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Some Unmet Challenges in the Immunology of Viral Infections

All Eyes on the Next Generation of HIV Vaccines: Strategies for Inducing a Broadly Neutralizing Antibody Response

Abstract: HIV-1 broadly neutralizing antibodies (BNAbs) develop after several years of infection through a recursive process of memory B cell adaptation and maturation against co-evolving virus quasispecies. Advances in single-cell sorting and memory B cell antibody cloning methods have identified many new HIV BNAbs targeting conserved epitopes on the HIV envelope (env) protein. 3D crystal structures and biophysical analyses of BNAbs bound to invariant virus structures expressed on monomeric gp120, epitope scaffolds, core structures, and native trimers have helped us to visualize unique binding interactions and paratope orientations that have been instrumental in guiding vaccine design. A paradigm shift in the approach to structure-based design of HIV-1 envelope immunogens came recently after several laboratories discovered that native viral envelopes or "env-structures" reverse-engineered to bind with high affinity to a handful of broadly neutralizing antibodies did not in fact bind the predicted germline precursors of these broadly neutralizing antibodies. A major challenge for HIV-1 B cell vaccine development moving forward is the design of new envelope immunogens that can trigger the selection and expansion of germline precursor and intermediate memory B cells to recapitulate B cell ontogenies associated with the maturation of a broadly neutralizing antibody response. Equally important for vaccine development is the identification of delivery systems, prime-boost strategies, and synergistic adjuvant combinations that can induce the magnitude and quality of antigen-specific T follicular helper (TFH) cell responses needed to drive somatic hypermutation (SHM) and B cell maturation against heterologous primary virus envelopes. Finding the combination of multi-protein envelope immunogens and immunization strategies that can evolve a potent broadly neutralizing antibody response portends to require a complex vaccine regimen that might be difficult to implement on any scale. This perspective strives to integrate recent insights into mechanisms associated with the evolution of an HIV-1 broadly neutralizing antibody response with current immunogen design and proffers a novel immunization strategy for skewing TH17/TFH cell responses that can drive B cell adaptation and affinity maturation associated with a broadly neutralizing antibody response. ... Read more

Immune Mechanisms in Atherosclerosis and Potential for an Atherosclerosis Vaccine

Abstract: A large body of evidence implicates the immune system in the pathogenesis and modulation of atherosclerosis. Dendritic cells and lymphocytes are among the many components of the immune system that are involved in modulating atherogenesis. This review focuses on the current knowledge of the complex role of the dendritic cells and lymphocytes in atherogenesis and the potential for immune-modulation therapies for atherosclerosis. ... Read more

The Development of Anti-inflammatory Drugs for Infectious Diseases

Abstract: Traditionally, disease is thought to result from an insufficient response of the host to infection, leading to increased replication of microorganisms and consequently disease. However, infection may not necessarily lead to disease and disease is not only the result of uncontrolled replication of a microorganism. Indeed, the inflammatory response triggered by certain infections is frequently the cause of tissue damage and death. The present review argues that it is possible to separate mechanisms necessary for the host response to deal with infection from those which cause unwanted inflammation and drive disease. By understanding mechanisms which drive disease and where/how interaction leads to disease, we may be able to devise novel therapies to alleviate suffering of patients. Below, we will describe three situations -- influenza, dengue and sepsis -- in which unwanted (excessive, misplaced or altered) inflammation is responsible for disease induction. In these three situations, we will also describe some examples of molecules which have been found to drive disease but appear not to be essential for the ability of the host to control infection. ... Read more

Vaccine Adjuvant Properties of Probiotic Bacteria

Abstract: Vaccine-preventable diseases are still responsible for the deaths of more than 1 million children under the age of 5 years annually, mostly in developing countries. A substantial number of these deaths are due to pneumococcal bacteria and infections with rotavirus. Important issues faced by the WHO, governments, vaccine manufacturers, and international organizations such as UNICEF and the Global Alliance for Vaccines and Immunization (GAVI) are the cost-effective introduction of these life-saving vaccines in resource-poor countries where there is a considerable disease burden, and achieving high rates of completion of vaccination schedules remains elusive. Problems with vaccine coverage and vaccine delivery in these regions are significant, as in some cases large proportions of the target population do not receive adequate vaccination. Consequently, there is a need to develop more effective vaccination strategies that can provide adequate protection with reduced schedules. To date, emphasis has been placed on identifying novel vaccine antigens and adjuvants that induce stronger protective immune responses, as well as developing mucosally-administered vaccines. These approaches would have enormous benefits in allowing safe administration of vaccines in remote areas and may overcome the necessity for multiple doses. In this regard, the use of probiotic bacteria as novel mucosal adjuvants to enhance existing vaccine specific-immune responses offers an exciting new approach. In this review, we discuss the evidence for the role of probiotics in enhancing vaccine responses and provide justification for further investigation into their clinical effects and mechanisms of action. ... Read more

