Hepatitis C Vaccines, Antibodies, and T Cells

The development of vaccines that protect against persistent hepatitis C virus (HCV) infection remain a public health priority. The broad use of highly effective direct-acting antivirals (DAAs) is unlikely to achieve HCV elimination without vaccines that can limit viral transmission. Two vaccines targeting either the antibody or the T cell response are currently in preclinical or clinical trials. Next-generation vaccines will likely involve a combination of these two strategies. This review summarizes the state of knowledge about the immune protective role of HCV-specific antibodies and T cells and the current vaccine strategies. In addition, it discusses the potential efficacy of vaccination in DAA-cured individuals. Finally, it summarizes the challenges to vaccine development and the collaborative efforts required to overcome them

The multifaceted role of macrophages during acute liver injury

The liver is situated at the interface of the gut and circulation where it acts as a filter for blood-borne and gut-derived microbes and biological molecules, promoting tolerance of non-invasive antigens while driving immune responses against pathogenic ones. Liver resident immune cells such as Kupffer cells (KCs), a subset of macrophages, maintain homeostasis under physiological conditions. However, upon liver injury, these cells and others recruited from circulation participate in the response to injury and the repair of tissue damage. Such response is thus spatially and temporally regulated and implicates interconnected cells of immune and non-immune nature. This review will describe the hepatic immune environment during acute liver injury and the subsequent wound healing process. In its early stages, the wound healing immune response involves a necroinflammatory process characterized by partial depletion of resident KCs and lymphocytes and a significant infiltration of myeloid cells including monocyte-derived macrophages (MoMFs) complemented by a wave of pro-inflammatory mediators. The subsequent repair stage includes restoring KCs, initiating angiogenesis, renewing extracellular matrix and enhancing proliferation/activation of resident parenchymal and mesenchymal cells. This review will focus on the multifaceted role of hepatic macrophages, including KCs and MoMFs, and their spatial distribution and roles during acute liver injury

IL28B SNP screening and distribution in the French Canadian population using a rapid PCR-based test

Single nucleotide polymorphisms (SNPs) in the proximity of the interleukin-28B (IL28B) gene can predict spontaneous resolution of hepatitis C virus (HCV) infection and response to interferon therapy. Screening for this polymorphism has become part of the standard criteria for the management of HCV-infected patients, hence the need for a rapid, cost-effective screening method. Here, we describe a rapid PCR-based test to screen for two IL28B SNPs (rs12979860 and rs8099917). We used this test to investigate IL28B polymorphism and prevalence in a cohort of French Canadian injection drug users who are part of a unique population known to have a strong genetic founder effect. This population had lower linkage disequilibrium between the two tested SNPs as compared to other cohorts (|d′| = 0.68, r = 0.59). The special genetic makeup should be considered in the management of HCV-infected patients within that population

Memory CD8+ T Cells Are Required for Protection from Persistent Hepatitis C Virus Infection

Few hepatitis C virus (HCV) infections resolve spontaneously but those that do appear to afford protective immunity. Second infections are usually shorter in duration and are less likely to persist but mechanisms of virus control in immune individuals have not been identified. In this study we investigated whether memory helper and/or cytotoxic T lymphocytes provide protection in chimpanzees serially reinfected with the virus. Clearance of the first infection took 3–4 mo and coincided with the delayed onset of CD4+ and CD8+ T cell responses. High frequencies of memory T cells targeting multiple HCV proteins were stable over 7 yr of follow-up. Animals were infected for a second time to assess the protective role of memory T cells. In contrast to the prolonged course of the first infection, viremia was terminated within 14 d. Control of this second infection was kinetically linked to rapid acquisition of virus-specific cytolytic activity by liver resident CD8+ T cells and expansion of memory CD4+ and CD8+ T cells in blood. The importance of memory CD8+ T cells in control of HCV infection was confirmed by antibody-mediated depletion of this lymphocyte subset before a third infection. Virus replication was prolonged despite the presence of memory CD4+ T helper cells primed by the two prior infections and was not terminated until HCV-specific CD8+ T cells recovered in the liver. These experiments demonstrate an essential role for memory CD8+ T cells in long-term protection from chronic hepatitis C

