ORCID Profile
0000-0001-8728-4146
Current Organisations
UNSW Sydney
,
University of Portsmouth
,
Noxopharm Limited
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Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2002
DOI: 10.1097/00126334-200212010-00003
Abstract: To investigate the effect of highly active antiretroviral therapy (HAART) on circulating Kaposi sarcoma (KS)-associated herpesvirus (KSHV) load in HIV-infected in iduals with and without KS. Twenty-nine HIV-infected subjects (21 with KS and 8 without KS) were recruited for the study they were prospectively studied before and at regular intervals during HAART. Patients with KS were clinically assessed using Adult Clinical Trials Group (ACTG) criteria, and sequential blood s les were obtained from all patients for determination of plasma HIV-1 load, CD4 cell count, titer of antibody to KSHV, and KSHV load. Ten of 21 patients with KS had a favorable KS response (complete response, 6 partial response, 4) with HAART alone. Of the 20 subjects with detectable KSHV viremia prior to HAART, over one half (12 [60%]) had an undetectable KSHV load with antiretroviral therapy. There was no significant difference between subjects receiving protease inhibitor- or nonnucleoside reverse transcriptase inhibitor-based treatment combinations. Achieving undetectable KSHV viremia is associated with a better clinical outcome in patients with KS. To our knowledge, we demonstrate for the first time that both protease inhibitor-based and nonnucleoside reverse transcriptase inhibitor-based antiretroviral treatment combinations may lead to an undetectable KSHV load and confirm that an undetectable KSHV load is associated with KS regression. There was no clear association between CD4 cell count response and KS response to HAART, but there was a significant relationship between HIV load response to HAART and clinical improvement of KS.
Publisher: Springer Science and Business Media LLC
Date: 08-02-2016
Publisher: Bentham Science Publishers Ltd.
Date: 2008
DOI: 10.2174/157016208783572008
Abstract: Human immunodeficiency virus (HIV)-specific CD8+ T cells can mediate anti-HIV activity by both cytolytic (cytotoxic T lymphocyte or CTL) and non-cytolytic mechanisms (antiviral) and play a crucial role in HIV pathogenesis. Both mechanisms actively contribute to the control of HIV in vivo. The non-cytolytic CD8+T cells from in iduals infected with HIV suppress virus replication in CD4+ T cells in vitro by a non-cytolytic mechanism that involves interplay of several chemokines and an unidentified secreted soluble CD8 (+)-cell antiviral factor (CAF). There is immense value of these two distinct CD8 activities in anti-HIV responses and their necessity to be maintained during highly active antiretroviral therapy (HAART). The aim of this review is to provide an overview of some of the novel aspects of CD8+ T cell interactions with HIV, their role in HIV pathogenesis, HAART therapy, HIV disease progression, gene expression and interactions with other cell types during HIV infection.
Publisher: American Society of Hematology
Date: 26-07-2012
DOI: 10.1182/BLOOD-2012-01-407395
Abstract: Macrophages are key target cells for HIV-1. HIV-1BaL induced a subset of interferon-stimulated genes in monocyte-derived macrophages (MDMs), which differed from that in monocyte-derived dendritic cells and CD4 T cells, without inducing any interferons. Inhibition of type I interferon induction was mediated by HIV-1 inhibition of interferon-regulated factor (IRF3) nuclear translocation. In MDMs, viperin was the most up-regulated interferon-stimulated genes, and it significantly inhibited HIV-1 production. HIV-1 infection disrupted lipid rafts via viperin induction and redistributed viperin to CD81 compartments, the site of HIV-1 egress by budding in MDMs. Exogenous farnesol, which enhances membrane protein prenylation, reversed viperin-mediated inhibition of HIV-1 production. Mutagenesis analysis in transfected cell lines showed that the internal S-adenosyl methionine domains of viperin were essential for its antiviral activity. Thus viperin may contribute to persistent noncytopathic HIV-1 infection of macrophages and possibly to biologic differences with HIV-1–infected T cells.
