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Search Results: 1 - 10 of 196212 matches for " Walter G Jaoko "
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European and Developing Countries Clinical Trials Partnership (EDCTP): the path towards a true partnership
Mecky I Matee, Christine Manyando, Peter M Ndumbe, Tumani Corrah, Walter G Jaoko, Andrew Y Kitua, Herman PA Ambene, Mathieu Ndounga, Lynn Zijenah, David Ofori-Adjei, Simon Agwale, Steven Shongwe, Thomas Nyirenda, Michael Makanga
BMC Public Health , 2009, DOI: 10.1186/1471-2458-9-249
Abstract: EDCTP promotes collaborative research supported by multiple funding agencies and harnesses networking expertise across different African and European countries. EDCTP is different from other similar initiatives. The organisation of EDCTP blends important aspects of partnership that includes ownership, sustainability and responds to demand-driven research. The Developing Countries Coordinating Committee (DCCC); a team of independent scientists and representatives of regional health bodies from sub-Saharan Africa provides advice to the partnership. Thus EDCTP reflects a true partnership and the active involvement and contribution of these African scientists ensures joint ownership of the EDCTP programme with European counterparts.The following have been the major achievements of the EDCTP initiative since its formation in 2003; i) increase in the number of participating African countries from two to 26 in 2008 ii) the cumulative amount of funds spent on EDCTP projects has reached € 150 m, iii) the cumulative number of clinical trials approved has reached 40 and iv) there has been a significant increase number and diversity in capacity building activities.While we recognise that EDCTP faced enormous challenges in its first few years of existence, the strong involvement of African scientists and its new initiatives such as unconditional funding to regional networks of excellence in sub-Saharan Africa is envisaged to lead to a sustainable programme. Current data shows that the number of projects supported by EDCTP is increasing. DCCC proposes that this success story of true partnership should be used as model by partners involved in the fight against other infectious diseases of public health importance in the region.Tuberculosis, human immunodeficiency virus (HIV) and malaria cross paths in sub-Saharan Africa, the epicentre of the three infections. Although HIV/AIDS, tuberculosis (TB) and malaria are three treatable and preventable diseases, they are having a devastatin
HIV-1 Superinfection in Women Broadens and Strengthens the Neutralizing Antibody Response
Valerie Cortez,Katherine Odem-Davis,R. Scott McClelland,Walter Jaoko,Julie Overbaugh
PLOS Pathogens , 2012, DOI: 10.1371/journal.ppat.1002611
Abstract: Identifying naturally-occurring neutralizing antibodies (NAb) that are cross-reactive against all global subtypes of HIV-1 is an important step toward the development of a vaccine. Establishing the host and viral determinants for eliciting such broadly NAbs is also critical for immunogen design. NAb breadth has previously been shown to be positively associated with viral diversity. Therefore, we hypothesized that superinfected individuals develop a broad NAb response as a result of increased antigenic stimulation by two distinct viruses. To test this hypothesis, plasma samples from 12 superinfected women each assigned to three singly infected women were tested against a panel of eight viruses representing four different HIV-1 subtypes at matched time points post-superinfection (~5 years post-initial infection). Here we show superinfected individuals develop significantly broader NAb responses post-superinfection when compared to singly infected individuals (RR = 1.68, CI: 1.23–2.30, p = 0.001). This was true even after controlling for NAb breadth developed prior to superinfection, contemporaneous CD4+ T cell count and viral load. Similarly, both unadjusted and adjusted analyses showed significantly greater potency in superinfected cases compared to controls. Notably, two superinfected individuals were able to neutralize variants from four different subtypes at plasma dilutions >1:300, suggesting that their NAbs exhibit elite activity. Cross-subtype breadth was detected within a year of superinfection in both of these individuals, which was within 1.5 years of their initial infection. These data suggest that sequential infections lead to augmentation of the NAb response, a process that may provide insight into potential mechanisms that contribute to the development of antibody breadth. Therefore, a successful vaccination strategy that mimics superinfection may lead to the development of broad NAbs in immunized individuals.
