Pathogenic Role of Type I Interferons in HIV-Induced Immune Impairments in Humanized Mice

Purpose of Review: Recent findings on the critical pathogenic role of type 1 interferons (IFN-I) in HIV-1 persistence in humanized mice suggest that inhibiting IFN-I signaling transiently will reverse HIV-induced inflammatory diseases and rescue anti-HIV immunity to control HIV-1 reservoirs. Recent Findings: In both humanized mice and in monkeys, IFN-I signaling is functionally defined to play an important role in suppressing early HIV-1 and SIV infection. During persistent infection in humanized mice, however, IFN-I signaling is revealed to induce T cell depletion and impairment. Interestingly, in HIV-infected mice with effective combination antiretroviral therapy (cART), blocking IFN-I signaling reverses HIV-induced inflammation, rescues anti-HIV T cells, and reduces HIV-1 reservoirs. Summary: These findings functionally define the role of IFN-I in HIV-1 reservoir persistence and suggest that blocking IFN-I signaling will provide a novel therapeutic strategy to (i) reverse inflammation-associated diseases in HIV patients under cART, (ii) rescue host anti-HIV immunity, and (iii) reduce or control HIV-1 reservoirs

Disruption of HBx-DDB1 by NTZ: New Mechanistic Insight Into an Old Drug With Broad Anti-infective Activities

Hepatitis B virus (HBV) infection leads to chronic hepatitis B (CHB) in approximately 250 million people worldwide, putting them at high risk for developing cirrhosis and hepatocellular carcinoma. HBV is a partially double-stranded DNA virus that belongs to the Hepadnaviridae family. After entry into host cells, the viral genome is transported into the nucleus and converted to a covalently closed circular DNA (cccDNA), which serves as the template for all HBV viral RNAs. Currently available HBV antiviral drugs inhibit the reverse transcription of HBV pregenomic RNA but fail to suppress the established cccDNA reservoir in infected hepatocytes, resulting in viral rebound after therapy. In addition, HBV surface antigen hepatitis B surface antigen expressed from the cccDNA maintains immune tolerance to prevent induction of antibodies to hepatitis B surface antigen, which are critical for a functional cure of CHB in patients

Impacts of mass media coverage of the economy during normal times and recessions on the Index of Consumer Confidence using time series analysis and Granger causal analysis

The level of consumer sentiment influences decision making of policy makers, and therefore it is important to examine if media have powerful impacts on consumer sentiment. Based on the theories of business cycles and second-level agenda-setting, this study applies Granger causal analysis and time series analysis to explore the causal relationships among economic reporting by media, consumer sentiment and the real state of the economy embodied in Business Week, the Index of Consumer Confidence (CCI) and the Standard & Poor\u27s 500 (S&P 500). The results indicate that interpretation by media have only limited effects on the level of consumer sentiment in general, and the real state of the economy plays a more important role in shaping consumer sentiment. However, during recessions and times of economic slowdowns, media have a more powerful effect on consumer sentiment though its impact is still smaller than the real state of the economy

Understanding psychological contract breach in the customer-firm relationship

ABSTRACT Because of great variation in service performance, service providers cannot avoid situations of service failures, in which customers feel that their consumption goals for services have not been achieved. Information about service attributes obtained through personal selling or online customer reviews may create different levels of psychological contract in customers\u27 minds and result in various customer reactions to service failure. This dissertation explores antecedents, consequences and the psychological process of psychological contract breach through role-playing activities using scenarios in three field experiments. Study 1 explored the role of psychological contract breach on the evolution of customers\u27 feelings of betrayal, anger and evaluation of partner quality. Results of a 2 (high vs. low psychological contract) Ã? 2 (high vs. low service failure) between-subject factorial experiment indicated that psychological contract breach mediated the effect of psychological contract and service failure on feelings of betrayal and anger; participants in the condition of high psychological contract and high service failure reported higher levels of psychological contract breach than did those in the other three conditions; psychological contract breach raised feelings of betrayal and anger and reduced customers\u27 evaluation of the service providers\u27 partner quality. Study 2a suggested that source-of-fault information (source of the mistake directly related to the failure) was one situational antecedent of psychological contract breach. Results of a 2 (high vs. low psychological contract) Ã? 2 (customer fault vs. provider fault) between-subject factorial experiment suggested that participants in the condition of high psychological contract and the provider fault reported higher levels of breach than did those in the other three conditions. Study 2b suggested that social obligation bias was a personal antecedent of psychological contract breach. Results of a 2 (customer fault vs. provider fault) Ã? 2 (self-obligation focus vs. others-obligation focus) between-subject factorial experiment indicated that participants in the condition of provider fault and others-obligation focus attributed more controllability to the service provider than did those in the other three conditions; attribution of controllability positively influenced psychological contract breach and mediated the influence of source of fault on psychological contract breach. Study 3 explored a situational factor, compensation relevance (i.e., compensation that is relevant to the consumption goal and promotes a perception of fairness), and a personal factor, justice salience (customers\u27 accessibility to their beliefs in a just world), which could influence recovery from negative outcomes brought about by psychological contract breach. Results of a 2 (high vs. relevant compensation) Ã? 2 (high vs. low justice salience) between-subject factorial experiment indicated that participants in the condition of high relevant compensation and low justice salience perceived higher levels of fairness than did those in the other three conditions; perception of fairness reduced levels of feelings of betrayal and anger and raised evaluation of partner quality; and perception of fairness mediated the interaction effect of compensation relevance and justice salience on feelings of betrayal, anger and partner quality

