Contents
Preface
Mucosal
HIV Vaccines: Where are We Now? Pp. 1-10
Liljana Stevceva and Warren Strober
B
Lymphocyte Dysfunctions in HIV Infection Pp. 11-21
Angelo De Milito
CD8+
T-Cells: Function and Response to HIV Infection Pp. 23-37
Naveed Gulzar and Karen F.T.
Copeland
HIV-1
Infection and Chemokine Receptor Modulation Pp. 39-50
Beatriz H. Ruibal-Ares,
Liliana Belmonte, Patricia C. Bare, Cecilia M. Parodi, Ivana Massud and Maria M.E. de Bracco
Role
of CD4 Receptor Down-regulation During HIV-1 Infection Pp. 51-59
Karine Levesque, Andres Finzi,
Julie Binette and Eric A. Cohen
Advances
in Neuroimaging for HIV-1 Associated Neurological Dysfunction: Clues to the
Diagnosis, Pathogenesis and Therapeutic Monitoring Pp. 61-78
Michael D. Boska, R. Lee
Mosley, Mehmood Nawab, Jay A. Nelson, Marina Zelivyanskaya, Larisa Poluektova,
Mariano Uberti, Huanyu Dou Travis B.
Lewis and Howard E. Gendelman
The
Chaperoning and Assistance Roles of the HIV-1 Nucleocapsid Protein in Proviral
DNA Synthesis and Maintenance Pp. 79-92
Carole Bampi, Sandrine
Jacquenet, Daniela Lener, Didier Decimo and Jean-Luc Darlix
Abstracts
[Back to top] Current HIV Research
celebrates its first anniversary of successfully providing our readers with stimulating, timely, and in-depth reviews in current HIV and AIDS research. As the Editor-in-Chief, I take this opportunity to thank the authors who contributed their ideas and insights into each article. The manuscripts published in volume 1 highlight a wide array of innovative scientific and medical research on HIV/AIDS.Approximately 100 million individuals worldwide have been infected with the human immunodeficiency virus (HIV) and developed the disease known as acquired immunodeficiency syndrome (AIDS). The pace of research in this field has produced challenges for scientists and clinicians to keep informed of the vast array of new information. In order to facilitate improved communication between HIV/AIDS researchers covering a diverse range of expertise, Current HIV Research was launched in order to provide a forum for interactive communication between researchers. Current HIV Research has aimed to cover all the latest and outstanding developments of HIV research. Comprehensive review articles on all areas of HIV research, including molecular aspects in virus replication and gene expression, HIV assembly, virus–cell interaction, viral pathogenesis, epidemiology, the latest developments in HIV/AIDS vaccines and animal models, anti-retroviral therapy, drug discovery, and clinical and molecular aspects for prevention of viral infection. Each issue of the journal contains a series of timely in-depth reviews written by leaders in the field covering a range of current topics on HIV research. I believe that each published issue of Current HIV Research shows that the journal is fulfilling its objectives.
Current HIV Research aims to be the international journal for comprehensive review articles on HIV research. The Editorial Advisory Board reflects the international representation of scientists and clinicians located in 14 different nations from some of the leading institutions in the world. We are proud that a similar diversity is reflected in the published and submitted articles as well. The journal fills a special void in the existing biomedical literature in that it is the only journal publishing both comprehensive and minireviews focused on all areas of HIV/AIDS research including molecular biology, biochemistry, immunology, pharmacology, epidemiology, antiviral agents and vaccine development, as well as clinical research, which should be of interest to both basic and clinical investigators.
In this issue of Current HIV Research, Stevceva and Strober summarize the various approaches for stimulating mucosal immunity during vaccination [1]. During HIV infection, the virus is attacked by the immune system. The virus yields a variety of mechanisms to evade and disable immune responses directed against the virus. De Milito [2] describes the mechanisms involved in the loss of B cell functions during HIV infection, whereas Gulzar and Copeland [3] review the variety of mechanisms that HIV uses to inhibit CD8+ T cell maturation, effector function, and memory induction. One of the results of integration of an HIV provirus into the host cell chromosome is the modulation of CXCR4 and CCR5 expression. Ruibal-Ares et al. [4] review the mechanisms of this modulation and its importance in HIV infection. Levesque et al. [5] described the role of CD4 receptor down-modulation during HIV infection and its importance in modulating immune function and viral infectivity. Finally, one of the lesser understood areas of HIV/AIDS research is the neurological disorders associated with HIV-1 associated dementia. Recent developments of quantitative magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and positron emission tomography (PET) are elegant described by Boska et al. [6] and the importance of these new techniques on measuring neuropathogenesis is discussed. And finally Bampi et al. [7] describe the chaperoning functions of nucleocapsid in proviral DNA synthesis.
