St Vincents Center for Applied Medical Research

Sydney, Australia

St Vincents Center for Applied Medical Research

Sydney, Australia
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Brew B.J.,University of New South Wales | Brew B.J.,St Vincents Hospital Sydney | Brew B.J.,St Vincents Center For Applied Medical Research | Chan P.,Queen Elizabeth Hospital
Current Neurology and Neuroscience Reports | Year: 2014

The introduction of combined antiretroviral therapy (cART) has dramatically reduced the risk of central nervous system opportunistic infection and severe dementia secondary to HIV infection in the last two decades. However, a milder form of HIV-associated neurocognitive disorder (HAND) remains prevalent in the cART era and has a significant impact on patients' quality of life. In this review, we outline updated research findings on investigating and monitoring cognitive impairment in HAND patients. The outcomes of recent research on the pathogenesis of HAND and how it overlaps with neurodegenerative diseases are discussed. Lastly, there is a brief discussion of the results of clinical trials using a brain-penetrating cART regimen. © 2014 Springer Science+Business Media.

Chen Y.,University of New South Wales | Brew B.J.,St Vincents Center for Applied Medical Research | Brew B.J.,St Vincents Hospital | Guillemin G.J.,University of New South Wales | Guillemin G.J.,St Vincents Center for Applied Medical Research
Journal of Neurochemistry | Year: 2011

Amyotrophic lateral sclerosis (ALS) is the most common type of motor neuron degenerative disease for which the aetiology is still unknown. The kynurenine pathway (KP) is a major degradative pathway of tryptophan ultimately leading to the production of NAD+ and is also one of the major regulatory mechanisms of the immune response. The KP is known to be involved in several neuroinflammatory disorders. Among the KP intermediates, quinolinic acid (QUIN) is a potent excitotoxin, while kynurenic acid and picolinic acid are both neuroprotectant. This study aimed to (i) characterize the components of the KP in NSC-34 cells (a rodent motor neuron cell line) and (ii) assess the effects of QUIN on the same cells. RT-PCR and immunocytochemistry were used to characterize the KP enzymes, and lactate dehydrogenase (LDH) test was used to assess the effect of QUIN in the absence and presence of NMDA receptor antagonists, kynurenines and 1-methyl tryptophan. Our data demonstrate that a functional KP is present in NSC-34 cells. LDH tests showed that (i) QUIN toxicity on NSC-34 cells increases with time and concentration; (ii) NMDA antagonists, 2-amino-5-phosphonopentanoic acid, MK-801 and memantine, can partially decrease QUIN toxicity; (iii) kynurenic acid can decrease LDH release in a linear manner, whereas picolinic acid does the same but non-linearly; and (iv) 1-methyl tryptophan is effective in decreasing QUIN release by the rodent microglial cell line BV-2 and thus protects NSC-34 from cell death. There is currently a lack of effective treatment for ALS and our in vitro results provide a novel therapeutic strategy for ALS patients. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

Munier C.M.L.,St Vincents Center for Applied Medical Research | Munier C.M.L.,University of New South Wales | Andersen C.R.,St Vincents Hospital | Kelleher A.D.,St Vincents Center for Applied Medical Research | Kelleher A.D.,University of New South Wales
Drugs | Year: 2011

The quest for an effective and safe HIV-1 vaccine has been and still is the aspiration of many scientists and clinicians worldwide. Until recently, the hopes for an effective vaccine were thwarted by the disappointing results and early termination in September 2007 of the STEP study, which saw a subgroup of male vaccine recipients at an increased risk of HIV-1 infection, and the failure of earlier trials of vaccines based on recombinant envelope proteins to provide any level of protection. The results of the STEP study raised important questions in the field of HIV vaccines, including the use of recombinant adenovirus vectors as immunogens, the rationale for the development of T-cell-based vaccines and the development pathway for these vaccines, in terms of assessment of immunogenicity and the challenge models used. The study of neutralizing antibodies has demonstrated that the induction of high-titre, broadly neutralizing antibodies in the majority of recipients is likely to be highly problematic. However, the results of the RV144 Thai trial released in September 2009 have brought new optimism to the field. This study employed envelope-based immunogens delivered as a priming vaccination with a recombinant poxvirus vector and boosting with recombinant proteins. This regimen provided modest protection to HIV-1 infection in a low-risk population. Although the correlates of protection are currently unknown, extensive studies are underway to try to determine these. Neutralizing antibodies were not induced in the RV144 study; however, considerable titres of binding antibodies to HIV-1 viral envelope (Env) were. It is speculated that these antibodies may have provided a means of protection by a mechanism such as antibody-dependent cell-mediated cytotoxicity. In addition, no CD8 T-cell responses were induced, but robust CD4 T-cell responses were, and correlates of protection are being sought by analysing the quality of this aspect of the vaccine-induced immune response.The current paradigm for an optimal HIV-1 vaccine is to design immunogens and vaccination protocols that allow the induction of both broadly neutralizing humoral and broadly reactive and effective cell-mediated immunity, to act at sites of possible infection and post-infection, respectively. However, this is challenged by the results of the RV144 trial as neither of these responses were induced but modest protection was observed.Understanding the biology and immunopathology of HIV-1 early following infection, its modes of transmission and the human immune systems response to the virus should aid in the rational design of vaccines of increased efficacy. © 2011 Adis Data Information BV. All rights reserved.