Vpr enhances HIV-1 Env processing and virion infectivity in macrophages by modulating TET2-dependent IFITM3 expression

HIV-1 Vpr enhances viral replication in human macrophages via multiple mechanisms that are not clearly defined. It does not affect HIV-1 virion production during the first round of infection. We have recently discovered that Vpr targets the DNA demethylase TET2 for degradation, which leads to sustained interleukin-6 (IL-6) expression and elevated HIV-1 replication. We report here that Vpr enhanced Env processing in infected macrophages, associated with increased Env incorporation into virions with higher infectivity. Interestingly, IFITM3 was constitutively expressed in macrophages in a TET2-dependent fashion. We showed that Vprenhanced Env processing depended genetically on TET2 and IFITM3. We further showed that Vpr reduced IFITM3 expression by reducing demethylation of the IFITM3 promoter in macrophages, associated with degradation of TET2 and reduced TET2 binding to the IFITIM3 promoter. Our findings indicate that the Vpr-TET2 axis enhances HIV-1 replication in macrophages via two independent mechanisms: Reduced IFTIM3 expression to enhance Env processing and virion infectivity and sustained IL-6 expression to increase HIV-1 replication. The Vpr-TET2 axis may provide a novel target to develop therapeutics to inhibit HIV-1 infection and pathogenesis

A pathogenic role of plasmacytoid dendritic cells in autoimmunity and chronic viral infection

Following the discovery of plasmacytoid dendritic cells (pDCs) and of their extraordinary ability to produce type I IFNs (IFN-I) in response to TLR7 and TLR9 stimulation, it is assumed that their main function is to participate in the antiviral response. There is increasing evidence suggesting that pDCs and/or IFN-I can also have a detrimental role in a number of inflammatory and autoimmune diseases, in the context of chronic viral infections and in cancers. Whether these cells should be targeted in patients and how much of their biology is connected to IFN-I production remains unclear and is discussed here

HIV-1 pathogenesis and therapeutic intervention in the SCID-hu Thy/Liv mouse: a model for primary HIV-1 infection in the human thymus

The SCID-hu Thy/Liv mouse is a model for the analysis of human thymopoiesis. It has been constructed by engrafting fragments of human fetal liver and thymus into the immunodeficient C.B-17 scid/scid (SCID) mouse. The resulting ‘Thy/Liv’ organ promotes long-term differentiation of human T cells. Given the apparently normal physiology of the SCID-hu Thy/Liv organ, it has been used to explore the pathophysiologic mechanisms of HIV-1 infection in vivo, and to test therapeutic modalities such as anti-HIV-1 drugs and haematopoietic stem cell (HSC)-based gene therapy. In this review, I will summarise what we have learned from the SCID-hu Thy/Liv model, with a focus on recent findings in HIV-1 replication and therapy. Unique HIV-1 determinants have been identified which are required for replication in the Thy/Liv organ but not for replication in PBMC or in T cell lines in vitro. The mechanism of HIV-1 induced thymus depletion is not clear. It is correlated with high levels of HIV-1 replication. Both direct and indirect mechanisms may be involved. In addition to preclinical evaluation of anti-HIV-1 drugs, the SCID-hu Thy/Liv mouse has also been successfully used to test the feasibility of HSC-based gene therapy

Delayed functional maturation of natural regulatory T cells in the medulla of postnatal thymus: role of TSLP

