Soluble Factors Mediating Innate Immune Responses to HIV Infection


by

Massimo Alfano

DOI: 10.2174/97816080500621100101
eISBN: 978-1-60805-006-2, 2010
ISBN: 978-1-60805-580-7

  
  


Indexed in: Chemical Abstracts , Scopus

Human Immunodeficiency Virus (HIV) infection represents one of the biggest challenges of current years. However, scientists and physic...[view complete introduction]
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Table of Contents

Foreword , Pp. i

Georges Herbein
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Preface , Pp. ii

Massimo Alfano
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Contributors , Pp. iii-v (3)

Massimo Alfano
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CD8 Antiviral Soluble Factors and Human Immunodeficiency Virus (HIV) Control , Pp. 1-16 (16)

Nitin K. Saksena, Jing Qin Wu, Katherine Lau, Li Zhou, Maly Soedjono and Bin Wang
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Cytokines and HIV Infection , Pp. 17-50 (34)

Massimo Alfano and Guido Poli
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Defensins and HIV Infection , Pp. 51-63 (13)

Theresa L. Chang and Mary Klotman
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Extracellular HMGB1: an Ambiguous Messenger During HIV-1 Infection , Pp. 64-80 (17)

Joel Gozlan, Chloe Borde and Vincent Marechal
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The uPA/uPAR System and suPAR in HIV Infection , Pp. 81-101 (21)

Sisse R. Ostrowski, Eva Haastrup, Anne Langkilde, Henrik Ullum and Jesper Eugen-Olsen
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α1Antitrypsin Therapy Increases CD4+ Lymphocytes to Normal Values in HIV-1 Patients , Pp. 102-110 (9)

Cynthia L. Bristow, Jose Cortes, Roya Mukhtarzad, Maylis Trucy, Aaron Franklin, Val Romberg and Ronald Winston
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Vitamin D and HIV Infection , Pp. 111-144 (34)

Joan Fibla and Antonio Caruz
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The Complement System and HIV-1 Infection , Pp. 145-155 (11)

Heribert Stoiber, Zoltan Banki and Doris Wilflingseder
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Index , Pp. 156-157 (2)

Massimo Alfano
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Abbreviations , Pp. 158-159 (2)

Massimo Alfano
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Foreword

Human Immunodeficiency Virus (HIV) and AIDS pathogenesis have been under investigation for almost three decades. Substantial scientific and medical data have been collected on the structure of the virus and its replication cycle in infected cells. In addition, our understanding of the pathogenesis of HIV infection has greatly improved: It depends on virus-induced immune suppression as well as the formation of cellular virion reservoirs. The role of non-viral factors in AIDS pathogenesis was first identified 20 years ago with the description of soluble factors, the cytokines, which modulate HIV-1 replication in infected cells. Since then, more soluble factors have been discovered, capable of either stimulating or inhibiting HIV replication. Two critical anti-viral arms of HIV-specific CD8+ T cells (cytolytic and non-cytolytic) were shown to play a significant role in HIV prevention, and were associated with asymptomatic survival and slower disease progression. The activity of cytokines and their role in modulating HIV infection have been investigated in vitro and in vivo, both in animal models and human tissues such as gut and lymphoid tissue. Moreover, modalities of using cytokines as immunotherapy, either alone or in combination with anti-retrovirals, have been described. Leukocytes and epithelial cells produce defensins, which are innate effectors and immunomodulators during HIV infection, taking a variety of actions against microorganisms. They also act as immunomodulators involved in inflammation, tissue repair, and angiogenesis. Other soluble factors, such as the high mobility group box 1 (HMGB1) protein and urokinase plasminogen activator and its receptor (uPA/uPAR system), have a critical task between innate and adaptative immunity, and may possibly interfere with HIV-1 infection. Alpha 1-antitrypsin levels, which are deficient in HIV-1 disease, and rate-limiting for CD4+ T lymphocytes, could be a therapeutic target. Research for a better understanding of the role of vitamin D during HIV infection and disease progression to AIDS is ongoing. The complement system, a prominent component of the innate immunity, is likely to aid in the control of HIV replication, although the virus has developed escape mechanisms to avoid complement-mediated destruction.

