Type I Interferon at the Interface of Antiviral Immunity and Immune Regulation: The Curious Case of HIV-1.

Type I interferon (IFN-I) play a critical role in the innate immune response against viral infections. They actively participate in antiviral immunity by inducing molecular mechanisms of viral restriction and by limiting the spread of the infection, but they also orchestrate the initial phases of the adaptive immune response and influence the quality of T cell immunity. During infection with the human immunodeficiency virus type 1 (HIV-1), the production of and response to IFN-I may be severely altered by the lymphotropic nature of the virus. In this review I consider the different aspects of virus sensing, IFN-I production, signalling, and effects on target cells, with a particular focus on the alterations observed following HIV-1 infection

Alloantigen-based AIDS vaccine: revisiting a "rightfully" discarded promising strategy.

This report revisits the accidental discovery that protection against simian immunodeficiency virus (SIV) infection in the early successful experimental AIDS vaccine studies in Rhesus macaques was due to antibodies directed against human leukocyte antigens (HLAs). The inactivated virus vaccine approach was discarded because protection was due to the hosts immune reaction against the HLA acquired by SIV from the human cell lines in which it was grown, rather than against antigenic determinants of SIV itself. Subsequent studies have revealed that immune recognition of HLA on uninfected leukocytes also induces other factors that inhibit infection by both SIV and the human immunodeficiency virus. Pro and con aspects of immunization against HLA as a potential AIDS vaccine strategy are discussed. © 2011 Faculty of 1000 Ltd

Blocking TLR7- and TLR9-mediated IFN-α Production by Plasmacytoid Dendritic Cells Does Not Diminish Immune Activation in Early SIV Infection

Persistent production of type I interferon (IFN) by activated plasmacytoid dendritic cells (pDC) is a leading model to explain chronic immune activation in human immunodeficiency virus (HIV) infection but direct evidence for this is lacking. We used a dual antagonist of Toll-like receptor (TLR) 7 and TLR9 to selectively inhibit responses of pDC but not other mononuclear phagocytes to viral RNA prior to and for 8 weeks following pathogenic simian immunodeficiency virus (SIV) infection of rhesus macaques. We show that pDC are major but not exclusive producers of IFN-α that rapidly become unresponsive to virus stimulation following SIV infection, whereas myeloid DC gain the capacity to produce IFN-α, albeit at low levels. pDC mediate a marked but transient IFN-α response in lymph nodes during the acute phase that is blocked by administration of TLR7 and TLR9 antagonist without impacting pDC recruitment. TLR7 and TLR9 blockade did not impact virus load or the acute IFN-α response in plasma and had minimal effect on expression of IFN-stimulated genes in both blood and lymph node. TLR7 and TLR9 blockade did not prevent activation of memory CD4+ and CD8+ T cells in blood or lymph node but led to significant increases in proliferation of both subsets in blood following SIV infection. Our findings reveal that virus-mediated activation of pDC through TLR7 and TLR9 contributes to substantial but transient IFN-α production following pathogenic SIV infection. However, the data indicate that pDC activation and IFN-α production are unlikely to be major factors in driving immune activation in early infection. Based on these findings therapeutic strategies aimed at blocking pDC function and IFN-α production may not reduce HIV-associated immunopathology. © 2013 Kader et al

Effect of Immunoglobin-Like Transcript 7 Cross-Linking on Plasmacytoid Dendritic Cells Differentiation into Antigen-Presenting Cells

Plasmacytoid dendritic cells (pDC) are innate immunity effector cells which play a critical role in the transition from innate to adaptive immune response. Circulating blood pDC present an immature phenotype and can differentiate into either antigen-presenting cells (APC) or type I interferon (IFN-I)-producing cells (IPC). The immunoglobulin-like transcript (ILT)7 is a surface receptor expressed by immature pDC, and ILT7 cross-linking (XL-ILT7) inhibits IFN-I production by pDC in response to toll-like receptor (TLR)7 and 9 stimulation. We used peripheral blood mononuclear cells (PBMC) from healthy donors to test the effect of XL-ILT7 on 1) TLR7/9-mediated regulation of gut mucosal (α4β7 integrin) and lymph node (CCR7) migration markers; and 2) the maturation of pDC into APC. We found that XL-ILT7 mitigated the upregulation of CCR7 and enhanced that of β7 on TLR7/9-stimulated pDC. TLR7/9 stimulation induced upregulation of CD40, CD80 and CD86. CD40 expression was partially reduced by XL-ILT7, whereas CD86 was further enhanced. Plasmacytoid DC stimulated with TLR9 ligand in presence of XL-ILT7 retained the ability to induce T cell proliferation and activation in response to staphylococcal enterotoxin B (SEB) in pDC-T cell co-cultures. Our results suggest that XL-ILT7 favours the differentiation of immature pDC into APC rather than IPC