BACKGROUND: Generation of functional CD4(+)CD8(-)CD25(+ )regulatory T cells (Treg) in the murine thymus depends on FoxP3. Removal of the thymus from neonatal mice has been shown to result in a multiple organ autoimmune disease phenotype that can be prevented by introducing the FoxP3(+ )Treg population to the animal. It has therefore, been proposed that functional FoxP3(+ )Treg cells are not made in the neonatal thymus; however, it remains unclear when and where functional FoxP3(+)CD4(+)CD8(-)CD25(+ )thymocytes are generated in postnatal thymus. RESULTS: We report that neither FoxP3 mRNA nor protein is expressed in CD4(+)CD8(-)CD25(+), or CD4(+)CD8(-)CD25(- )thymocytes until 3–4 days post birth, despite the presence of mature CD4(+)CD8(-)CD25(+/- )thymocytes in the thymus by 1–2 days after birth. FoxP3(-)CD4(+)CD8(-)CD25(+ )thymocytes from day 2 newborn mice show no Treg activity. Interestingly, we are able to detect low numbers of FoxP3(+ )thymocytes dispersed throughout the medullary region of the thymus as early as 3–4 days post birth. Expression of FoxP3 is induced in embryonic day 17 fetal thymus organ culture (FTOC) after 4–6 days of in vitro culture. Treatment of FTOCs with thymic stromal derived lymphopoietin (TSLP) enhanced expression of FoxP3, and blocking the TSLP receptor reduces FoxP3 expression in FTOC. Furthermore, TSLP stimulates FoxP3 expression in purified CD4(+)CD8(- )thymocytes, but not in CD4(+)CD8(+), CD4(-)CD8(+ )and CD4(-)CD8(- )thymocytes. CONCLUSION: Expression of FoxP3 or Treg maturation is ontogenically distinct and kinetically delayed from the generation of CD4(+)CD8(-)CD25(+ )or CD4(+)CD8(-)CD25(- )thymocytes in the postnatal thymus. TSLP produced from medullary thymic epithelia cells (mTEC) contributes to the expression of FoxP3 and the maturation of natural regulatory T cells. Overall, these results suggest that the development of Treg cells requires paracrine signaling during late stages of thymocyte maturation that is distinct from signaling during positive or negative selection

LYAR, a novel nucleolar protein with zinc finger DNA-binding motifs, is involved in cell growth regulation

A cDNA encoding a novel zinc finger protein has been isolated from a mouse T-cell leukemia line on the basis of its expression of a Ly-1 epitope in λgt11 library. The putative gene was mapped on mouse chromosome 1, closely linked to Idh-1, but not linked to the Ly-1 (CD5) gene. The cDNA is therefore named Ly-1 antibody reactive clone (LYAR). The putative polypeptide encoded by the cDNA consists of 388 amino acids with a zinc finger motif and three copies of nuclear localization signals. Antibodies raised against a LYAR fusion protein reacted with a protein of 45 kD on Western blots and by immunoprecipitation. Immunolocalization indicated that LYAR was present predominantly in the nucleoli. The LYAR mRNA was not detected in brain, thymus, bone marrow, liver, heart, and muscle. Low levels of LYAR mRNA were detected in kidney and spleen. However, the LYAR gene was expressed at very high levels in immature spermatocytes in testis. The LYAR mRNA is present at high levels in early embryos and preferentially in fetal liver and fetal thymus. A number of B- and T-cell leukemic lines expressed LYAR at high levels, although it was not detectable in bone marrow and thymus. During radiation-induced T-cell leukemogenesis, high levels of LYAR were expressed in preleukemic thymocytes and in acute T leukemia cells. Fibroblast cells overexpressing the LYAR cDNA from a retrovirus vector, though not phenotypically transformed in vitro, had increased ability to form tumors in nu/nu mice. Therefore, LYAR may function as a novel nucleolar oncoprotein to regulate cell growth

A Leucine Zipper Motif in the Cytoplasmic Domain of gp41 Is Required for HIV-1 Replication and Pathogenesis in Vivo

AbstractA leucine zipper motif is conserved in the cytoplasmic domain of glycoprotein gp41 (gp41c) of all HIV-1 subtypes, but is not present in HIV-2 or SIV. The second leucine residue of the leucine zipper was mutated (L95R) to determine the role of this motif in HIV-1 replication and pathogenesis. The L95R mutant replicated to wild-type levels in activated peripheral blood mononuclear cells and CEMx174 cells. However, L95R replication was impaired in SupT1 cells and in the SCID-hu Thy/Liv mouse. Although the infectivity of wild-type virions and that of L95R mutant virions were equally sensitive to heat treatment, we found that L95R produced more defective virions, due to reduced surface expression and virion incorporation of the env glycoprotein. These results suggest that the L95 residue in the leucine zipper of gp41c of HIV-1 plays an important role in the env expression and virion incorporation that is required for viral replication and pathogenesis in the SCID-hu Thy/Liv mouse. The leucine zipper motif in gp41c may provide a novel anti-HIV-1 target