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OPEN ACCESS PLUS
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Contents
10(5): Pp. 435 - 452
Kurt F. Hauser, Sylvia Fitting, Seth M. Dever, Elizabeth M. Podhaizer and Pamela E. Knapp
[Open Access Plus] |
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Opiate abuse and HIV-1 have been described as interrelated epidemics, and even in the advent of combined anti-retroviral therapy, the additional abuse of opiates appears to result in greater neurologic and cognitive deficits. The central nervous system (CNS) is particularly vulnerable to interactive opiate-HIV-1 effects, in part because of the unique responses of microglia and astroglia. Although neurons are principally responsible for behavior and cognition, HIV-1 infection and replication in the brain is largely limited to microglia, while astroglia and perhaps glial progenitors can be latently infected. Thus, neuronal dysfunction and injury result from cellular and viral toxins originating from HIV-1 infected/exposed glia. Importantly, subsets of glial cells including oligodendrocytes, as well as neurons, express µ-opioid receptors and therefore can be direct targets for heroin and morphine (the major metabolite of heroin in the CNS), which preferentially activate µ-opioid receptors. This review highlights findings that neuroAIDS is a glially driven disease, and that opiate abuse may act at multiple glial-cell types to further compromise neuron function and survival. The ongoing, reactive cross-talk between opiate drug and HIV-1 co-exposed microglia and astroglia appears to exacerbate critical proinflammatory and excitotoxic events leading to neuron dysfunction, injury, and potentially death. Opiates enhance synaptodendritic damage and a loss of synaptic connectivity, which is viewed as the substrate of cognitive deficits. We especially emphasize that opioid signaling and interactions with HIV-1 are contextual, differing among cell types, and even within subsets of the same cell type. For example, astroglia even within a single brain region are heterogeneous in their expression of µ-, δ-, and κ-opioid receptors, as well as CXCR4 and CCR5, and Toll-like receptors. Thus, defining the distinct targets engaged by opiates in each cell type, and among brain regions, is critical to an understanding of how opiate abuse exacerbates neuroAIDS.
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10(4): Pp. 327 - 333
Johan K. Sandberg, Sofia K. Andersson, Susanna M. Bachle, Douglas F. Nixon and Markus Moll
[Open Access Plus] |
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The HIV-1 accessory protein Vpu is emerging as a viral factor with a range of activities devoted to counteracting host innate immunity. Here, we review recent findings concerning the role of Vpu in hampering activation of cellular immune responses mediated by CD1d-restricted invariant natural killer T (iNKT) cells and natural killer (NK) cells. The two key findings are that Vpu interferes with CD1d expression and antigen presentation, and also with expression of the NK cell activation ligand NK-T and B cell antigen (NTB-A). Both these activities are mechanistically distinct from CD4 and Tetherin (BST-2) down-modulation. We summarize the mechanistic insights gained into Vpu interference with CD1d and NTB-A, as well as important challenges going forward, and discuss these mechanisms in the context of the role that iNKT and NK cells play in HIV-1 immunity and immunopathogenesis
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10(4): Pp. 283 - 291
Juan F. Arias, Yukie Iwabu and Kenzo Tokunaga
[Open Access Plus] |
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The interferon-inducible host restriction factor bone marrow stromal antigen 2 (BST-2/tetherin) blocks the release of human immunodeficiency virus type 1 (HIV-1) by directly cross-linking virions to the membrane of infected cells. This antiviral effect is counteracted by the HIV-1 accessory protein viral protein U (Vpu) through mechanisms that remain unclear. Accumulating evidence suggests that Vpu antagonizes BST-2 by removing it from the plasma membrane; however, neither the cellular sites of interaction nor the effector mechanisms that result in the downregulation of BST-2 cell-surface expression have been fully determined. Based on current evidence regarding the subcellular localization of Vpu and BST-2 and the latter's trafficking defects induced by their interaction, three models have been proposed. In the first, Vpu is hypothesized to block the traffic of newly synthesized BST-2 towards the cell surface by retaining it in the biosynthetic/secretory compartment. The second model suggests that Vpu sequesters BST-2 within intracellular compartments corresponding to recycling endosomes and the trans-Golgi network by blocking its recycling after endocytosis. In the third model, we and others have proposed that Vpu directly internalizes BST-2 from the plasma membrane and induces its enhanced endolysosomal trafficking and degradation. As for its intracellular fate, the viral antagonism of BST-2 is likely dependent on the intracellular sequestration, or the proteasomal/lysosomal degradation of the restriction factor. This review summarizes the current advances in our understanding of the cellular pathways and sites of action of Vpu in the downregulation of cell-surface BST-2.
