Page: 1-16 (16)
Author: Nitin K. Saksena, Jing Qin Wu, Katherine Lau, Li Zhou, Maly Soedjono and Bin Wang
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CD8 antiviral activity is a subject of intense studies. Two very critical anti-viral arms of HIVspecific CD8+ T cells (cytolytic and non-cytolytic) have been shown to play a significant role in protection against HIV and appear to associate with asymptomatic survival and slower disease progression. The cytotoxic CD8+ T cells (CTL) recognize and eliminate HIV-infected cells displaying MHC class-I proteins. Along with recognition and elimination of HIV-infected cells, CD8+ T cells potentially influence various stages in HIV life cycle. For instance the chemokines produced by CD8+ T cells block the entry of the virus into T cells and macrophages. The activated CD8+ T cells also produce soluble factors that act at the transcriptional level. In contrast, the non-cytolytic CD8+T cells from HIV+ individuals suppress virus replication in CD4+ T cells in vitro, involving interplay of soluble factors such as chemokines and other antiviral factors such as unidentified soluble CD8 Antiviral Factor (CAF), urokinase-type plasminogen activator (uPA) and antiviral membrane-bound factor. In light of these factors, it is clear that the cell-mediated immune responses are critical in controlling HIV replication in vivo. Although the constituents of antiviral activity of CD8+ T cells remain largely elusive, the restoration of this activity during Highly Active Antiretroviral Therapy (HAART) and IL-2 treatment confers significant improvement in antiviral activity. The aim of this chapter is to provide a comprehensive and unbiased snapshot of antiviral potential of these cells and mechanisms involved in conferring this protective activity in HIV+ individuals and its overall relevance in HIV disease.
Page: 17-50 (34)
Author: Massimo Alfano and Guido Poli
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HIV is the ethiological agent of the Acquired Immunodeficiency Syndrome (AIDS). HIV infects mostly CD4+ immune cells, such as T lymphocytes, mononuclear phagocytes and myeloid dendritic cells and induces a progressive and deadly state of immunodeficiency if untreated with potent combinations of antiretroviral agents. The immunodeficient status of the host allows the development of several opportunistic infections as well as “opportunistic” tumors such as Kaposis’ sarcoma and B cell lymphomas. In addition, the ability of HIV-1 infected immune cells to localize in various tissues leads to tissue specific HIV-associated pathology, such as AIDS dementia, interstitial lung disease, nephropathy, enteropathy, and wasting syndrome. Of note, all these processes involve the upregulation or modulation of cytokines, soluble factors that regulate the immune responses and inflammation in addition to hematopoiesis. Due to space limitation and to the extent of informations about HIV and cytokines, this chapter will not discuss topics such as interactions between intracellular signalings by cytokines and HIV or the effect of the single viral proteins, such as gp120 Env, Tat and Nef, for which updated reviews/book chapters are available. In this chapter, we describe the general activities of cytokines and their role in modulating HIV infection, both in vitro and in vivo, animal models and human tissues such as gut and lymphoid tissue, and finally ways to which cytokines have been used as immunotherapy, either alone or in combination with anti-retrovirals.
Page: 51-63 (13)
Author: Theresa L. Chang and Mary Klotman
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The innate immune system provides the first line of defense against a wide variety of microorganisms before the development of an adaptive immune response. Epithelial cells at mucosal surfaces and recruited leukocytes are often the first to contact microbial pathogens and mount an innate immune response including the production of Antimicrobial Peptides (AMPs) such as defensins and cathelicidins and pro-inflammatory cytokines through pattern recognition receptors (e.g. Toll-like receptors, TLRs). Defensins exhibit a broad spectrum of action against microorganisms including Grampositive and Gram-negative bacteria, fungi and viruses. In addition to their microbicidal effects they act as immunomodulators involved in inflammation, tissue repair and angiogenesis. However, increasing evidence suggests that the innate immunity including production of AMPs can act as a double-edged sword by providing protection against invading pathogens but at the same time causing potentially harmful inflammation. This review focuses on the role of defensins as innate effectors and immunodulators in HIV infection, the multiple and complex mechanisms by which defensins inhibit or enhance HIV infection in vitro as well as recent clinical evidence supporting an association between defensins and HIV transmission.
Page: 64-80 (17)
Author: Joel Gozlan, Chloe Borde and Vincent Marechal
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High Mobility Group Box 1 (HMGB1) protein is an abundant nuclear protein that is released outside the cell, upon immune activation or primary cell necrosis. In the extra-cellular space, HMGB1 acts as a potent soluble factor that coordinates cellular events that are crucial for the amplification of inflammation, establishment of early immune responses and tissue repair. HMGB1 is therefore considered as the leading member of a subgroup of the Damage Associated Pattern Molecules named “Alarmins”.
Its critical position between innate and adaptive immunity targets HMGB1 is an important soluble factor that may interfere with HIV-1 infection. Indeed, recent works from our laboratory and others brought evidences for significant - although ambiguous - impact of HMGB1 on HIV-1 infection and/or expression.
This review will summarize the current understanding of this exciting molecule, before focusing on the main data available in the literature regarding its relationship with HIV-1. Its potential role during AIDS pathogenesis will be discussed.