Innovative Structural and Joining Concepts for Lightweight Design of Heavy Vehicle Systems

The extensive research and development effort was initiated by the U.S. Department of Energy (DOE) in 2002 at West Virginia University (WVU) in order to investigate practical ways of reducing the structural weight and increasing the durability of heavy vehicles through the judicious use of lightweight composite materials. While this project was initially focused on specific Metal Matrix Composite (MMC) material, namely Aluminum/Silicon Carbide (Al/SiC) commercially referenced as ''LANXIDE'', the current research effort was expanded from the component level to the system level and from MMC to other composite material systems. Broadening the scope of this research is warranted not only by the structural and economical deficiencies of the ''LANXIDE'' MMC material, but also by the strong coupling that exists between the material and the geometric characteristics of the structure. Such coupling requires a truly integrated design approach, focused on the heaviest sections of a van trailer. Obviously, the lightweight design methods developed in this study will not be implemented by the commercial industry unless the weight savings are indeed impressive and proven to be economically beneficial in the context of Life Cycle Costs (LCC). ''Bulk Haul'' carriers run their vehicles at maximum certified weight, so that each pound saved in structural weight would translate into additional pound of cargo, and fewer vehicles necessary to transport a given amount of freight. It is reasonable to ascertain that a typical operator would be ready to pay a premium of about $3-4 for every additional pound of cargo, or every pound saved in structural weight. The overall scope of this project is to devise innovative, lightweight design and joining concepts for heavy vehicle structures, including cost effective applications of components made of metal matrix composite (MMC) and other composite materials in selected sections of such systems. The major findings generated by this research effort in its first two years have been summarized in the 2003 and 2004 Annual Progress Reports of DOE's Freedom Car and Vehicle Technologies Program. Consistent interactions with producers of heavy trailers, such as Great Dane and Wabash, as well as with their users, such as Old Dominion Freight Lines, have continued during this period to ensure that the research conducted at WVU will yield practical results that will benefit the industry in the near future. Furthermore, Dr. Gergis William and Mr. Thomas Evans participated in the 2005 Technology and Maintenance Council (TMC) annual meeting held in Tampa, Florida, in February 2005. This event offered the WVU researchers an effective opportunity to explore various technical needs and concerns of the industry, both from the performance and maintenance viewpoints, as well as to assess realistically potential benefits and barriers associated with practical implementation of lightweight materials and design technologies in heavy vehicle structures

Thermodynamic Investigation and Mixed Ligand Complex Formation of 1,4-Bis-(3-aminopropyl)-piperazine and Biorelevant Ligands

Thermodynamic parameters for protonation of 1,4-bis(3-aminopropyl)-piperazine (BAPP) and its metal complexation with some divalent metal ions were determined in aqueous solution at constant ionic strength (0.1 M NaNO3) using a potentiometric technique. The order of –ΔG0 and –ΔH0 was found to obey , in accordance with the Irving-Williams order. The formation equilibria of zinc (II) complexes and the ternary complexes Zn(BAPP)L, where L = amino acid, amides, or DNA constituents), have been investigated. Ternary complexes are formed by a simultaneous mechanism. The concentration distribution of the complexes in solution was evaluated as a function of pH. Stoichiometry and stability constants for the complexes formed are reported and discussed. The stability of ternary complexes was quantitatively compared with their corresponding binary complexes in terms of the parameter Δlog K

Protonation Equilibria of Biologically Active Ligands in Mixed Aqueous Organic Solvents

The review is mainly concerned with the protonation equilibria of biologically active ligands like amino acids, peptides, DNA constituents, and amino acid esters in nonaqueous media. Equilibrium concentrations of proton-ligand formation as a function of pH were investigated. Also, thermodynamics associated with protonation equilibria were also discussed

Limited T Cell Receptor Diversity of HCV-specific T Cell Responses Is Associated with CTL Escape