Elusive Alzheimer's Disease: Can Immune Signatures Help Our Understanding of This Challenging Disease? Part 2: New Immune Paradigm

Abstract: Alzheimer's disease (AD) is the most common form of dementia. Its most important pathological hallmarks are profound neuronal loss, presence of intracellular neurofibrillary tangles, and extracellular deposition of beta-amyloid protein (Aβ) as beta-amyloid plaques. One of the most important risk factors for AD is age and with the increase of life-expectancy AD has become the most common form of dementia. The current "Holy Grail" is to be able to diagnose variants of AD before they manifest clinically and before irreparable brain damage is done. To be able to do so, we need robust and reliable biomarkers which reflect the pathogenesis of AD. This is essential because such biomarkers might indicate pathways that could be targeted for interventions aiming at disease prevention or amelioration. Although much attention has been focused on Aβ in this respect, it may not be as attractive a target as thought if current doubts concerning its causative role are substantiated. This review will be in two parts, the first part dealt with the current clinical knowledge and the questions raised by the Aβ cascade hypothesis in the pathogenesis of AD and this second part aims to synthesize our current knowledge and new data suggesting how immunity may contribute to the development of AD and may itself be targeted in future treatments. ... Read more

New Developments in Vaccine Research -- Unveiling the Secret of Vaccine Adjuvants

Abstract: Since the first mass vaccination against smallpox and its eventual eradication, many more vaccines have been developed based on advances in bacteriology and virology and the use of attenuated live or killed whole pathogens. Immunological discoveries have allowed the development of more refined anti-toxin and conjugate vaccines, while biotechnology provided the tools for rationally designed, genetically engineered vaccines. Many challenges remain in developing safer and more effective vaccines against the more complex diseases such as tuberculosis and HIV-AIDS, and for the rapid protection against newly emerging pathogens or pathogen strains. These vaccines are likely to require the isolation of the "protective" antigenic molecules from the whole pathogen, as well as ways to deliver these to induce effective immune responses with minimal side effects. It has long been recognized that most antigens require the addition of an "adjuvant," an ill-defined substance that non-specifically triggers the innate immune system and boosts an immune response, with aluminum-based adjuvants the most commonly used in most present vaccines. Recent immunological breakthroughs have uncovered that the innate immune system has a much higher degree of complexity than previously thought and can be activated along a wide range of different pathways, depending on the engagement of different innate immune receptors. This in turn determines the type of immune response that will be generated against the vaccine antigens or pathogens. Harvesting the complexity and exquisite specificity of this innate immune system has inspired a new direction in vaccine research, towards the generation of novel adjuvant formulations, tailored to induce defined immune responses effective against specific pathogens. This review gives a brief overview of vaccine development and summarizes different aspects of adjuvant formulation that may influence their activity and specificity. ... Read more

Optimizing siRNA Delivery to the Genital Mucosa

Abstract: RNA interference (RNAi) describes a highly conserved pathway, present in eukaryotic cells, for regulating gene expression. Small stretches of double-stranded RNA, termed small interfering RNAs (siRNAs), utilize this pathway to bind homologous mRNA, resulting in site-specific mRNA cleavage and subsequent protein degradation. The ubiquitous presence of the RNAi machinery, combined with its specificity and efficacy, makes it an attractive mechanism for reducing aberrant gene expression in therapeutic settings. However, a major obstacle to utilizing RNAi in the clinic is siRNA delivery. Administered siRNAs must make contact with the appropriate cell types and, following internalization, gain access to the cytosol where the RNAi machinery resides. This must be achieved so that silencing is maximized, whilst minimizing any undesirable off-target effects. Recently, the utility of siRNAs as a microbicide, usually applied to the genital mucosa for preventing transmission of sexually transmitted diseases including HIV-1 and HSV-2, has been investigated. In this review we will describe these studies and discuss potential strategies for improving gene silencing. ... Read more

Naked DNA and the new generation of therapeutic vaccines

Numerous developments in molecular biology and cellular engineering techniques have given a fresh impetus to the rational design of immunotherapies aimed at combating difficult-to-treat diseases such as cancer and AIDS. Such advances have catalyzed the identification of several potential tumor antigens and HIV-1 viral antigens. This has subsequently permitted the generation of vectors for the delivery of genetic material encoding these tumor-specific and HIV-1 specific antigens.