Selective blockade of interferon-α and -β reveals their non-redundant functions in a mouse model of West Nile virus infection

Although type I interferons (IFNs) were first described almost 60 years ago, the ability to monitor and modulate the functional activities of the individual IFN subtypes that comprise this family has been hindered by a lack of reagents. The major type I IFNs, IFN-β and the multiple subtypes of IFN-α, are expressed widely and induce their effects on cells by interacting with a shared heterodimeric receptor (IFNAR). In the mouse, the physiologic actions of IFN-α and IFN-β have been defined using polyclonal anti-type I IFN sera, by targeting IFNAR using monoclonal antibodies or knockout mice, or using Ifnb-/- mice. However, the corresponding analysis of IFN-α has been difficult because of its polygenic nature. Herein, we describe two monoclonal antibodies (mAbs) that differentially neutralize murine IFN-β or multiple subtypes of murine IFN-α. Using these mAbs, we distinguish specific contributions of IFN-β versus IFN-α in restricting viral pathogenesis and identify IFN-α as the key mediator of the antiviral response in mice infected with West Nile virus. This study thus suggests the utility of these new reagents in dissecting the antiviral and immunomodulatory roles of IFN-β versus IFN-α in murine models of infection, immunity, and autoimmunity

Complement-Mediated Virus Infectivity Neutralisation by HLA Antibodies Is Associated with Sterilising Immunity to SIV Challenge in the Macaque Model for HIV/AIDS.

Sterilising immunity is a desired outcome for vaccination against human immunodeficiency virus (HIV) and has been observed in the macaque model using inactivated simian immunodeficiency virus (SIV). This protection was attributed to antibodies specific for cell proteins including human leucocyte antigens (HLA) class I and II incorporated into virions during vaccine and challenge virus preparation. We show here, using HLA bead arrays, that vaccinated macaques protected from virus challenge had higher serum antibody reactivity compared with non-protected animals. Moreover, reactivity was shown to be directed against HLA framework determinants. Previous studies failed to correlate serum antibody mediated virus neutralisation with protection and were confounded by cytotoxic effects. Using a virus entry assay based on TZM-bl cells we now report that, in the presence of complement, serum antibody titres that neutralise virus infectivity were higher in protected animals. We propose that complement-augmented virus neutralisation is a key factor in inducing sterilising immunity and may be difficult to achieve with HIV/SIV Env-based vaccines. Understanding how to overcome the apparent block of inactivated SIV vaccines to elicit anti-envelope protein antibodies that effectively engage the complement system could enable novel anti-HIV antibody vaccines that induce potent, virolytic serological response to be developed

Osteocondrite dissecante e sua potencial relação com o estilo de vida agropastoril do noroeste pré-hispânico argentino: o sítio Rincón Chico 21 (Santa María, Catamarca)