[Back to top] Mucosal HIV
Vaccines: Where are We Now?
Liljana Stevceva
and Warren Strober
Around the world, approximately 5 million people became infected with HIV in 2001, an estimated 70% via sexual transmission. Numerous studies have demonstrated that it is difficult to achieve total protection from vaginally or rectally acquired HIV/SIV when using parenteral immunization. Mucosal immunization was seen as the best approach to achieve sustainable immune responses at mucosal sites of viral entry. This was further emphasized when several studies implicated rectal and vaginal mucosa as latent reservoirs for the HIV virus and virus-specific CD8+ T cell immune responses in gastrointestinal mucosa were shown to be less efficient than in systemic tissues.
Mucosal vaccines utilizing various routes of immunization including intranasal, intrarectal, intravaginal and oral immunization have been tested for their potency to induce virus-specific immune responses systemically but especially at mucosal sites of viral entry. The unsatisfactory results in initiating simultaneously sufficient immune responses at mucosal and systemic sites are being overcomed by use of appropriate and novel adjuvants such as Cholera toxin, Escherichia coli heat-labile toxin, immunostimulatory CpG motifs, coinjection of cytokines and others. Various routes of immunization are now being compared and combinations of mucosal immunization and parenteral boost and vice versa have also been tested. Generations of new vaccines, such as DNA-based vaccines, multipeptide, lipopeptide and alphavirus replicon particles-based vaccines have been created and studied for their efficiency.
[Back to top] B Lymphocyte
Dysfunctions in HIV Infection
Angelo De Milito
HIV establishes a chronic and latent infection that is not eliminated by the host immune defences. The virus induces extensive damage to the immune system, through virus-related and indirect pathogenic mechanisms. Both the cellular and the humoral arms of the immune system are unable to control the infection, which ultimately results in severe exhaustion of several lymphocyte functions and increased susceptibility to secondary and opportunistic infections. A striking pathological feature induced by the persistent viral replication is the aberrant activation of cells of the immune system. Among these cells, B lymphocytes are severely damaged and show signs of phenotypic and functional alterations. In parallel to the polyclonal B cell activation and hypergammaglobulinemia, B cells from patients show impaired reactivity to immunisation and in vitro activation signals. In addition, B lymphocytes from HIV-infected subjects are primed for apoptosis. The role of protective humoral immunity in the control and clinical progression of HIV infection is still much debated and controversial. The aim of the present review is to discuss the mechanisms involved in the loss of B cell functions during HIV infection. In particular, we discuss the role that T and B cell immune activation plays for B cell polyclonal activation and loss of memory B lymphocytes. The current knowledge on B cell damage is also discussed in the context of anti-HIV therapeutic treatment.
[Back to top] CD8+ T-Cells:
Function and Response to HIV Infection
Naveed Gulzar and Karen F.T. Copeland
CD8+ T-cells are a critical component of the cellular immune response and they play an important role in the control of viral infection. During HIV infection, CD8+ T-cells are able to recognize infected cells through an MHC-I dependent process and are able to lyse cells harboring viral infection by the secretion of perforin and granzymes. These cytotoxic T-lymphocytes (CTL) can also eliminate virally infected cells through the engagement of death-inducing ligands expressed by CD8+ T-cells with death receptors on the surface of the infected cell. In addition, CD8+ CTL secrete soluble factors such as β-chemokines and the CD8+ antiviral factor (CAF) that suppress viral binding and transcription, respectively. In order for HIV to survive the pressures placed upon it by the immune system, the virus has adopted numerous strategies to evade the CD8+ T-cell response. The high mutation rate of HIV has allowed the virus to escape CD8+ T-cell recognition in addition to its ability to down-regulate surface MHC-I expression from infected cells. Also, by altering the pattern of cytokine production and engagement of cellular receptors, HIV disrupts proper CD8+ T-cell signaling. The resultant improper T-cell receptor (TcR) stimulation creates an anergic state in these cells. By affecting the function of CD4+ T-cells and antigen presenting cells that are required for proper CD8+ T-cell maturation, HIV is able to decrease the circulating pool of effector and memory CD8+ T-cells that are able to combat viral infection. The end result is the aberration of CD8+ T-cell function.
[Back
to top] HIV-1 Infection and Chemokine Receptor
Modulation
Beatriz H. Ruibal-Ares, Liliana Belmonte, Patricia C.