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9(8): Pp. 554 - 567
Jonathan Karn and Uri Mbonye
[Open Access Plus] |
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Intensive antiretroviral therapy successfully suppresses viral replication but is unable to eradicate the virus. HIV persists in a small number of resting memory T cells where HIV has been transcriptionally silenced. This review will focus on recent insights into the HIV transcriptional control mechanisms that provide the biochemical basis for understanding latency. There are no specific repressors of HIV transcription encoded by the virus, instead latency arises when the regulatory feedback mechanism driven by HIV Tat expression is disrupted. Small changes in transcriptional initiation, induced by epigenetic silencing, lead to profound restrictions in Tat levels and force the entry of proviruses into latency. In resting memory T cells, which carry the bulk of the latent viral pool, additional restrictions, especially the limiting cellular levels of the essential Tat cofactor P-TEFb and the transcription initiation factors NF-κB and NFAT ensure that the provirus remains silenced unless the host cell is activated. The detailed understanding of HIV transcription is providing a framework for devising new therapeutic strategies designed to purge the latent viral pool. Importantly, the recognition that there are multiple restrictions imposed on latent proviruses suggest that proviral reactivation will not be achieved when only a single reactivation step is targeted and that any optimal activation strategy will require both removal of epigenetic blocks and the activation of P-TEFb.
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9(7): Pp. 496 - 504
Alessia Landi, Veronica Iannucci, Anouk Van Nuffel, Pieter Meuwissen and Bruno Verhasselt
[Open Access Plus] |
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The HIV-1, HIV-2 and SIV Nef protein are known to modulate the expression of several cell surface receptors and molecules to escape the immune system, to alter T cell activation, to enhance viral replication, infectivity and transmission and overall to ensure the optimal environment for infection outcome. Consistent and continuous efforts have been made over the years to characterize the modulation of expression of each of these molecules, in the hope that a better understanding of these processes essential for HIV infection and/or pathogenesis will eventually highlight new therapeutic targets. In this article we provide an extensive review of the knowledge gained so far on this important and evolving topic.
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9(7): Pp. 474 - 489
Jolien Vermeire, Griet Vanbillemont, Wojciech Witkowski and Bruno Verhasselt
[Open Access Plus] |
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The Nef protein is an essential factor for lentiviral pathogenesis in humans and other simians. Despite a multitude of functions attributed to this protein, the exact role of Nef in disease progression remains unclear. One of its most intriguing functions is the ability of Nef to enhance the infectivity of viral particles. In this review we will discuss current insights in the mechanism of this well-known, yet poorly understood Nef effect. We will elaborate on effects of Nef, on both virion biogenesis and the early stage of the cellular infection, that might be involved in infectivity enhancement. In addition, we provide an overview of different HIV-1 Nef domains important for optimal infectivity and briefly discuss some possible sources of the frequent discrepancies in the field. Hereby we aim to contribute to a better understanding of this highly conserved and therapeutically attractive Nef function.
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9(4): Pp. 237 - 246
Jens J. Kort, Stella Aslanyan, Joseph Scherer, John P. Sabo, Veronika Kohlbrenner and Patrick Robinson
[Open Access Plus] |
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The use of HIV protease inhibitors (PIs) as part of antiretroviral therapy in the treatment of HIV-1 infection may be associated with an increased risk of bleeding. This prospective, randomized, open-label trial in healthy volunteers compared the effects of tipranavir/ritonavir (TPV/r), darunavir/ritonavir (DRV/r), and ritonavir (RTV) alone on platelet aggregation after a single dose and at steady-state concentrations. Subjects were selected on the basis of normal platelet aggregation and arachidonic acid (AA)-induced platelet aggregation inhibition after administration of a single 325-mg dose of aspirin. All 3 PI therapies were administered twice daily for 10 days. In some but not all subjects, TPV/r inhibited AA-induced platelet aggregation and prolonged PFA-100® closure time with collagen-epinephrine cartridge, which was of lesser magnitude and consistency compared with aspirin, but greater when compared to DRV/r and RTV. At least 2 subjects in each treatment arm showed complete inhibition of AA-induced platelet aggregation on treatment, and the magnitude of change in all platelet-function tests did not correlate with PI plasma concentrations. Effects of TPV/r on platelet aggregation were reversed 24 hours after the last TPV/r dose. None of the PI treatments tested were associated with increases in bleeding time, decreases in plasma coagulation factors, or increase in fibrinolysis. There was large inter-patient variability in antiplatelet effect for all PI treatments, ranging from no effect to complete inhibition of AA-induced platelet aggregation.