Publisher: American Society for Microbiology
Date: 15-03-2002
DOI: 10.1128/JVI.76.6.2634-2640.2002
Abstract: Following the introduction of highly active antiretroviral therapy (HAART), the incidence of Kaposi's sarcoma (KS) has significantly declined in human immunodeficiency virus type 1 (HIV-1)-positive (HIV-1 + ) in iduals and clinical remission is often observed. We hypothesize that these effects are partly due to anti-KS-associated herpesvirus (KSHV) immune restoration. Here, 15-mer overlapping peptides from proteins K12 and K8.1 were used to identify novel KSHV-specific cytotoxic T-lymphocyte epitopes. Three immunogenic peptides, two lytic and one latent, were subsequently used to monitor the anti-KSHV CD8 + T-cell responses in a cohort of 19 HIV-1 + KSHV +/− KS +/− in iduals during 52 weeks of HAART. KSHV and HIV-1 loads, KSHV antibody titers, and both CD4 + and CD8 + T-lymphocyte counts were enumerated. Prior to HAART, the total number of spot-forming cells (SFC) for all three peptides correlated with both CD4 + and CD8 + T-lymphocyte counts ( P ≤ 0.05) in the KSHV-positive KS-positive cohort ( n = 11). Following 52 weeks of HAART, significant decreases in HIV-1 and KSHV loads were associated with significant increases in CD4 + T-lymphocyte counts and number of SFC for the three KSHV-specific peptides. Although these increases were modest in comparison to the number of SFC observed with the HIV-1 gag peptide SLYNTVATL, they represented a fourfold increase from the baseline, continuing an upward trend to week 52.
Publisher: Oxford University Press (OUP)
Date: 07-1999
DOI: 10.1086/314833
Abstract: CD8+ anti-human immunodeficiency virus (HIV) suppressor activity (CASA) defines the noncytolytic suppression of HIV mediated by secreted soluble factors. Changes in CASA in patients receiving combination antiretroviral therapy have not been described. Thirty-two HIV-infected patients receiving mono- or dual therapy for 52 weeks followed by highly active antiretroviral therapy (HAART) for a further 52 weeks were analyzed. T cell number and functional subsets, cutaneous delayed-type hypersensitivity, and plasma HIV RNA were assessed in 17 patients for CASA. Prior to therapy, CASA correlated inversely with HIV RNA (P<.001). Dual therapy yielded greater and more sustained changes in CASA than monotherapy, but HAART decreased CASA to levels observed in HIV-uninfected in iduals. The magnitude of HIV RNA suppression correlated significantly with a decrease in activated CD8+ T lymphocytes (CD38+HLA-DR+), increases in naive CD4+ T lymphocytes (CD45RA+62L+), and increases in the delayed-type hypersensitivity score. However, changes in CASA did not correlate with changes in any T lymphocyte subset. CASA increases with improving immune function but appears more dependent on ongoing HIV replication.
Publisher: American Society of Hematology
Date: 15-03-2004
DOI: 10.1182/BLOOD-2003-09-3129
Abstract: HIV-1 subverts antigen processing in dendritic cells (DCs) resulting in viral uptake, infection, and transfer to T cells. Although DCs bound monomeric gp120 and HIV-1 similarly, virus rarely colocalized with endolysosomal markers, unlike gp120, suggesting HIV-1 alters endolysosomal trafficking. Virus within DC intracellular compartments rapidly moved to DC-CD4+ lymphocyte synapses when introduced to CD4+ lymphocyte cultures. Although viral harboring and transfer from nonlysosomal compartments was transient, given DC-associated virus protein, nucleic acids, and infectious HIV-1 transfer to CD4+, lymphocytes decayed within 24 hours. However a second long-term transfer phase was apparent in immature DCs after 48 hours as a zidovudine-sensitive rise in proviral DNA. Therefore, DCs transfer HIV-1 to CD4+ lymphocytes in 2 distinct phases. Immature and mature DCs first ert virus from the endolysosomal pathway to the DC–T-cell synapse. Secondly, the later transfer phase from immature DCs is through de novo HIV-1 production. Thus, the controversy of DCs being infected or not infected for the mechanics of viral transfer to CD4+ lymphocytes can be addressed as a function of time.
