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Publication History View all

  • Journal of Viral Hepatitis 09/2013; 20(9):600-1.
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    ABSTRACT: The Ig-like transcript (ILT) 7 is a surface molecule selectively expressed by human plasmacytoid dendritic cells (pDCs). ILT7 cross-linking suppresses pDC activation and type I IFN (IFN-I) secretion following TLR7/9 engagement. The bone marrow stromal cell Ag 2 (BST2, aka HM1.24, tetherin, or CD317) is expressed by different cell types upon exposure to IFN-I and is a natural ligand for ILT7. In this study, we show that ILT7 expression decreased spontaneously in pDCs upon in vitro culture, which correlates with pDC differentiation measured as increased side scatter properties and CCR7 expression. TLR7/9 ligands, as well as HIV, induced BST2 upregulation on all tested cell types except T cells, which required TCR stimulation to respond to TLR9L-induced IFN-I. IFN-γ, IL-4, IL-10, and TNF-α had only marginal effects on BST2 expression in blood leukocytes compared with TLR9L. Preincubation with ILT7 cross-linking Ab inhibited IFN-I production in PBMCs treated with TLR7/9L or HIV, whereas BST2 blockade did not affect IFN-I responses even when BST2 upregulation was further boosted with TCR agonists or immunoregulatory cytokines. Our data indicate that BST2-mediated ILT7 cross-linking may act as a homeostatic regulatory mechanism on immature circulating pDC, rather than a negative feedback for activated mature pDCs that have downregulated ILT7.
    The Journal of Immunology 03/2013; 190(6):2622-30.
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    ABSTRACT: Co-infection with Hepatitis C (HCV) and HIV is common and HIV accelerates hepatic disease progression due to HCV. However, access to HCV treatment is limited and success rates are generally poor. We conducted a systematic review and meta-analysis to assess HCV treatment outcomes in observational cohorts. Two databases (Medline and EMBASE) were searched using a compound search strategy for cohort studies reporting HCV treatment outcomes (as determined by a sustained virological response, SVR) in HIV-positive patients initiating HCV treatment for the first time. 40 studies were included for review, providing outcomes on 5339 patients from 17 countries. The pooled proportion of patients achieving SVR was 38%. Significantly poorer outcomes were observed for patients infected with HCV genotypes 1 or 4 (pooled SVR 24.5%), compared to genotypes 2 or 3 (pooled SVR 59.8%). The pooled proportion of patients who discontinued treatment due to drug toxicities (reported by 33 studies) was low, at 4.3% (3.3-5.3%). Defaulting from treatment, reported by 33 studies, was also low (5.1%, 3.5-6.6%), as was on-treatment mortality (35 studies, 0.1% (0-0.2%)). These results, reported under programmatic conditions, are comparable to those reported in randomised clinical trials, and show that although HCV treatment outcomes are generally poor in HIV co-infected patients, those infected with HCV genotypes 2 or 3 have outcomes comparable to HIV-negative patients.
    PLoS ONE 02/2013; 8(2):e55373.
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    ABSTRACT: It is now around 30 years since the discovery of HIV, the virus that causes AIDS. More than 70 million people have been infected in that time and around 35 million have died. The majority of those currently living with HIV/AIDS are in low- and middle-income countries, with sub-Saharan Africa bearing a disproportionate burden of the global disease. In high-income countries, the introduction of antiretroviral therapy (ART) has drastically reduced the morbidity and mortality associated with HIV. Patients on ART are now predicted to have near-normal life expectancy and the role of treatment is increasingly recognized in preventing new infections. In low- and middle-income countries, treatment is now more widely available and around half of those who need ART are currently receiving it. Early diagnosis of HIV is essential if ART is to be optimally implemented. Lab-based diagnostics for screening, diagnosis, treatment initiation, and the monitoring of treatment efficacy are critical in managing the disease and reducing the number of new infections each year. The introduction of point-of-care HIV rapid tests has transformed the epidemic, particularly in low- and middle-income countries. For the first time, these point-of-care tests allow for the rapid identification of infected individuals outside the laboratory who can undergo counseling and treatment and, in the case of pregnant women, allow the timely initiation of ART to reduce the risk of vertical transmission. Although survival is markedly improved with ART even in the absence of laboratory monitoring, long-term management of people living with HIV on ART, and their partners, is essential to ensure successful viral suppression. The burden of disease in many resource-poor settings with high HIV prevalence has challenged the ability of local laboratories to effectively monitor those on ART. Diagnostics used to initiate and monitor treatment are now moving out of the laboratory and into the field. These new point-of-care tests for viral load and CD4 are poised to further transform the disease and shift the treatment paradigm in low- and middle-income countries.
    Clinical Epidemiology 01/2013; 5:387-396.
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    ABSTRACT: Bronchiectasis is a complex pathological endpoint arrived at through a diverse interplay between lung infection and altered immune function. It comprises irreversible, abnormal dilatation of one or more bronchi, with chronic airway inflammation and is associated with recurrent chest infections, airflow obstruction, chronic cough, excessive sputum production, and malaise. Many pathogens are associated with this disease, including chronic bacterial infections, nontuberculous mycobacteria, and aspergillis. However, the etiology is poorly defined. Disease-associated genes indicate a likely contribution to disease mechanism both from innate and adaptive immunity. The role of immune mechanisms is highlighted by the occurrence of bronchiectasis in a subset of patients with rheumatoid arthritis or inflammatory bowel disease as well as diseases of immune dysregulation such as combined variable immune deficiency, transporter associated with antigen processing (TAP) deficiency syndrome, and hyper-IgE syndrome. Recent evidence indicates a possible role of excessive natural killer cell activation in pathogenesis.
