Contents
Can
HIV be Cured? Mechanisms of HIV Persistence and Strategies to Combat It Pp.
99-111
Dean H. Hamer
Enigmas
and Paradoxes: the Genetic Diversity and Prevalence of the Primate Lentiviruses
Pp. 113-125
Jonathan P. Clewley
Humoral
Immunity in HIV-1 Exposure: Cause or Effect of HIV Resistance? Pp. 127-139
Lucia Lopalco
HIV/SIV
Escape from Immune Surveillance: Focus on Nef Pp. 141-151
Martin Tolstrup, Lars
Ostergaard, Alex L. Laursen, Skou Finn Pedersen and Mogens Duch
HIV-Specific
CD8+ T Cells: Serial Killers Condemned To Die? Pp. 153-162
Constantinos Petrovas, Yvonne
M. Mueller and Peter D. Katsikis
The
Selective Packaging and Annealing of Primer tRNALys3 in HIV-1 Pp. 163-175
Lawrence Kleiman, Rabih
Halwani and Hassan Javanbakht
The
Thymus During HIV Disease: Role in Pathogenesis and in Immune Recovery Pp.
177-183
Ping Ye, Denise E. Kirschner
and Athena P. Kourtis
Anti-HIV-1
Gene Expressing Lentiviral Vectors as an Adjunctive Therapy for HIV-1 Infection
Pp. 185-191
Kevin V. Morris and John J.
Rossi
Progress
Towards the Development of a HIV-1 gp41-Directed Vaccine Pp. 193-204
Georgia B. McGaughey, Gaetano
Barbato, Elisabetta Bianchi, Roger M. Freidinger, Victor M. Garsky, William M.
Hurni, Joseph G. Joyce, Xiaoping Liang, Michael D. Miller, Antonello Pessi,
John W. Shiver and Michael J. Bogusky
Abstracts
[Back to top] Can HIV be
Cured? Mechanisms of HIV Persistence and Strategies to Combat It
Dean H. Hamer
Stable remission is the ultimate goal of HIV therapy. A review of recent studies on the ability of HIV to persist despite highly active antiretroviral therapy (HAART) and immune stimulation suggests that achieving this goal will require four developments in basic and clinical science. First, more effective antiretroviral therapies, targeted at proteins other than reverse transcriptase and protease, in order to eliminate the cryptic replication that continues despite best available HAART. Second, agents that activate latent HIV gene expression in quiescent CD4 memory T cells, thereby exposing this viral reservoir to therapeutic intervention by a “shock and kill” strategy. Third, molecules such as immunotoxins that specifically recognize HIV-encoded membrane proteins and thereby potentiate the destruction of infected cells. Fourth, and still most distant, novel approaches such as genetically engineered cytotoxic T lymphocytes or anti-HIV microbes to suppress rekindling of infection by residual virus sequestered in anatomical and cellular reservoirs. Although each of these steps will be difficult to achieve, the many benefits of a cure for HIV make this a worthwhile pursuit.
[Back to top] Enigmas and
Paradoxes: the Genetic Diversity and Prevalence of the Primate Lentiviruses
Jonathan P. Clewley
In a comparatively few years a previously unknown virus has spread from its animal host to infect more than 40 million people by the end of 2003, causing an estimated 3 million deaths in that year (World Health Organization figures). The size of this human immunodeficiency virus (HIV) epidemic and its associated health, social and economic problems make it imperative that we understand how its two types, HIV-1 and HIV-2, have evolved from their simian relatives, the primate lentiviruses (PLVs). There are several features of the PLVs that may be considered enigmatic or even paradoxical, and which are relevant to studies of their evolution. These reflect the difference in the natural history of PLV-infected apes and humans compared with PLV-infected monkey species, and the apparent host-dependent evolution of some PLV sequences in spite of the relative ease of transmission between primate species.
[Back to top] Humoral
Immunity in HIV-1 Exposure: Cause or Effect of HIV Resistance?
Lucia Lopalco
More than two decades since its discovery, human immunodeficiency virus (HIV) epidemic is still a major burden for health, social and economical reasons on all over the world. Despite the huge effort in basic and applied research, aimed to control virus spread and to design effective therapeutic strategies, an HIV vaccine is not available yet and current therapeutics approaches cannot prevent the infection.
To date, both host genetic repertoire, innate and acquired immune responses, viral mutation or attenuation have been invoked to explain the higher or lower individual susceptibility to the infection. The existence of some people somewhat “immune” from infection, despite dealing with repeated HIV exposure, as well as the extremely slow disease progression in some HIV infected individuals, offers valuable clues to elucidate mechanisms underlying natural HIV resistance.
Strikingly, both such cohorts, the so-called Exposed Seronegative (ESN, EU, HEPS) and the Slow Progressor (SP, LTNP, LTS) individuals have common immune responses, e.g. the generation of neutralising antibodies directed against common targets, which can play a protective role in virus entry and/or spread.