Publisher: Oxford University Press (OUP)
Date: 29-11-2015
DOI: 10.1093/JAC/DKV389
Abstract: BIT225 (N-carbamimidoyl-5-(1-methyl-1H-pyrazol-4-yl)-2-naphthamide), a novel acyl-guanidine, is a novel antiviral drug that blocks Vpu ion channel activity and has anti-HIV-1 activity in vitro. The antiviral effect of BIT225 is most pronounced in cells of the myeloid lineage. With infected circulating monocytes and tissue-resident macrophages representing a key cellular reservoir of HIV-1, BIT225 has a potential role in the eradication of the virus from the host. BIT225-004 is a Phase 1b/2a, placebo-controlled, randomized study of the safety, pharmacokinetics and antiviral activity of BIT225 in 21 HIV-1-infected, ART-naive subjects. Twenty-one subjects were enrolled and received BIT225 (400 mg twice daily) or placebo treatment for 10 days (randomized 2:1). The anti-HIV-1 effect of BIT225 in the monocyte reservoir was measured in CD14+ monocytes isolated from the peripheral blood on days 1 (pre-dose), 5, 10 and 20 isolated monocytes were co-cultured ex vivo with MT4 T cells. De novo HIV-1 replication was measured by p24 activity of released virus into the culture supernatant to day 25 of co-culture. In addition, monocyte s les were collected for analysis by RT-PCR total HIV-1 DNA single-copy assay. Measurement of HIV-1 directly within the patient's monocyte population indicated that BIT225 treatment significantly reduced the viral burden in myeloid lineage cells, which was more evident in those in iduals with the highest viral loads. In addition, BIT225-treated subjects demonstrated a significantly reduced level of monocyte activation (sCD163) compared with the placebo controls. This study's unique design demonstrates that BIT225 can significantly reduce the dissemination of HIV-1 from infected monocytes. This has important ramifications for diminishing the seeding/re-seeding of the viral reservoir.
Publisher: Springer US
Date: 2007
Publisher: The American Association of Immunologists
Date: 26-11-0011
DOI: 10.4049/JIMMUNOL.177.10.7103
Abstract: In HIV infection, dendritic cells (DCs) may play multiple roles, probably including initial HIV uptake in the anogenital mucosa, transport to lymph nodes, and subsequent transfer to T cells. The effects of HIV-1 on DC maturation are controversial, with several recent conflicting reports in the literature. In this study, microarray studies, confirmed by real-time PCR, demonstrated that the genes encoding DC surface maturation markers were among the most differentially expressed in monocyte-derived dendritic cells (MDDCs), derived from human blood, treated with live or aldrithriol-2-inactivated HIV-1BaL. These effects translated to enhanced cell surface expression of these proteins but differential expression of maturation markers was only partial compared with the effects of a conventional potent maturation stimulus. Such partially mature MDDCs can be converted to fully mature cells by this same potent stimulus. Furthermore, live HIV-1 stimulated greater changes in maturation marker surface expression than aldrithriol-2-inactivated HIV-1 and this enhanced stimulation by live HIV-1 was mediated via CCR5, thus suggesting both viral replication-dependent and -independent mechanisms. These partially mature MDDCs demonstrated enhanced CCR7-mediated migration and are also able to stimulate interacting T cells in a MLR, suggesting DCs harboring HIV-1 might prepare CD4 lymphocytes for transfer of HIV-1. Increased maturation marker surface expression was also demonstrated in native DCs, ex vivo Langerhans cells derived from human skin. Thus, HIV initiates maturation of DCs which could facilitate subsequent enhanced transfer to T cells.
Publisher: Oxford University Press (OUP)
Date: 11-2003
DOI: 10.1189/JLB.0503208
Abstract: Dendritic cells play a major role in HIV pathogenesis. Epithelial dendritic cells appear to be one of the first cells infected after sexual transmission and transfer of the virus to CD4 lymphocytes, simultaneously activating these cells to produce high levels of HIV replication. Such transfer may occur locally in inflamed mucosa or after dendritic cells have matured and migrated to local lymph nodes. Therefore, the mechanism of binding, internalization, infection and transfer of HIV to CD4 lymphocytes is of great interest. Recently, the role of the C-type lectin DC-SIGN as a dendritic cell receptor for HIV has been intensively studied with in vitro monocyte-derived dendritic cells. However, it is clear that other C-type lectin receptors such as Langerin on Langerhan cells and mannose receptor on dermal dendritic cells are at least equally important for gp120 binding on epithelial dendritic cells. C-type lectin receptors play a role in virus transfer to T cells, either via de novo infection (“cis transfer”) or without infection (“in trans” or transinfection). Both these processes are important in vitro, and both may have a role in vivo, although the low-level infection of immature dendritic cells may be more important as it leads to R5 HIV strain selection and persistence of virus within dendritic cells for at least 24 h, sufficient for these cells to transit to lymph nodes. The exact details of these processes are currently the subject of intense study.
Publisher: American Society of Hematology
Date: 14-05-2009
Publisher: Oxford University Press (OUP)
Date: 09-2001
DOI: 10.1093/BMB/58.1.187
Abstract: A better understanding of the immune response to HIV and the deleterious effect that HIV infection may have on the immune system in general, allows us to consider how best to restore protective immune responses to HIV and other opportunistic pathogens in the immunocompromised host. In this chapter, we summarise areas of current innovation and provide an update of the current state of knowledge concerning interventions which could result in the immunocompromised state being reversed. We describe the kinds of immune responses, which are thought to be useful in combating both the human immunodeficiency virus and other pathogenic organisms, and methods which are being considered to stimulate such responses. Lessons which may be learned from other disease states, which lead to immunodeficiency and methods for measuring successful outcome of treatment will be described.