Bare, Cecilia M. Parodi, Ivana Massud
and Maria M.E. de Bracco
In addition to the CD4 molecule that binds to the human immunodeficiency virus type-1 (HIV-1) envelope glycoprotein gp120, productive HIV-1 infection requires interaction with cellular receptors for α- or β- chemokines (CXCR4 and CCR5 respectively). Isolates of HIV-1 exhibit different tropism depending on the chemokine receptor type that they use to infect their cellular targets. HIV-1 strains that use preferentially CCR5 are known as R5 strains. They are more frequently found in asymptomatic individuals during the initial stages of the disease and are involved in the transmision of infection from mother to child. HIV-1 species using CXCR4 (X4 strains) are observed mainly in patients with advanced disease. While X4 isolates are associated with syncitium formation, in general R5 strains are not. Interaction of X4 and R5 with their specific receptors is necessary to establish productive HIV-1 infection and trigger a series of intracellular signals. Modulation of CXCR4 and CCR5 expression after HIV-1 infection is one of the results of such interaction and may have important consequences on the course of the infection. Down regulation of CCR5 and CXCR4 after HIV-1 infection could be the result of indirect events linked to HIV-1 infection, such as the induction of α- or β-chemokines competing with the virions for receptor binding. They could also reflect direct effects of HIV-1 on chemokine-receptor turnover. In this review, the mechanisms of modulation of CXCR4 and CCR5 expression after HIV-1 infection will be discussed.
[Back to top] Role of CD4 Receptor Down-regulation During HIV-1
Infection
Karine Levesque, Andres Finzi, Julie Binette and Eric A. Cohen
Human immunodeficiency virus has evolved several redundant mechanisms to remove its receptor, the CD4 molecule, from the cell surface. Indeed, HIV-1 encodes three proteins, Nef, Vpu and Env, that have a profound effect on CD4 trafficking and catabolism. Given this functional convergence, it is believed that cell surface CD4 regulation constitutes an important determinant of viral replication and pathogenesis in vivo. This review highlights recent progress made in our understanding of the molecular mechanisms underlying the down-regulation of the CD4 receptor by HIV-1 and describes our current comprehension of the role of CD4 down-regulation during HIV-1 infection.
[Back to top] Advances
in Neuroimaging for HIV-1 Associated Neurological Dysfunction: Clues to the
Diagnosis, Pathogenesis and Therapeutic Monitoring
Michael D. Boska, R. Lee Mosley, Mehmood Nawab, Jay A.
Nelson, Marina Zelivyanskaya, Larisa Poluektova, Mariano Uberti, Huanyu
Dou Travis B. Lewis and Howard E. Gendelman
Persons with advanced human immunodeficiency virus type one (HIV-1) infection seek medical advice for a wide range of neurological disorders including, but not limited to, peripheral neuropathy, toxoplasmosis, cryptococcal meningitis, cytomegalovirus retinitis progressive multifocal leukoencephalopathy, lymphoma and dementia. The diagnosis of HIV-1-associated dementia (HAD) induced as a direct consequence of HIV infection of the brain comes commonly by exclusion. Diagnostic decisions can often be clouded by concomitant depression, motor impairments, and lethargy that follow debilitating immune suppression and weight loss. Indeed, cognitive, motor and behavior abnormalities underlie a variety of neurological dysfunctions associated with advanced HIV-1 infection. Thus, even combinations of clinical, laboratory and neuroimaging tests [for example, magnetic resonance imaging (MRI), computed tomography (CT), single photon emission computed tomography (SPECT) and positron emission tomography (PET)] often fail to provide conclusive diagnostic information. Nonetheless, the recent development of quantitative MR spectroscopic imaging has improved diagnostic possibilities for HAD. We are pleased to discuss these developments as well as taking a forward look into what will soon be made available to improve neuroimaging diagnostic precision. New MR and SPECT testing are being developed in our laboratories and elsewhere both for animal model systems and in humans with HIV-1 disease. Such tests can facilitate dynamic measures of HIV-1 neuropathogenesis providing information for disease events that even 2 years ago were unattainable.
[Back to top] The Chaperoning and
Assistance Roles of the HIV-1 Nucleocapsid Protein in Proviral DNA Synthesis
and Maintenance
Carole Bampi, Sandrine Jacquenet, Daniela Lener, Didier Decimo and Jean-Luc Darlix
In the following three sections we will briefly review the seminal roles of the HIV-1 nucleocapsid protein NCp7 in the fate of the HIV-1 full length RNA from genomic RNA in a dimeric form to the proviral DNA. Emphasis will be given to the mechanisms of NC-directed assistance to the genomic RNA and reverse transcriptase in the course of proviral DNA synthesis and to DNA integrity at the end of the polymerization process, and to the NC-assisted repair and recombination reactions fueling the viability and variability of the virus.