Mothobi N.Z.,St Vincents Hospital | Brew B.J.,St Vincents Hospital | Brew B.J.,St Vincents Center for Applied Medical Research
Current Opinion in Infectious Diseases | Year: 2012

PURPOSE OF REVIEW: The aim is to review the recent confirmation of the continued high prevalence of HIV-associated neurocognitive disorders (HAND) despite highly active antiretroviral therapy (HAART) in a large cohort study and to review the recent studies that have begun to address the potential reasons for such persistence. RECENT FINDINGS: HAND remains prevalent, despite effective viral suppression in cerebrospinal fluid and plasma. Several studies have shown the benefit of a central nervous system (CNS) penetrating HAART regimen (neuro-HAART) in improving neurocognitive outcomes. New evidence supports the early initiation of HAART. There are recent data to suggest that HAART may be CNS toxic, but evidence is still limited. Ageing does not currently explain the persistence of HAND. A recent study has also shown a correlation between cardiovascular risk factors and HAND. SUMMARY: The prevalence of HAND remains high in the HAART era. Most studies point towards the benefit of neuro-HAART in the prevention and treatment of HAND. The possible neurotoxicity of HAART needs to be further evaluated. It may be too early to detect a combined ageing and HIV effect and long-term studies are required. The link between cardiovascular disease and neurocognitive decline in HIV needs further exploration. Effective screening in clinical practice is paramount in prevention of the morbidity and mortality associated with HAND. Copyright © Lippincott Williams & Wilkins.

Ahlenstiel C.L.,St Vincents Center for Applied Medical Research | Ahlenstiel C.L.,University of New South Wales | Lim H.G.W.,St Vincents Center for Applied Medical Research | Lim H.G.W.,University of New South Wales | And 6 more authors.
Nucleic Acids Research | Year: 2012

Mammalian RNAi machinery facilitating transcriptional gene silencing (TGS) is the RNA-induced transcriptional gene silencing-like (RITS-like) complex, comprising of Argonaute (Ago) and small interfering RNA (siRNA) components. We have previously demonstrated promoter-targeted siRNA induce TGS in human immunodeficiency virus type-1 (HIV-1) and simian immunodeficiency virus (SIV), which profoundly suppresses retrovirus replication via heterochromatin formation and histone methylation. Here, we examine subcellular co-localization of Ago proteins with promoter-targeted siRNAs during TGS of SIV and HIV-1 infection. Analysis of retrovirus-infected cells revealed Ago1 co-localized with siRNA in the nucleus, while Ago2 co-localized with siRNA in the inner nuclear envelope. Mismatched and scrambled siRNAs were observed in the cytoplasm, indicating sequence specificity. This is the first report directly visualizing nuclear compartment distribution of Ago-associated siRNA and further reveals a novel nuclear trafficking mechanism for RITS-like components involving the actin cytoskeleton. These results establish a model for elucidating mammalian TGS and suggest a fundamental mechanism underlying nuclear delivery of RITS-like components. © 2012 The Author(s).

Boyd M.A.,University of New South Wales | Boyd M.A.,St Vincents Hospital | Cooper D.A.,University of New South Wales | Cooper D.A.,St Vincents Hospital | Cooper D.A.,St Vincents Center for Applied Medical Research
The Lancet | Year: 2012

The unprecedented, successful collaborative international effort to provide universal access to HIV care, including effective antiretroviral therapy, has reached a crucial point. Global economic downturn, changing donor priorities, and competing priorities in the health sector threaten the target of provision of 15 million people with HIV/AIDS with treatment by 2015, as agreed by the UN General Assembly. This aspiration has received added impetus from the finding that treatment prevents transmission by reduction of infectiousness of patients. In this report we critically review success thus far and examine efforts to optimise delivery of HIV care including antiretroviral therapy in low-income and middle-income countries for four main domains: treatment strategy, drug dosing, monitoring, and service delivery.

Guillemin G.J.,University of New South Wales | Guillemin G.J.,St Vincents Center for Applied Medical Research
FEBS Journal | Year: 2012

This minireview series reviews some of the most recent findings about quinolinic acid's cellular toxicity and its implications in diseases such as HIV associated neurocognitive disorders, depressive disorders and schizophrenia, and finally therapeutic strategies with drugs able to interfere with quinolinic acid production and/or effects © 2012 The Author Journal compilation © 2012 FEBS.