Page: 81-101 (21)
Author: Sisse R. Ostrowski, Eva Haastrup, Anne Langkilde, Henrik Ullum and Jesper Eugen-Olsen
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The urokinase Plasminogen Activator Receptor (uPAR) is linked to the surface of immune cells and involved in multiple immune functions including cell adhesion, chemotaxis, migration, angiogenesis, fibrinolysis, proliferation, differentiation and signal transduction. uPAR binds and activates urokinase resulting in extracellular matrix degradation and remodeling. Also, uPAR can bind the extracellular matrix protein vitronectin promoting cell adhesion and migration.
uPAR can be cleaved from the cell surface resulting in soluble uPAR (suPAR). suPAR levels are increased by various infectious diseases associated with systemic inflammation such as HIV infection. Several studies have shown that those with the highest suPAR levels have increased disease progression and high risk of mortality.
Furthermore, uPA was demonstrated to exert antiretroviral activity by inhibiting late steps in HIV replication cycle in various cell lines, through mechanisms dependent on cell adhesion. Future research will determine whether the emerging role of the uPA/uPAR/suPAR-system in HIV infection can be implemented in HIV drug development and in the use of suPAR measurements for initiating antiretroviral therapy and for monitoring treatment efficacy.
Page: 102-110 (9)
Author: Cynthia L. Bristow, Jose Cortes, Roya Mukhtarzad, Maylis Trucy, Aaron Franklin, Val Romberg and Ronald Winston
Adult thymopoiesis is a multi-step process that in adult mice is highlighted by a 21-day cycle of coordinated journeying of progenitor cells between adult bone marrow and thymus. In the analogous human system, cell surface human leukocyte elastase (HLECS), the chemokine receptor CXCR4, and its ligand stromal-derived factor-1 (SDF-1, CXCL12) are required for progenitor cells to vacate bone marrow. We have recently observed that the number of circulating CD4+ lymphocytes is correlated with the HLECS ligand, α1antitrypsin (α1proteinase inhibitor, α1PI). In HIV-1 disease, α1PI levels are deficient and rate limiting for CD4+ lymphocytes. We demonstrate herein that α1PI therapy increases the number of CD4+ lymphocytes in blood. In HIV-1 patients the number of CD4+lymphocytes is increased to normal values after 2 weeks of therapy. Importantly, the 23-day periodicity of appearance of CD4+ lymphocytes suggests that α1PI regulates adult human thymopoiesis.
Page: 111-144 (34)
Author: Joan Fibla and Antonio Caruz
Among environmental factors related to pathogen infection, vitamin D is largely considered to be protective and promoter of good health. For these reasons, a general concern exists about vitamin D insufficiency that has been found around world reaching epidemic dimensions. In the last few years, interest about the role of vitamin D on immune response has been increased after encouraging data illustrated the well-known contribution of the binomial sunlight exposure/vitamin D on protection to mycobacterium infections. The vitamin D mediated induction of microbicide factors against bacterial infections runs in parallel with the vitamin D immunosuppressant activity induced to control the exacerbation of the cellular immune response. These complementary effects can be modulated to guarantee a correct vitamin D action. Concerning HIV infection a protective role can be expected from the vitamin D mediated microbicide activity, but no single effects can be deduced from the vitamin D immunosuppressant activity. In addition, the direct effects of vitamin D by promoting HIV replication can act as a confounding factor when trying to understand the role of vitamin D in HIV infection. In the present review we have evaluated available bibliography of vitamin D action on the immune system response crossing it with data on HIV immunopathology trying to find common pathways that can shed light on the role of vitamin D on HIV infection and disease progression to AIDS.
Page: 145-155 (11)
Author: Heribert Stoiber, Zoltan Banki and Doris Wilflingseder
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Already at the endothelial barrier of the host, HIV triggers responses of the innate immune system. A prominent component of the innate immunity is the complement system, which is immediately activated upon viral entry. Although the complement contributes to the control of viral replication by various strategies, HIV has evolved mechanisms to escape from complement-meditated neutralization and turns this part of the immune system to its advantage. Here we discuss the complex interactions of complement and complement receptors with HIV and review the escape mechanisms, which protect HIV from complement-mediated destruction.
Human Immunodeficiency Virus (HIV) infection represents one of the biggest challenges of current years. However, scientists and physicians still do not have an efficient therapy for preventing or eradicating the virus. The selection of drug-resistant strains as well as side-effects, represent common problems encountered in all anti-viral therapies. However, it has been clearly demonstrated that the potency of early immune responses profoundly regulates levels of HIV, and hence also the generation of virus mutants as well as the velocity of disease progression to AIDS. A prominent feature of this e-book is the focus on interaction between innate immunity and HIV infection. This topic has been investigated by many authors from the late 80's, and many soluble factors responsible for such activity have been discovered, such as suPAR and HMGB1. At present, these two novel factors are the subject of very intense research on HIV infections. A key advantage of this e-book is the selection of authors, recognized worldwide as leading experts in their field. Because of the comprehensive coverage, as well as the eminence of the authors, this e-book provides a detailed and high quality description about the role of innate immune responses regulating HIV replication. It should prove to be a useful resource for readers interested in immunology and HIV research.