Osteochondritis dissecans is a rare pathological condition characterized by partial or total separation of a fragment of necrotic articular cartilage from its underlying subchondral bone. Although its etiology is multifactorial, it is mainly associated with mechanical stress. From a paleopathological perspective, its analysis offers great potential to explore the lifestyles of past populations. The aim of this work is to analyze the expression of osteochondritis dissecans in 57 skeletal individuals from Rincón Chico 21 site (Santa María, Catamarca). This cemetery is a burial area used between the periods of Regional Development and the initial Spanish Indigenous contact (ca. 1,200-1,550 AD). The ages of the individuals analyzed range from adolescents to middle/older adults, and both sexes are represented. The presence of lesions was recorded in 47 elements belonging to at least 20 individuals (35.09 % of the sample). The knee (26.32 % of individuals) and the metatarsophalangeal joint (15.79 % of individuals) were the most affected. Females and middle/older adults showed higher prevalences. The results suggest that these populations might have been exposed to high levels of mechanical stress linked to cultural practices associated with an agropastoral subsistence economy.La osteocondritis disecante es una rara condición patológica caracterizada por la separación de un fragmento de cartílago articular necrótico del hueso subcondral subyacente. Si bien su etiología sería multifactorial, se la asocia principalmente al estrés mecánico. Desde la paleopatología, su análisis ofrece un gran potencial para explorar los modos de vida de las poblaciones pasadas. El objetivo de este trabajo es analizar la expresión de osteocondritis disecante en 57 individuos esqueléticos procedentes del sitio Rincón Chico 21 (Santa María, Catamarca). Este cementerio constituye un área de entierro utilizada entre los períodos de Desarrollos Regionales y de contacto Hispano-Indígena inicial (ca. 1.200-1.550 AD). Los individuos analizados abarcan los rangos etarios comprendidos entre los adolescentes y adultos medios/mayores y ambos sexos están representados. Se registró la presencia de lesiones en 47 elementos pertenecientes al menos a 20 individuos (35,09% de la muestra). La rodilla (26,32% de los individuos) y la articulación metatarsofalángica (15,79% de los individuos) fueron las más afectadas. Los femeninos y los adultos medios/mayores manifestaron mayores prevalencias. Los resultados sugieren que estas poblaciones habrían estado expuestas a altos niveles de estrés mecánico vinculados con las prácticas culturales asociadas a una economía de subsistencia agropastoril.A osteocondrite dissecante é uma condição patológica rara caracterizada pela separação de um fragmento de cartilagem articular necrótica do osso subcondral subjacente. Embora a sua etiologia seja multifatorial, está associada principalmente ao estresse mecânico. A partir da paleopatologia, sua análise oferece um grande potencial para explorar os modos de vida das populações passadas. O objetivo deste trabalho é analisar a expressão da osteocondrite dissecante em 57 indivíduos esqueléticos do sítio Rincón Chico 21 (Santa María, Catamarca). Este cemitério constitui uma área de enterramento utilizada entre os períodos de Desenvolvimento Regional e o contato inicial Espanhol-Indígena (ca. 1.200-1.550 d.C.). Os indivíduos analisados abrangem as faixas etárias entre adolescentes e adultos médios/idosos, e ambos os sexos estão representados. A presença de lesões foi registrada em 47 elementos pertencentes a pelo menos 20 indivíduos (35,09% da amostra). O joelho (26,32% dos indivíduos) e a articulação metatarsofalângica (15,79% dos indivíduos) foram os mais afetados. As mulheres e os adultos de meia idade/idosos apresentaram maior prevalência. Os resultados sugerem que estas populações teriam sido expostas a elevados níveis de estresse mecânico ligados a práticas culturais associadas a uma economia agropastoril de subsistência

NUDT2 Disruption Elevates Diadenosine Tetraphosphate (Ap4A) and Down-Regulates Immune Response and Cancer Promotion Genes.

Regulation of gene expression is one of several roles proposed for the stress-induced nucleotide diadenosine tetraphosphate (Ap4A). We have examined this directly by a comparative RNA-Seq analysis of KBM-7 chronic myelogenous leukemia cells and KBM-7 cells in which the NUDT2 Ap4A hydrolase gene had been disrupted (NuKO cells), causing a 175-fold increase in intracellular Ap4A. 6,288 differentially expressed genes were identified with P < 0.05. Of these, 980 were up-regulated and 705 down-regulated in NuKO cells with a fold-change ≥ 2. Ingenuity® Pathway Analysis (IPA®) was used to assign these genes to known canonical pathways and functional networks. Pathways associated with interferon responses, pattern recognition receptors and inflammation scored highly in the down-regulated set of genes while functions associated with MHC class II antigens were prominent among the up-regulated genes, which otherwise showed little organization into major functional gene sets. Tryptophan catabolism was also strongly down-regulated as were numerous genes known to be involved in tumor promotion in other systems, with roles in the epithelial-mesenchymal transition, proliferation, invasion and metastasis. Conversely, some pro-apoptotic genes were up-regulated. Major upstream factors predicted by IPA® for gene down-regulation included NFκB, STAT1/2, IRF3/4 and SP1 but no major factors controlling gene up-regulation were identified. Potential mechanisms for gene regulation mediated by Ap4A and/or NUDT2 disruption include binding of Ap4A to the HINT1 co-repressor, autocrine activation of purinoceptors by Ap4A, chromatin remodeling, effects of NUDT2 loss on transcript stability, and inhibition of ATP-dependent regulatory factors such as protein kinases by Ap4A. Existing evidence favors the last of these as the most probable mechanism. Regardless, our results suggest that the NUDT2 protein could be a novel cancer chemotherapeutic target, with its inhibition potentially exerting strong anti-tumor effects via multiple pathways involving metastasis, invasion, immunosuppression and apoptosis