Publisher: Oxford University Press (OUP)
Date: 21-08-2006
DOI: 10.1189/JLB.0306158
Abstract: Although few in number, dendritic cells (DCs) are heterogeneous, ubiquitous, and are crucial for protection against pathogens. In this review, the different DC subpopulations have been described and aspects of DC biology are discussed. DCs are important, not only in the pathogenesis of HIV, but also in the generation of anti-HIV immune responses. This review describes the roles that DC are thought to play in HIV pathogenesis, including uptake and transport of virus. We have also discussed the effects that the virus exerts on DCs such as infection and dysfunction. Then we proceed to focus on DC subsets in different organs and show how widespread the effects of HIV are on DC populations. It is clear that the small number of studies on tissue-derived DCs limits current research into the pathogenesis of HIV.
Publisher: Bentham Science Publishers Ltd.
Date: 05-06-2020
DOI: 10.2174/1568009620666200102122830
Abstract: Idronoxil has been the subject of more than 50 peer-reviewed publications over the last two decades. This isoflavone is an intriguing regulator of multiple signal transduction pathways, capable of causing a range of biological effects, including cell cycle arrest, apoptosis, an ability to stimulate the immune system, and inhibition of angiogenesis. These multifaceted actions suggest that idronoxil has the potential to synergize with, or complement, a wide range of cancer therapies. Whilst clinically tested in the past, idronoxil’s journey was discontinued as a result of its low bioavailability in humans when administered either intravenously or orally, though strategies to overcome this issue are currently being explored. Here, we summarize the current literature regarding the key cellular targets of idronoxil and the mechanisms by which idronoxil exerts its anticancer effects, laying a new foundation toward giving this unique molecule a second chance of contributing to the future of cancer treatment.
Publisher: Springer Science and Business Media LLC
Date: 12-2007
Abstract: The choice of an appropriate housekeeping gene for normalisation purposes has now become an essential requirement when designing QPCR experiments. This is of particular importance when using QPCR to measure viral and cellular gene transcription levels in the context of viral infections as viruses can significantly interfere with host cell pathways, the components of which traditional housekeeping genes often encode. In this study we have determined the reliability of 10 housekeeping genes in context of four heavily studied viral infections human immunodeficiency virus type 1, herpes simplex virus type 1, cytomegalovirus and varicella zoster virus infections using a variety of cell types and virus strains. This provides researchers of these viruses with a shortlist of potential housekeeping genes to use as normalisers for QPCR experiments.
Publisher: Elsevier BV
Date: 05-2010
DOI: 10.1016/J.ANTIVIRAL.2010.02.312
Abstract: The novel small molecule, BIT225 (N-[5-(1-methyl-1H-pyrazol-4-yl)-napthalene-2-carbonyl]-guanidine: CAS No. 917909-71-8), was initially identified using a screening strategy designed to detect inhibitors of Hepatitis C virus (HCV) p7 ion channel activity. Here we report that BIT225 has potent stand-alone antiviral activity against the HCV model pestivirus bovine viral diarrhea virus (BVDV) with an IC(50) of 314nM. Combinations of BIT225 with recombinant interferon alpha-2b (rIFNalpha-2b) show synergistic antiviral action against BVDV and the synergy is further enhanced by addition of ribavirin. Synergy was also observed between BIT225 and two nucleoside analogues known to inhibit the HCV RNA-dependent RNA polymerase. BIT225 has successfully completed a phase Ia dose escalating, single dose safety trial in healthy volunteers and a phase Ib/IIa trial to evaluate the safety and pharmacokinetics of repeated dosing for selected doses of BIT225 in HCV-infected persons. A modest, but statistically significant drop in patient viral load was detected over the 7 days of dosing (ref. www.biotron.com.au). Given the critical role of the p7 protein in the HCV life cycle and pathogenicity, our data indicate that molecules like BIT225, representing a new class of antiviral compounds, may be developable for therapeutic use against HCV infection, either as monotherapy, or in combination with other HCV drugs.
