novel therapeutic approaches are currently tested in combination with cART, some with disappointing, other with encouraging results with regard to a reduction in the size of the HIV reservoir and/or delays in viral rebound after cessation of cART. Additional strategies are currently developed in addition to improve the antiviral function of the IFN-I, by using for instance other IFN subtypes than IFN-Iα2. In parallel, the development of innovative strategies aimed at counteracting the excessive activation of the IFN-pathways have been continued and their results are reviewed here as well. Altogether, the use of IFN-I in anti-HIV therapies has gone through distinct phases and many lessons could be drawn. Novel combinations are currently be tested that might provide interesting results.

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Toll-like receptor 3 adjuvant in combination with virus-like particles elicit a humoral response against HIV

Cited by 21 publications

References 34 publications

Recognition of microbial viability via TLR8 drives TFH cell differentiation and vaccine responses

Recognition of microbial viability via TLR8 drives TFH cell differentiation and vaccine responses

Retrovirus-Based Virus-Like Particle Immunogenicity and Its Modulation by Toll-Like Receptor Activation

Interferon-associated therapies toward HIV control: The back and forth

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