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Antiviral Innate Immune Activation in HIV-Infected Adults Negatively Affects H1/IC31-Induced Vaccine-Specific Memory CD4+ T Cells.

ABSTRACT: Tuberculosis (TB) remains a global health problem, with vaccination being a necessary strategy for disease containment and elimination. A TB vaccine should be safe and immunogenic as well as efficacious in all affected populations, including HIV-infected individuals. We investigated the induction and maintenance of vaccine-induced memory CD4(+) T cells following vaccination with the subunit vaccine H1/IC31. H1/IC31 was inoculated twice on study days 0 and 56 among HIV-infected adults with CD4(+) lymphocyte counts of >350 cells/mm(3). Whole venous blood stimulation was conducted with the H1 protein, and memory CD4(+) T cells were analyzed using intracellular cytokine staining and polychromatic flow cytometry. We identified high responders, intermediate responders, and nonresponders based on detection of interleukin-2 (IL-2), tumor necrosis factor alpha (TNF-?), and gamma interferon (IFN-?) expressing central (TCM) and effector memory CD4(+) T cells (TEM) 182 days after the first immunization. Amplicon-based transcript quantification using next-generation sequencing was performed to identify differentially expressed genes that correlated with vaccine-induced immune responses. Genes implicated in resolution of inflammation discriminated the responders from the nonresponders 3 days after the first inoculation. The volunteers with higher expression levels of genes involved in antiviral innate immunity at baseline showed impaired H1-specific TCM and TEM maintenance 6 months after vaccination. Our study showed that in HIV-infected volunteers, expression levels of genes involved in the antiviral innate immune response affected long-term maintenance of H1/IC31 vaccine-induced cellular immunity. (The clinical trial was registered in the Pan African Clinical Trials Registry [PACTR] with the identifier PACTR201105000289276.).

SUBMITTER: Lenz N

PROVIDER: S-EPMC4478517 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Antiviral Innate Immune Activation in HIV-Infected Adults Negatively Affects H1/IC31-Induced Vaccine-Specific Memory CD4+ T Cells.

Lenz Nicole N Schindler Tobias T Kagina Benjamin M BM Zhang Jitao David JD Lukindo Tedson T Mpina Maxmillian M Bang Peter P Kromann Ingrid I Hoff Søren T ST Andersen Peter P Reither Klaus K Churchyard Gavin J GJ Certa Ulrich U Daubenberger Claudia A CA

Clinical and vaccine immunology : CVI 20150429 7

Tuberculosis (TB) remains a global health problem, with vaccination being a necessary strategy for disease containment and elimination. A TB vaccine should be safe and immunogenic as well as efficacious in all affected populations, including HIV-infected individuals. We investigated the induction and maintenance of vaccine-induced memory CD4(+) T cells following vaccination with the subunit vaccine H1/IC31. H1/IC31 was inoculated twice on study days 0 and 56 among HIV-infected adults with CD4(+) ...[more]

PMID: 25924764

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Project description:Circular RNAs (circRNAs) are an important subclass of noncoding RNAs implicated in the regulation of multiple biological processes. However, the functional involvement of circRNAs in the pathogenesis of influenza A viruses (IAVs) remains largely unknown. Here, we employed RNA sequencing (RNA-Seq) to examine the differentially expressed circRNAs in mouse lung tissues challenged or not challenged with IAV to evaluate the impact of viral infection on circRNAs in vivo. We observed that 413 circRNAs exhibited significantly altered levels following IAV infection. Among these, circMerTK, the derivative of myeloid-epithelial-reproductive tyrosine kinase (MerTK) pre-mRNA, was highly induced by IAV. Interestingly, circMerTK expression was also increased upon infection with multiple DNA and RNA viruses in human and animal cell lines, and thus it was selected for further studies. Poly(I:C) and interferon β (IFN-β) stimulated circMerTK expression, while RIG-I knockout and IFNAR1 knockout cell lines failed to elevate circMerTK levels after IAV infection, demonstrating that circMerTK is regulated by IFN signaling. Furthermore, circMerTK overexpression or silencing accelerated or impeded IAV and Sendai virus replication, respectively. Silencing circMerTK enhanced the production of type I IFNs and interferon-stimulating genes (ISGs), whereas circMerTK overexpression suppressed their expression at both the mRNA and protein levels. Notably, altering circMerTK expression had no effect on the MerTK mRNA level in cells infected or not infected with IAV, and vice versa. In addition, human circMerTK and mouse homologs functioned similarly in antiviral responses. Together, these results identify circMerTK as an enhancer of IAV replication through suppression of antiviral immunity. IMPORTANCE CircRNAs are an important class of noncoding RNAs characterized by a covalently closed circular structure. CircRNAs have been proven to impact numerous cellular processes, where they conduct specialized biological activities. In addition, circRNAs are believed to play a crucial role in regulating immune responses. Nevertheless, the functions of circRNAs in the innate immunity against IAV infection remain obscure. In this study, we employed transcriptomic analysis to investigate the alterations in circRNAs expression following IAV infection in vivo. It was found that expression of 413 circRNAs was significantly altered, of which 171 were upregulated, and 242 were downregulated following the IAV infection. Interestingly, circMerTK was identified as a positive regulator of IAV replication in both human and mouse hosts. CircMerTK was shown to influence IFN-β production and its downstream signaling, enhancing IAV replication. This finding provides new insights into the critical roles of circRNAs in regulating antiviral immunity.

Dataset Information

Antiviral Innate Immune Activation in HIV-Infected Adults Negatively Affects H1/IC31-Induced Vaccine-Specific Memory CD4+ T Cells.

Publications

Antiviral Innate Immune Activation in HIV-Infected Adults Negatively Affects H1/IC31-Induced Vaccine-Specific Memory CD4+ T Cells.

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