Among the cells of the innate immune system, macrophages, NK cells, and dendritic cells (DC) have been shown to be actively involved in the defence against HIV infection. Many cellular and environmental factors influence viral replication in cells of the innate immune system. These factors include: status of cellular activation, macrophage or DC/T cell interaction, cytokines and chemokines, immune complexes, and opportunistic pathogens. The effects of soluble factors and the innate immune cells on HIV pathogenesis also depend on the localization of the immune cells. Regarding viral replication, cellular activation status, and expression of chemokine receptors on the cell surface, macrophages do not behave in the same manner as viral reservoirs in lymph nodes, intestinal tissue, lung, and central nervous system. Therefore, in addition to the adaptative immune system, a complex network of soluble factors and innate immune cells appears to be a critical component in disease development. A better understanding of the pivotal role played by soluble factors in mediating innate immune responses to HIV infection should ultimately enable the development of new antiretroviral treatments. These treatments would make it possible to target not only the virus but also to modify its cellular environment, leading to a more complete control of HIV replication.

The present book strategically places the soluble factors and innate immune cells at the forefront of AIDS pathogenesis. Reading this book is essential to the understanding of the future development of therapeutic approaches for HIV infection.

Georges Herbein, M.D. Ph.D
University of Franche-Comté
Besançon
France


Preface

The Human Immunodeficiency Virus (HIV) infection represents one of the biggest challenges faced by the scientific community in recent years. HIV was discovered in the early ‘80s and has caused one of the most dramatic epidemics (known as the Acquired Immuno Deficiency Syndrome, AIDS) of the last (and current) century. Very extensive knowledge has been accumulated on the virus as well as on the deleterious effect of viral proteins for the host, leading to efficient therapies controlling viral replication. However, in the face of the great advances in antiretroviral therapy, scientists and physicians still do not have effective countermeasures for preventing infection with microbicides or vaccines and for eradicating the infection in those who have already acquired HIV, while the selection of drug-resistant strains, as well as side-effects, represent frequent problems for those under antiretroviral regimens.

The earliest defense against microbial infections is represented by the responses of the innate immune system that is finely tuned by different cellular types and several soluble factors. Related to HIV infection, soluble molecules of the innate immune system target multiple steps in the virus life cycle, sometimes in favor of the host and sometimes of the virus, for example for cytokines and the complement system. On the other hand, it has been clearly demonstrated that the potency of early immune responses profoundly regulates the levels of HIV replication and spreading and, overall, the speed of disease progression towards AIDS. Findings obtained with clinical trials based on α1-antitrypsin or IL-2 therapy in HIV individuals have clearly shown that strategies aimed at the manipulation of the immune system responses are feasible ways to enhance the control of virus replication, for example by boosting the ability of CD8+ T cells to release soluble, non-lytic anti-viral factors (CAF). Therefore, better characterization of the interactions between soluble factors mediating innate immune system responses and HIV might lead to the design of immunological compounds boosting the innate immune system against HIV. Most of these soluble mediators owing to anti-viral activity are independent of co-receptor usage, drug-resistance mutations, thus widening their therapeutic window in all stages of disease. In addition, a better comprehension of anti-viral activities delivered by innate immune response might turn fundamental for the design of anti-HIV vaccines.

Common denominator of all chapters described in this e-book is the mutual interaction between innate immunity and HIV infection, a topic that has been investigated from the late ’80s. Different authors describe different soluble factors responsible for the regulation of HIV infection and replication in various cell types and model systems of infection.

Therefore, this e-book provides a very detailed description about the role of innate immune responses regulating HIV replication according to the studies of several international experts. I do hope that this book will be a key reference text for a wide range of scientists, such as graduate students, for which it represents a good starting point, as well as for investigators in general, for whom it may represent a collection of the state of the art of 20 years of HIV research

Massimo Alfano, Ph.D

List of Contributors

Editor(s):
Massimo Alfano
DIBIT, San Raffaele Scientific Institute
Italy




Contributor(s):
Massimo Alfano
AIDS Immunopathogenesis Unit, Department of Immunology, Transplantation and Infectious Diseases
San Raffaele Scientific Institute
Milan, 20132
Italy


Zoltàn Banki
Department of Hygiene and Medical Microbiology
Innsbruck Medical University
Innsbruck, A-6020
Austria