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9(4): Pp. 209 - 222
Marc C.E. Wagner
[Open Access Plus] |
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Extracellular adenosine triphosphate (eATP) is a potent molecule that has the capacity to modulate various aspects of cell functions including gene expression. This element of modulation is essential to the role of ATP as a therapeutic agent. The hypothesis presented is that ATP can have an important impact on the treatment of HIV infection. This is supported in part by published research, although a much greater role for ATP is suggested than prior authors ever thought possible. ATP has the ability to enhance the immune system and could thus improve the hosts own defense mechanisms to eradicate the virus-infected cells and restore normal immune function. This could provide effective therapy when used in conjunction with highly active antiretroviral therapies (HAART) to eliminate the latently infected cells. The key lies in applying ATP through the methodology described. This article presents a strategy for using ATP therapeutically along with background evidence to substantiate the importance of using ATP in the treatment of HIV infection.
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8(8): Pp. 638 - 640
Susanna L. Lamers, Gary B. Fogel, Leanne C. Huysentruyt and Michael S. McGrath
[Open Access Plus] |
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This letter refers to the recent demonstration that HIV-1 infected macrophages form specialized conduits that connect to B-cells (1). The conduit selectively transports the HIV-1 nef protein, providing nef with numerous means to interfere with cellular processes. Currently, no consideration of the connection between the conduit and the development of AIDS-related lymphoma (ARL) has been offered. ARL is one of the primary causes of death in the HIV-infected population and is related to B-cell proliferation and activation. In this letter we discuss several studies that link HIVinfected macrophages and specific forms of the nef protein to the development of ARL. The conduits discovered by Xu et al. [1] may lead to a better understanding of how HIV infection results in lymphomagenesis.
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8(4): Pp. 282 - 298
Rosamund Chapman, Gerald Chege, Enid Shephard, Helen Stutz and Anna-Lise Williamson
[Open Access Plus] |
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HIV-1 has resulted in a devastating AIDS pandemic. An effective HIV/AIDS vaccine that can be used to either, prevent HIV infection, control infection or prevent progression of the disease to AIDS is needed. In this review we discuss the use of Mycobacterium bovis BCG, the tuberculosis vaccine, as a vaccine vector for an HIV vaccine. Numerous features make BCG an attractive vehicle to deliver HIV antigens. It has a good safety profile, elicits long-lasting cellular immune responses and in addition manufacturing costs are affordable, a necessary consideration for developing countries. In this review we discuss the numerous factors that influence generation of a genetically stable recombinant BCG vaccine for HIV.
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7(5): Pp. 497 - 503
Robert Sealy, Xiaoyan Zhan, Timothy D. Lockey, Louis Martin, James Blanchard, Vicki Traina-Dorge and Julia L. Hurwitz
[Open Access Plus] |
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A current debate in the HIV-1 vaccine field concerns the ability of an immunodeficiency virus to elicit a protective response. One argument is that HIV-1 superinfections are frequent in healthy individuals, because virus evades conventional immune surveillance, a serious obstacle to vaccine design. The opposing argument is that protection from superinfection is significant, reflecting a robust immune response that might be harnessed by vaccination to prevent disease. In an experiment designed to address the debate, two macaques received an I.V. inoculation with SHIV KU-1-d (a derivative of SHIV KU-1) and were rested for > 10 months. Infection elicited diverse neutralizing antibody activities in both animals. Animals were then exposed to SHIV 89.6P (I.V.), a virus carrying a heterologous envelope protein relative to the vaccine strain. Infection was monitored by viral load and CD4+ T-cell measurements. All control animals were infected and most succumbed to disease. In contrast, protection from superinfection was statistically significant in test monkeys; one animal showed no evidence of superinfection at any time point and the second showed evidence of virus at only one time point over a 6-month observation period. Neither animal showed signs of disease. Perhaps this protective state may serve as a ‘gold-standard’ for HIV-1 vaccine development, as a similar degree of protection against immunodeficiency virus infections in humans would be much desired.