Escape mutations are believed to be important contributors to immune evasion by rapidly evolving viruses such as hepatitis C virus (HCV). We show that the majority of HCV-specific cytotoxic T lymphocyte (CTL) responses directed against viral epitopes that escaped immune recognition in HCV-infected chimpanzees displayed a reduced CDR3 amino acid diversity when compared with responses in which no CTL epitope variation was detected during chronic infection or with those associated with protective immunity. Decreased T cell receptor (TCR) CDR3 amino acid diversity in chronic infection could be detected long before the appearance of viral escape mutations in the plasma. In both chronic and resolved infection, identical T cell receptor clonotypes were present in liver and peripheral blood. These findings provide a deeper understanding of the evolution of CTL epitope variations in chronic viral infections and highlight the importance of the generation and maintenance of a diverse TCR repertoire directed against individual epitopes

Potential of Saudi natural clay as an effective adsorbent in heavy metals removal from wastewater

This study aims to examine the potential of natural clay mineral from the southern part of Saudi Arabia as an effective adsorbent material for the removal of heavy metal ions of cadmium (Cd) and nickel (Ni) from aqueous solutions. The SEM analysis showed that clay particles had mixed shapes such as elongated rod-like and rectangular shape having rough corners with larger particles of 2-8 µm in size and smaller particles in the sub-micron size range. X-ray diffraction data revealed that clay particles had a good crystalline structure and composed of a mixture of various minerals including feldspar, illite, quartz, calcite, and gypsum. The BET surface area was found to be 35 ± 1 m ² /g and the average pore size and pore volume of 6.5 ± 0.5 nm and 5.7e-02 cc/g, respectively. The X-ray fluorescence analysis of clay showed main compounds of SiO₂ (47.33%), Al₂O₃ (18.14%), Fe₂O₃ (15.89%) with many others such as CaO, MgO, TiO₂, and K₂O in minor quantities. It was found that 1.2 g of clay removed up to 99.5% of Ni and 97.5% of Cd from 40 ppm aqueous solutions. The metal removal efficiencies were increased from around 95% up to 99% by increasing the pH of aqueous solutions from 4 to 11. The adsorption of Ni and Cd ions on Saudi clay was relatively fast, and up to 97% of ions were removed from solution within 45 min. The SEM-EDX and BET analysis for recycled clays further confirmed that the metal ions were removed from water through adsorption onto the clay. The experimental data fitted well with Langmuir and Freundlich isotherms. The maximum adsorption capacity of clay for Cd and Ni from isotherms was found to be 3.3 and 2.7 mg/g respectively. The findings of this study confirm the potential role of Saudi natural clay in wastewater treatment processes as a cheap, environment-friendly and safe natural adsorbent material

Induction of multi-functional T cells in a phase I clinical trial of dendritic cell immunotherapy in Hepatitis C virus infected individuals

We have previously reported a world-first phase I clinical trial to treat HCV patients using monocyte-derived dendritic cells (Mo-DC) loaded with HCV-specific lipopeptides. While the brief treatment proved to be safe, it failed to reduce the viral load and induced only transient cell-mediated immune responses, measured by IFNc ELIspot. Here we reanalysed the PBMC samples from this trial to further elucidate the immunological events associated with the Mo-DC therapy. We found that HCV-specific single- and multi-cytokine secreting T cells were induced by the Mo-DC immunotherapy in some patients, although at irregular intervals and not consistently directed to the same HCV antigen. Despite the vaccination, the responses were generally poor in quality and comprised of primarily single-cytokine secreting cells. The frequency of FOXP3+ regulatory T cells (Treg) fluctuated following DC infusion and eventually dropped to below baseline by week 12, an interesting trend suggesting that the vaccination may have resulted in a more subtle outcome than was initially apparent. Our data suggested that Mo-DC therapy induced complex immune responses in vivo that may or may not lead to clinical benefit.Shuo Li, Stuart Roberts, Magdalena Plebanski, Maelenn Gouillou, Tim Spelman, Philippe Latour, David Jackson, Lorena Brown, Rosemary L. Sparrow, H. Miles Prince, Derek Hart, Bruce E. Loveland and Eric J. Gowan