Swaminathan S.,Frederick National Laboratory for Cancer Research | Murray D.D.,St Vincents Center for Applied Medical Research | Murray D.D.,University of New South Wales | Kelleher A.D.,St Vincents Center for Applied Medical Research | Kelleher A.D.,University of New South Wales
Immunological Reviews | Year: 2013

Our understanding of the complexity of gene regulation has significantly improved in the last decade as the role of small non-coding RNAs, called microRNAs (miRNAs), has been appreciated. These 19-22 nucleotide RNA molecules are critical regulators of mRNA translation and turnover. The miRNAs bind via a protein complex to the 3′ untranslated region (3′ UTR) of mRNA, ultimately leading to mRNA translational inhibition, degradation, or repression. Although many mechanisms by which human immunodeficiency virus-1 (HIV-1) infection eventually induces catastrophic immune destruction have been elucidated, the important role that miRNAs play in HIV-1 pathogenesis is only now emerging. Accumulating evidence demonstrates that changes to endogenous miRNA levels following infection is important: in maintaining HIV-1 latency in resting CD4+ T cells, potentially affect immune function via changes to cytokines such as interleukin-2 (IL-2) and IL-10 and may predict disease progression. We review the roles that both viral and host miRNAs play in different cell types and disease conditions that are important in HIV-1 infection and discuss how miRNAs affect key immunomodulatory molecules contributing to immune dysfunction. Further, we discuss whether miRNAs may be used as novel biomarkers in serum and the potential to modulate miRNA levels as a unique approach to combating this pathogen. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Braidy N.,University of New South Wales | Guillemin G.J.,University of New South Wales | Guillemin G.J.,St Vincents Center for Applied Medical Research | Mansour H.,University of Sydney | And 4 more authors.
PLoS ONE | Year: 2011

The cofactor nicotinamide adenine dinucleotide (NAD+) has emerged as a key regulator of metabolism, stress resistance and longevity. Apart from its role as an important redox carrier, NAD+ also serves as the sole substrate for NAD-dependent enzymes, including poly(ADP-ribose) polymerase (PARP), an important DNA nick sensor, and NAD-dependent histone deacetylases, Sirtuins which play an important role in a wide variety of processes, including senescence, apoptosis, differentiation, and aging. We examined the effect of aging on intracellular NAD+ metabolism in the whole heart, lung, liver and kidney of female wistar rats. Our results are the first to show a significant decline in intracellular NAD+ levels and NAD:NADH ratio in all organs by middle age (i.e.12 months) compared to young (i.e. 3 month old) rats. These changes in [NAD(H)] occurred in parallel with an increase in lipid peroxidation and protein carbonyls (o- and m- tyrosine) formation and decline in total antioxidant capacity in these organs. An age dependent increase in DNA damage (phosphorylated H2AX) was also observed in these same organs. Decreased Sirt1 activity and increased acetylated p53 were observed in organ tissues in parallel with the drop in NAD+ and moderate over-expression of Sirt1 protein. Reduced mitochondrial activity of complex I-IV was also observed in aging animals, impacting both redox status and ATP production. The strong positive correlation observed between DNA damage associated NAD+ depletion and Sirt1 activity suggests that adequate NAD+ concentrations may be an important longevity assurance factor. © 2011 Braidy et al.

Savkovic B.,University of New South Wales | Symonds G.,St Vincents Center For Applied Medical Research | Murray J.M.,University of New South Wales
PLoS ONE | Year: 2012

The emergence of X4 tropic viral strains throughout the course of HIV infection is associated with poorer prognostic outcomes and faster progressions to AIDS than for patients in whom R5 viral strains predominate. Here we investigate a stochastic model to account for the emergence of X4 virus via mutational intermediates of lower fitness that exhibit dualmixed DM tropism, and employ the model to investigate whether the administration of CCR5 blockers in-vivo is likely to promote a shift towards X4 tropism. We show that the proposed stochastic model can account for X4 emergence with a median time of approximately 4 years postinfection as a result of 1. random stochastic mutations in the V3 region of env during the reverse transcription step of infection 2. increasing numbers of CXCR4expressing activated naive CD4 T cells with declining total CD4 T cell counts, thereby providing increased numbers of activated target cells for productive infection by X4 virus. Our model indicates that administration of the CCR5 blocker maraviroc does not promote a shift towards X4 tropism, assuming sufficient efficacy of background therapy BT. However our modelling also indicates that administration of maraviroc as a monotherapy or with BT of suboptimal efficacy can promote emergence of X4 tropic virus, resulting in accelerated progression to AIDS. Taken together, our results demonstrate that maraviroc is safe and effective if coadministered with sufficiently potent BT, but that suboptimal BT may promote X4 emergence and accelerated progression to AIDS. These results underscore the clinical importance for careful selection of BT when CCR5 blockers are administered in-vivo. © 2012 Savkovic et al.

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