    Annals of the New York Academy of Sciences 12/2012; 1272(1):68-72.
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    ABSTRACT: Background: Once-daily nucleoside-sparing combination antiretroviral therapy (cART) regimens, such as maraviroc/darunavir/ritonavir, may be attractive therapeutic options. However, the pharmacokinetic (PK) profiles of such regimens have not been established. Methods: HIV-1-infected subjects on stable cART comprising of tenofovir/emtricitabine (TDF/FTC) 245/200 mg plus darunavir/ritonavir 800/100 mg once daily with plasma HIV-1 RNA <50 copies/mL were eligible to enter this phase I, open-label, prospective, two-period PK study. On day 1 (period 1) maraviroc 150 mg daily was added to subjects cART regimen and on day 11 (period 2) TDF/FTC discontinued. At steady state (days 10 and 20) intensive PK sampling was undertaken. Geometric mean (GM) ratios for PK parameters between periods 2 versus 1 were calculated. In addition the number of subjects with trough (Ctrough) and average (Cave) maraviroc concentrations below 25 and 75 ng/mL (values previously associated with optimal virological response) were calculated and factors associated with total maraviroc exposure assessed. Results: Eleven subjects completed study procedures with a mean age 49 years (range 35-59 years), 82% male and 27% and 73% of black and Caucasian ethnicity, respectively. Maraviroc GM (95% confidence interval [CI]) Ctrough and Cave concentrations in both study periods (see Table) were > 25 and > 75 ng/mL (concentrations associated with near maximal efficacy). No individual subjects had a maraviroc Cave below 75 ng/mL in either study period. One subject had a maraviroc Ctrough concentration below 25 ng/mL in period 1 (14 ng/mL) and one other subject in period 2 (21 ng/mL). Although no statistically significant differences in PK parameters were observed between period 2 and period 1 for any drug (see Table), a trend was observed towards lower maraviroc, darunavir and ritonavir concentrations in period 2 (TDF/FTC discontinued) versus period 1.AUC, area under the plasma concentration-time curve; CI, confidence interval; GMR, geometic mean ratio. On day 20, in a multivariate model, only total ritonavir exposure (AUC0-24) was statistically significantly associated with total maraviroc exposure (AUC0-24) at day 20 (p = 0.045; 95% CI: 0.01-0.89). No clinically relevant safety concerns were observed. Conclusions: The PK profile of maraviroc/darunavir/ritonavir 150/800/100 mg all once daily appears favourable. Maraviroc exposure is dependent on ritonavir exposure which was slightly reduced in the absence of TDF/FTC.
    Journal of the International AIDS Society 11/2012; 15(6):18332.
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    ABSTRACT: Avian-origin influenza polymerase activity can be dramatically increased in human cells with the PB2 E627K mutation. Previously others have proposed that this mutation increases the stability of the viral ribonucleoprotein complex (vRNP) measured by the interaction between PB2 and NP. However, we demonstrate here that a variety of PB2 adaptive mutations including E627K do not enhance the stability of the vRNP but rather increase the amount of replicated RNA that results in more PB2-NP co-precipitation.
    Journal of Virology 10/2012;
  • The Lancet Infectious Diseases 10/2012;
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    ABSTRACT: Streptococcus pyogenes M/emm3 strains have been epidemiologically linked with enhanced infection severity and risk of streptococcal toxic shock syndrome (STSS), a syndrome triggered by superantigenic stimulation of T cells. Comparison of S. pyogenes strains causing STSS demonstrated that emm3 strains were surprisingly less mitogenic than other emm-types (emm1, emm12, emm18, emm28, emm87, emm89) both in vitro and in vivo, indicating poor superantigenic activity. We identified a 13 bp deletion in the superantigen smeZ gene of all emm3 strains tested. The deletion led to a premature stop codon in smeZ, and was not present in other major emm-types tested. Expression of a functional non-M3-smeZ gene successfully enhanced mitogenic activity in emm3 S. pyogenes and also restored mitogenic activity to emm1 and emm89 S. pyogenes strains where the smeZ gene had been disrupted. In contrast, the M3-smeZ gene with the 13 bp deletion could not enhance or restore mitogenicity in any of these S. pyogenes strains, confirming that M3-smeZ is non-functional regardless of strain background. The mutation in M3-smeZ reduced the potential for M3 S. pyogenes to induce cytokines in human tonsil, but not during invasive infection of superantigen-sensitive mice. Notwithstanding epidemiological associations with STSS and disease severity, emm3 strains have inherently poor superantigenicity that is explained by a conserved mutation in smeZ.
    PLoS ONE 10/2012; 7(10):e46376.
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    ABSTRACT: The overall purpose of these guidelines is to provide guidance on best clinical practice in the treatment and management of human immunodeficiency virus (HIV)-positive pregnant women in the UK. The scope includes guidance on the use of antiretroviral therapy (ART) both to prevent HIV mother-to-child transmission (MTCT) and for the welfare of the mother herself, guidance on mode of delivery and recommendations in specific patient populations where other factors need to be taken into consideration,such as coinfection with other agents. The guidelines are aimed at clinical professionals directly involved with, and responsible for, the care of pregnant women with HIV infection.
    HIV Medicine 09/2012; 13 Suppl 2:87-157.
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