This review focuses on naturally occurring humoral responses to HIV exposure/infection. Moreover, whether such antibodies are induced in response to a peculiar scenario of HIV infection or are generated in the context of an individual innate mode to clear virus infection is a puzzling question, which will be addressed here.
The comprehension of mechanisms of natural resistance to HIV infection may have implications for the identification of anti-viral novel strategies and in particular for the development of innovative diagnostics, therapeutics and vaccine design.
[Back
to top] HIV/SIV Escape from Immune Surveillance:
Focus on Nef
Martin Tolstrup, Lars Ostergaard, Alex L. Laursen, Skou
Finn Pedersen and Mogens Duch
During a progressive HIV-1 infection, the gradual decrease in functional CD4+ Thelper cells leads to immunodeficiency and eventually death in the untreated patient. The virulence role of the lentiviral accessory gene nef was first reported from deletion studies in the macaque model, and research during the past decade has revealed a pluripotent protein capable of multiple points of interference with cellular mechanisms. Importantly, Nef has the capacity to modify the plasma membrane signalling by regulation of receptor/ligand endocytosis as well as to modulate cellular regulation such as apoptosis and lymphocyte activation. This effective defence against an apparent vigorous and specific immune response is crucial for the ability of HIV-1 to persist in the host. Here we review the multitude of functions exerted by Nef and discuss the functional domains of the protein in terms of cellular interaction partners and the effect of nef mutations in the course of AIDS disease progression.
[Back to top] HIV-Specific CD8+ T Cells: Serial Killers Condemned To
Die?
Constantinos Petrovas, Yvonne M. Mueller and Peter D.
Katsikis
An increasing body of evidence supports a key role for cytotoxic CD8+ T cells (CTL) in controlling HIV infection. Although a vigorous HIV-specific CD8+ T cell response is raised during the primary infection, these cells ultimately fail to control virus and prevent disease progression. The failure of CTL to control HIV infection has been attributed to a number of strategies HIV employs to evade the immune system. Recently, intrinsic defects in the CTL themselves have been proposed to contribute to the failure of CTL to control HIV. HIV-specific CD8+ T cells differ in their effector/memory phenotype from other virus-specific CD8+ T cells indicating that their differentiation status differs. This altered differentiation may affect effector functions as well as homing properties of these cells. Other studies have indicated that activation of HIV-specific CTL may be impaired and this contributes to their dysfunction. The effector function of these CTL may also be affected. There are conflicting reports about their ability to kill, whereas IFNg production does not appear to be impaired in these cells. In this review we focus on recent work indicating that apoptosis may be an important mechanism through which HIV evades the CTL response. In particular, HIV-specific CD8+ T cells are highly susceptible to CD95/Fas-induced apoptosis. This leads to the hypothesis that virus-specific cytotoxic T cells can be eliminated upon binding CD95L/FasL on HIV-infected cells. Understanding the intrinsic defects of CTL in HIV infection could lead to new therapeutic strategies and optimized vaccination protocols that enhance the HIV-specific cytotoxic response.
[Back to top] The
Selective Packaging and Annealing of Primer tRNALys3 in HIV-1
Lawrence
Kleiman, Rabih Halwani and Hassan Javanbakht
In HIV-1, tRNALys3 serves as the primer for reverse transcriptase, and during viral assembly, the tRNALys isoacceptors, tRNALys1,2 and tRNALys3, are selectively packaged into the virion. In this review, we shall first discuss the evidence for the formation of a tRNALys packaging complex, whose components include Gag, GagPol, genomic RNA, lysyl-tRNA synthetase (LysRS), and tRNALys. Evidence suggests that the formation of this complex involves a Gag/GagPol/viral genomic RNA complex interacting with a tRNALys/ LysRS complex, with Gag interacting with both GagPol and LysRS, and GagPol interacting with the tRNALys. The interaction of Gag with LysRS is quite specific, does not require the presence of tRNALys, and LysRS is believed to be the target that allows the specific packaging of tRNALys into the virion. The parameters influencing these interactions, and the molecular sites of interaction, will be discussed. The selective packaging of tRNALys3 into HIV-1 facilitates annealing of tRNALys3 to the 5´ region of viral RNA genome. This region contains a series of stem loops, and there exists several regions in both the viral RNA and the tRNALys3 that are believed to be important for tRNALys3 annealing. The annealing is facilitated by viral proteins such as unprocessed Gag, nucleocapsid, and reverse transcriptase.