Vaccines can be defined as genetic when the antigen they deliver is present as DNA or RNA. Numerous viral vectors such as adenovirus, adeno-associated virus or lentiviral retroviruses can be exploited for the delivery of ... Read more

A Feedback Regulatory Pathway Between LDL and Alpha 1 Proteinase Inhibitor in Chronic Inflammation and Infection

Abstract: Dietary lipids are transported via lymph to the liver and transformed to lipoproteins which bind to members of the low density lipoprotein receptor family (LDL-RFMs). Certain LDL-RFMs, e.g., very low density lipoprotein receptor (VLDLR), are also bound by inactivated proteinase inhibitors, the most abundant being α1proteinase inhibitor (α1PI, α1antitrypsin). Inflammation/infection, including HIV-1 infection, is accompanied by low levels of CD4+ T cells and active α1PI and high levels of inactivated α1PI. By inducing LDL-RFMs-mediated cellular locomotion, active α1PI regulates the number of CD4+ T cells. We sought to investigate whether CD4+ T cells and α1PI directly impact lipoprotein levels. At the cellular level, we show that active α1PI is required for VLDLR-mediated uptake of receptor-associated cargo, specifically CD4-bound HIV-1. We show that active α1PI levels linearly correlate with LDL levels in HIV-1 infected individuals (P<0.001) and that therapeutic, weekly infusions of active α1PI elevate the number of CD4+ T cells and HDL levels while lowering LDL levels in patients on antiretroviral therapy with controlled HIV-1. Based on the unusual combination of lipodystrophy and low levels of α1PI and CD4+ T cells in HIV-1 disease, we reveal that LDL and α1PI participate in a feedback regulatory pathway. We demonstrate integral roles for sequentially acting active and inactive α1PI in the uptake and recycling of receptors and cargo aggregated with VLDLR including CD4 and chemokine receptors. Evidence supports a role for α1PI as a primary sentinel to deploy the immune system as a consequence of its role in lipoprotein transport. ... Read more

New Paradigms for Generating Effective CD8+ T Cell Responses Against HIV-1/AIDS

Abstract: CD8+ CTL responses are critical for eliminating virus infected cells in acute infection and in controlling virus replication during chronic infection. Despite evidence of potent HIV-1-specific CD8+ CTL responses during the earliest stage of acute infection leading to replacement of founder virus sequence(s) and resolution of peak viral load, in the majority of infected individuals, these responses are inadequate to prevent the establishment or control of persistent infection. Protective CD8+ CTL responses have yet to be achieved by vaccine approaches for HIV-1 or other viruses causing persistent infections, Mycobacterium tuberculosis, malaria, and cancer. Understanding the limitations of CD8+ CTL responses to keep pace with the diversity of rapidly evolving virus in the case of HIV-1 and HCV and to overcome the diverse and complex mechanisms persistent pathogens employ to escape immune recognition should lead to more effective prophylactic and therapeutic approaches for these diseases. Recent technological advances including single genome amplification (SGA) of plasma viral RNA along with direct amplicon sequencing to identify virus quasispecies, bioinformatics, and statistical methods for the systematic identification of HLA-class I associated escape mutations, and mathematical models that better define the kinetics of virus replication and decay, have provided significant insight into mechanisms of viral transmission and sequence evolution, virus-host interactions, and HIV-1 pathogenesis. In this review we attempt to integrate recent findings from studies in HIV-1, persistent virus infections, and cancer that predict effective T cell responses and suggest approaches that could shift the balance of control in favor of the host immune response. Here, we highlight factors considered essential for effective HIV-1 vaccine CD8+ T cell responses: vaccine antigens, quality, magnitude and breadth, mucosal targeting, and formation of CD8+ T cell mucosal memory. ... Read more

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