Publisher: Elsevier BV
Date: 04-2009
Publisher: Public Library of Science (PLoS)
Date: 14-11-2011
Publisher: American Society for Microbiology
Date: 02-2010
DOI: 10.1128/AAC.01308-09
Abstract: Building on previous findings that amiloride analogues inhibit HIV-1 replication in monocyte-derived macrophages (MDM), Biotron Limited has generated a library of over 300 small-molecule compounds with significant improvements in anti-HIV-1 activity. Our lead compound, BIT225, blocks Vpu ion channel activity and also shows anti-HIV-1 activity, with a 50% effective concentration of 2.25 ± 0.23 μM (mean ± the standard error) and minimal in vitro toxicity (50% toxic concentration, 284 μM) in infected MDM, resulting in a selectivity index of 126. In this study, we define the antiretroviral efficacy of BIT225 activity in macrophages, which are important drug targets because cells of the monocyte lineage are key reservoirs of HIV-1, disseminating virus to the peripheral tissues as they differentiate into macrophages. In assays with acutely and chronically HIV-1 Ba-L -infected MDM, BIT225 resulted in significant reductions in viral integration and virus release as measured by real-time PCR and a reverse transcriptase (RT) activity assay at various stages of monocyte-to-macrophage differentiation. Further, the TZM-bl assay showed that the de novo virus produced at low levels in the presence of BIT225 was less infectious than virus produced in the absence of the compound. No antiviral activity was observed in MDM chronically infected with HIV-2, which lacks Vpu, confirming our initial targeting of and screening against this viral protein. The activity of BIT225 is post-virus integration, with no direct effects on the HIV-1 enzymes RT and protease. The findings of this study suggest that BIT225 is a late-phase inhibitor of the viral life cycle, targeting Vpu, and is a drug capable of significantly inhibiting HIV-1 release from both acute and chronically infected macrophages.
Publisher: Bentham Science Publishers Ltd.
Date: 12-2006
DOI: 10.2174/138945006779025482
Abstract: Worldwide the heterosexual route is the prevalent mode of transmission of HIV, increasing the demand for measures that block the sexual spread of HIV infection. Vaccines designed to prevent mucosal transmission of HIV should be considered a component of vaccine strategies against HIV (in addition to cytotoxic T cells required for clearance and to prevent viral dissemination) and include antibodies, which are capable of blocking HIV entry at mucosal epithelial barriers, and prevent initial infection of target cells in the mucosa. However, in the interim and in the absence of an effective vaccine, the development of microbicides, topical preparations that block the early steps of HIV infection and transmission, may represent a more viable alternative to condom use in many HIV infected regions of the world especially by empowering women. To date there has been some success with antiviral antibodies applied as a microbicide capable of preventing SIV infection in macaques and reports of vaccines capable of preventing intravaginal and intrarectal inoculated SIV. However, for such success in humans a much greater understanding of the mechanisms involved in the very early stages of mucosal transmission in HIV infection are required. These may lead to additional strategies to inactivate or inhibit viral uptake and replication before a potentially life threatening acute infection develops. Such measures will lead to the development of effective microbicides and vaccines that will diminish the global spread of HIV.
Publisher: Elsevier BV
Date: 12-2004
Publisher: Oxford University Press (OUP)
Date: 2002
DOI: 10.1046/J.1365-2249.2002.01744.X
Abstract: A panel of 22 CD8+ T cell lines, with a broad range of CD8+ anti-HIV-1 suppressor activity (CASA) were generated from a single patient with HIV-1 infection. CD8+ T cell lines with either strong or weak CASA were examined and compared for cell surface and intracellular markers, constitutive chemokine and lymphokine mRNA levels and inducible lymphokine expression. Strong CASA significantly correlated with CD8+ T cell lines that highly coexpressed the molecule CD28+ (r = 0·52, P = 0·01) and Ki67+ (r = 0·88, P = 0·02), with strong CASA CD8+ T cell lines demonstrating significantly higher (P & 0·05) expression of CD8+CD28+ and CD8+Ki67+ compared to those with weak activity. No such correlations or findings were observed for the markers CD38, HLA-DR, CD57 or perforin. The Th1 cytokines were expressed at greater levels than the Th2 cytokines, with strong CASA significantly associated with an increased inducible level of IL-2 production (P = 0·05). Constitutive RANTES, IP-10 and I-309 mRNA expression were significantly (P & 0·05) elevated in CD8+ T cell lines exhibiting strong CASA compared to those with weak CASA. There was no significant difference in the mRNA expression of the lymphokines IL-2, 4, 5, 8, 9, 10, 14, 15, or chemokines MIP-1α, MIP-1β, MCP-1, and Ltn. Strong CASA was therefore associated with rapidly replicating CD8+ T cells of the phenotype CD8+CD28+Ki67+ that expressed greater levels of IL-2 and the ligands RANTES and I-309.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for john wilkinson.