[Back to top] The Thymus During HIV
Disease: Role in Pathogenesis and in Immune Recovery
Ping
Ye, Denise E. Kirschner and Athena P. Kourtis
The thymus is the primary lymphoid organ supplying new lymphocytes to the periphery. Clinical and morphologic studies of HIV-infected children and adults indicate that the thymus is affected by HIV. Thymic dysfunction and thymic involution occur during HIV disease and have been associated with rapid progression in infants infected perinatally with HIV. In vitro information of thymic organ culture, thymic epithelial cell culture, the SCID-hu mouse system and SHIV infection of primates have supported HIV-induced thymic damage. The mechanisms underlying this could be many, including direct thymocyte killing by the virus, apoptosis, or disruption of thymic stromal architecture. T cell receptor excision circles (TREC) have been developed as a marker of new thymic emigrants. Decreases in TREC concentrations have been found in both HIV-infected pediatric and adult patients. Mathematical models have suggested that thymic infection in children is more severe than in adults, particularly during infection with strains that use CXCR4 as coreceptor. Recent evidence suggests that thymic recovery may be achieved in some patients as a result of potent antiretroviral therapy. Extensive thymic damage may, however, hamper immune reconstitution, particularly in pediatric patients. This review attempts to summarize evidence for thymic involvement during HIV infection in children and in adults, the role of thymic infection in disease progression, and the contribution of the thymus to immune restoration following potent antiviral therapy. Immunologic interventions aiming at restoring thymic function in AIDS patients are also reviewed.
[Back to top] Anti-HIV-1 Gene Expressing Lentiviral
Vectors as an Adjunctive Therapy for HIV-1 Infection
Kevin V. Morris and John J. Rossi
Lentiviral based gene therapy may provide a valuable addition to the current anti-HIV arsenal. Many lentiviral vector systems have been described including those based on feline immunodeficiency virus (FIV), human immunodeficiency virus 1 (HIV) and 2 (HIV-2/SIV) as well as replication incompetent, self-inactivating (sin) vs. conditionally replicating (mobilizable) vectors. Lentiviral vectors offer promise in treating HIV-1 infection as they are capable of stably transducing both dividing and nondividing cells, specifically those cells involved in HIV-1 replication and immune restoration: T-cells, hematopoietic stem cells, and dendritic cells. Moreover, some of the HIV-1 and 2 based vectors can be mobilized by wildtype HIV-1 in vivo and spread to those cells targeted by the virus as well as can compete with viral RNA for packaging and access to viral proteins such as Tat and Rev required for viral replication. Finally, lentiviral vectors can be designed to express therapeutic anti-HIV-1 genes, which specifically target various stages of viral replication. Many candidate RNA based anti-HIV-1 genes have been expressed from lentiviral vectors including ribozymes and anti-sense RNA [1]. Recently, small interfering RNAs (siRNAs) have been shown to potently suppress HIV replication [2-6]. This review will focus on the current status of lentiviral vector development and the feasibility of using lentiviral vectors in delivering anti-HIV genes, specifically ribozymes, and siRNAs as a therapeutic approach to employ in conjunction with current anti-retroviral therapies.
[Back to top] Progress Towards the Development of a HIV-1
gp41-Directed Vaccine
Georgia B. McGaughey, Gaetano Barbato, Elisabetta
Bianchi, Roger M. Freidinger, Victor M. Garsky, William M. Hurni, Joseph G.
Joyce, Xiaoping Liang, Michael D. Miller, Antonello Pessi, John W. Shiver and
Michael J. Bogusky
The HIV-1 gp41 envelope glycoprotein mediates fusion of the viral and cellular membranes. The core of the gp41 ectodomain undergoes a receptor-triggered conformational transition forming a trimeric, a-helical coiled-coil structure. This trimer-of-hairpins species facilitates insertion of the viral envelope protein into the host cell membrane promoting viral entry. The prefusogenic conformation of gp41 is capable of stimulating a neutralizing antibody immune response and is therefore an attractive therapeutic target. Several broadly neutralizing HIV-1 monoclonal antibodies which bind to gp41 have been characterized and include 4E10, Z13 and 2F5. A conserved segment of gp41 (residues 661-684) has been identified as the epitope for the HIV-1 neutralizing antibody 2F5 (MAb 2F5). MAb 2F5 has attracted considerable attention because of the highly conserved recognition epitope and the ability to neutralize both laboratory-adapted and primary viral isolates. Antibodies which recognize the immunodominant regions of gp41 may provide protection against HIV infection if elicited at appropriate concentrations. Here we review the rational design, structure-activity relationships and conformational features of both linear and constrained peptide immunogens incorporating variants of both the 2F5 epitope and the gp41 ectodomain. This review describes a rational design approach combining structural characterization with traditional SAR to optimize MAb 2F5 antibody affinities of gp41-based peptide immunogens. The immunogens are shown to stimulate a high titer, peptide-specific immune response; however, the resulting antisera were incapable of viral neutralization. The implication of these findings with regard to structural and immunological considerations is discussed.