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5(2): Pp. 155 - 187
Daniele Dionisio, Robert Gass, Peter McDermott, Vincenzo Racalbuto, Marina Madeo, Giuseppe Braghieri, Siobhan Crowley, Eloan Dos Santos Pinheiro, Peter Graaff, Ashwin Vasan, Achara Eksaengsri, Helene Moller, Arun Kumar Khanna, Krisana Kraisintu, Sandeep Juneja, Stavros Nicolaou, Aloka Sengupta, Francesco Esperti and Daniela Messeri
[Open Access Plus] |
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Background: No more than 8% of HIV positive children needing treatment in low- and middle-income countries have access to antiretroviral drugs (ARVs). Children presently account for about 4% of all treated patients, while for equitable access they should make up at least 13%. Aims: This study explores key issues, implications and interaction dynamics to boost production of easy-to-use and affordable fixed-dose combination (FDC) ARVs for children in the developing world. Potentials for equitable solutions are examined including priority steps and actions, appropriate treatment options and reliable forecasting methods for paediatric ARVs, as well as combination incentives to generic companies against market unattractiveness and enforced intellectual property (IP) rights. Moreover, implementation strategies to enhance the development and production of affordable ARV paediatric formulations and appropriate supply systems to ensure availability are investigated. Results: The current market for FDC paediatric ARVs is already substantial and will only grow with improved and scaled up diagnosis and monitoring of children. This provides an argument for immediate increase of production and development of FDC ARVs for children. These formulations must be low cost and included in the list of Essential Medicines to avoid children continuing to lag behind in access to treatment. Access-oriented, long-term drug policy strategies with the ability to pass muster of governments, the UN system, as well as generic and research-based enterprises are needed to let children gain expanded and sustained access to FDC ARVs. Under the requirements listed above, IP-bound Voluntary License (VL) flexibilities do appear, if coupled with substantial combination incentives to generic firms, as a fitting tool into the needs. Policies must consider enhancing human resource capacity in the area of caregivers and social and health workers aiming to spread correct information and awareness on effectiveness and rationale of FDC ARVs for children. Policies should urge that paediatric ARV treatment programmes entwine with extant interventions on prevention of mother-to-child transmission, as well as with HIV treatment initiatives focused on mothers and household members. Policies, again, should consider centralising functions and pooling resources to help overcome drug supply barriers. WHOs brokering role in VL-based agreements between wealthy and developing country industries, as well as its technical guidance in setting international standards should not be waived while looking for sustained access to optimised ARV treatments for children. Strategies discussed in this paper, while taking unavoidability of marketing and profit rules into account, look closely into the trade and drug policy directions of China and India according to frontier crossing implications of their IP management trends as well as their multi-faceted penetration strategies of both the wealthy and under-served markets the world over.
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5(2): Pp. 139 - 153
Kirsty Little, Claire Thorne, Chewe Luo, Madeleine Bunders, Ngashi Ngongo, Peter McDermott and Marie-Louise Newell
[Open Access Plus] |
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Approximately 700,000 children become newly infected with HIV annually, mainly through mother-to-child transmission (MTCT), making paediatric HIV a leading cause of morbidity and mortality worldwide. The substantial interest in preventing MTCT (PMTCT) has generated information on rates of transmission and associated factors, but there is a lack of information on disease progression and mortality in vertically-infected children, especially from resource-poor settings. Peer-review journals with titles or abstracts containing reference to the reviews themes were selected using widely available search engines. We review relevant literature on mortality in children born to HIV infected mothers; morbidity and mortality associated with paediatric HIV infections; eligibility to and efficacy of antiretroviral therapy (ART). Child mortality is independently associated with maternal HIV status and maternal death, with paediatric infection resulting in ∼4 fold increase in mortality by age 2 years. Morbidities seen in infected children were similar to those seen in uninfected children, although the rates and recurrences of illness were greater. There is some evidence that progression to AIDS may be more rapid in resource poor settings, although data on this are very limited. PMTCT and paediatric ART have been shown to be highly successful in resource-limited settings, but are not universally applied. Further efforts to increase coverage of both PMTCT and paediatric ART could substantially reduce the numbers of children becoming infected and improve survival of those infected. Additionally, improvements in health infrastructures could improve care provision, not only through improved detection and monitoring but also through treatment of co-morbidities and nutritional support
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4(2): Pp. 131 - 139
Alper Yilmaz, Cheryl Bolinger and Kathleen Boris-Lawrie
[Open Access Plus] |
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Human immunodeficiency virus type 1 (HIV-1) has a small, multifunctional genome that encodes a relatively large and complex proteome. The virus has adopted specialized post-transcriptional control mechanisms to maximize its coding capacity while economically maintaining the information stored in cis-acting replication sequences. The conserved features of the 5 untranslated region of all viral transcripts suggest they are poor substrates for cap-dependent ribosome scanning and provide a compelling rationale for internal initiation of translation. This article summarizes key experimental results of studies that have evaluated HIV-1 translation initiation. A model is discussed in which capdependent and cap-independent initiation mechanisms of HIV-1 co-exist to ensure viral protein production in the context of 1) structured replication motifs that inhibit ribosome scanning, and 2) alterations in host translation machinery in response to HIV-1 infection or other cellular stresses. We discuss key issues that remain to be understood and suggest parameters to validate internal initiation activity in HIV-1 and other retroviruses.
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