Chloe Borde
Centre de Recherche des Cordeliers
Universitè Pierre et Marie Curie
INSERM Paris
Paris, F-75006
France


Bristow Cynthia L.
Department of Medicine, Weill Medical College of Cornell University
Institute for Human Genetics and Biochemistry, Laboratory for AIDS Virus Research
New York
NY, 10065
USA


Antonio Caruz
Immunogenetics Unit,Faculty of Sciences
Universidad de Jaén
Pasaje Las Lagunillas s/n 23071
Jaén
Spain


Theresa L. Chang
Department of Medicine, Division of Infectious Diseases
Mount Sinai School of Medicine, Box 1090, One Gustave L. Levy Place
New York
NY, 10029
USA


Jose Cortes
Beth Israel Medical Center
New York
NY, 10003
USA


Jesper Eugen-Olsen
Clinical Research Centre 136
Copenhagen University Hospital Hvidovre Hospital
Hvidovre, 2650
Denmark


Joan Fibla
Human Genetics Unit, Departament de Ciències Mèdiques Bàsiques
Universitat de Lleida and Institut de Recerca Biomèdica de Lleida
Catalunya
LLEIDA, 25199
Spain


Aaron Franklin
University of Toledo College of Medicine
Toledo
OH , 43614
USA


Joel Gozlan
Laboratoire de Virologie
Hôpital Saint-Antoine
Paris
F, F-75012
France


Eva Haastrup
Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet
Copenhagen
Denmark


Mary E. Klotman
Department of Medicine, Division of Infectious Diseases
Mount Sinai School of Medicine, Box 1090, One Gustave L. Levy Place
New York
NY, 10029
USA


Anne Langkilde
Clinical Research Centre 136, Copenhagen University Hospital Hvidovre Hospital
Hvidovre, 2650
Denmark


Katherine Lau
Retroviral Genetics Division Center for Virus Research
Westmead Millennium Institute, Westmead Hospital
Westmead NSW 2145
Sydney
Australia


Vincent Marechal
Centre de Recherche des Cordeliers
Universitè Pierre et Marie Curie
Paris, F-75006
France


Roya Mukhtarzad
ingsbrook Jewish Medical Center, Brooklyn
Brooklyn
New York , NY 11203
USA


Sisse Rye Ostrowski
Department of Clinical Immunology , Rigshospitalet
Copenhagen University Hospital
Copenhagen
Denmark


Guido Poli
Vita-Salute San Raffaele University School of Medicine
San Raffaele Scientific Institute
Milan, 20132
Italy


Val Romberg
CSL Behring
Bern
CH, 3000
Switzerland


Nitin K. Saksena
Retroviral Genetics Division Center for Virus Research
Westmead Millennium Institute, Westmead Hospital Westmead
Sydney
NSW , 2145



Maly Soedjono
Retroviral Genetics Division Center for Virus Research, Westmead Millennium Institute, Westmead Hospital, Westmead
Sydney
NSW , 2145
Australia


Heribert Stoiber
Department of Hygiene and Medical Microbiology
Innsbruck Medical University
Innsbruck, A-6020
Austria


Maylis Trucy
Department of Medicine, Weill Medical College of Cornell University
Institute for Human Genetics and Biochemistry, Laboratory for AIDS Virus Research
New York
NY , 10065
USA


Henrik Ullums
Department of Clinical Immunology
Copenhagen University Hospital, Rigshospitalet
Copenhagen
Denmark


Bin Wang
Retroviral Genetics Division Center for Virus Research
Westmead Millennium Institute, Westmead Hospital
Sydney
NSW, 2145
Australia


Doris Wilflingseder
Department of Hygiene and Medical Microbiology
Innsbruck Medical University
Innsbruck, A-6020
Austria


Ronald Winston
Department of Medicine, Weill Medical College of Cornell University
Institute for Human Genetics and Biochemistry, Laboratory for AIDS Virus Research
New York, NY10065
USA


Jing Qin Wu
Retroviral Genetics Division Center for Virus Research
Westmead Millennium Institute,Westmead Hospital Westmead
Sydney
NSW, 2145
Australia


Li Zou
Retroviral Genetics Division Center for Virus Research
Westmead Millennium Institute,Westmead Hospital Westmead
Sydney
NSW, 2145
Australia




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