Time to Complete Wound Healing in HIV-Positive and HIV-Negative Men following Medical Male Circumcision in Kisumu, Kenya: A Prospective Cohort Study
John H. Rogers, Elijah Odoyo-June, Walter Jaoko, Robert C. Bailey
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0061725
Abstract: Background While voluntary medical male circumcision (VMMC) has been shown to be protective against HIV-acquisition, the procedure may place men and their partners at risk of HIV infection in the period following circumcision if sex is resumed before the wound is healed. This prospective cohort study evaluates post-circumcision wound healing to determine whether the 42-day post-circumcision abstinence period, recommended by the World Health Organization and adopted by VMMC programs, is optimal. Methods and Findings Men were circumcised by forceps-guided method and their post-circumcision wounds examined weekly for seven weeks and at 12 weeks. Time to complete healing was recorded in completed weeks since circumcision, and its associations with baseline covariates were assessed by Kaplan-Meier methods and Cox Proportional Hazard Models. A total of 215 HIV-negative and 108 HIV-positive men aged 18–35 years (median 26, IQR 23–30) were enrolled. 97.1% of scheduled follow-up visits were completed. At week 4, 59.3% of HIV-positive men and 70.4% of age-matched HIV-negative men were healed. At week 6, these percentages rose to 93.4% in HIV-positive men and 92.6% in age-matched HIV-negative men. There was no difference in the hazard of healing between 108 HIV-positive and 108 age-matched HIV-negative men (HR 0.91 95% CI 0.70–1.20). Early post-operative infection was associated with delayed healing in both HIV-positive and HIV-negative men (HR 0.48 95% CI 0.23–1.00). Conclusions Our results indicate that the WHO recommendation for 42-days post-circumcision sexual abstinence should be maintained for both HIV-positive and HIV-negative men. It is important to stress condom use upon resumption of sex in all men undergoing circumcision.
Effectiveness of antiretroviral therapy and development of drug resistance in HIV-1 infected patients in Mombasa, Kenya
Kim Steegen, Stanley Luchters, Kenny Dauwe, Jacqueline Reynaerts, Kishor Mandaliya, Walter Jaoko, Jean Plum, Marleen Temmerman, Chris Verhofstede
AIDS Research and Therapy , 2009, DOI: 10.1186/1742-6405-6-12
Abstract: Recent data show an HIV prevalence in Kenya of 7.4%, resulting in 1.4 million Kenyans living with HIV [1]. An estimated 190,000 HIV-infected Kenyans receive ART, representing 44% of those in need of treatment [1]. At the Comprehensive HIV Care Centre (CCC) in Mombasa, the decision on when to start or switch treatment is based on clinical and immunological parameters [2,3]. Information on the rate of treatment failure and the development of drug resistance in public hospitals in RLS, where treatment decisions are guided by clinical parameters and CD4 count only, is limited. Virologic treatment failure and accompanying resistance are of concern with regard to the risk of disease progression and potential transmission of drug resistant virus to partners. The aim of this study was to assess, in a cross-sectional survey, the rate of viral suppression and drug resistance among individuals receiving ART.From the patients attending the CCC in Coast Province General Hospital, Mombasa, a total of 150 consecutive patients, over 18 years of age and receiving ART, were asked to participate in this surveillance study by a trained adherence counsellor. Fifty (50) patients were recruited in April 2006, 100 patients were recruited in May 2007. Participants gave written informed consent, and refusal to participate did not influence the standard of care. Ethical approval was obtained from the Kenyatta National Hospital Ethics and Research Committee.Using a structured questionnaire, basic socio-demographic and clinical data was obtained from each participant. ART adherence was measured by self-report and pill count over the last month and recorded as satisfactory (>95%) or unsatisfactory (<95%). Ten (10) ml of EDTA blood was collected for CD4 cell count (FACScount Becton & Dickinson Immunocytometry, Oxford, UK). The remainder of the blood was centrifuged to collect plasma, which was stored at -80°C until processing for viral load measurement and genotyping.Plasma HIV RNA quantification
HIV-1 RNA Dysregulates the Natural TLR Response to Subclinical Endotoxemia in Kenyan Female Sex-Workers
Richard T. Lester, Xiao-Dan Yao, T. Blake Ball, Lyle R. McKinnon, Were R. Omange, Rupert Kaul, Charles Wachihi, Walter Jaoko, Kenneth L. Rosenthal, Francis A. Plummer
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0005644
Abstract: Background Subclinical endotoxemia has been reported in HIV-1 infected persons and may drive systemic immune activation and pathogenesis. Proinflammatory responsiveness to endotoxin (LPS) is mediated by Toll-like receptor 4 (TLR4). We therefore examined the association between plasma LPS levels, HIV RNA, and TLR4 expression and cytokine responses in the blood of HIV infected and uninfected participants in a cohort of female sex-workers in Kenya. Methodology/Principal Findings Ex vivo plasma and peripheral blood mononuclear cells (PBMC) were assessed for LPS and TLR mRNA, respectively. The effects of HIV single stranded RNA, a TLR8 ligand, on TLR4 and LPS signaling were further assessed in short term PBMC culture. Both HIV uninfected and infected subjects frequently had low detectable LPS levels in their plasmas. Significantly increased LPS levels were associated with chronic HIV-1 infection, both treated and untreated, but not with other acute or semi-chronic conditions reported. In HIV-uninfected subjects, TLR4 mRNA expression levels correlated inversely with plasma LPS levels, suggesting chronic endotoxin ‘tolerance’ in vivo. A similar effect of reduced TLR4 mRNA was seen in short term PBMC culture after stimulation with LPS. Interestingly, the apparent in vivo tolerance effect was diminished in subjects with HIV infection. Additionally, pre-stimulation of PBMC with LPS lead to proinflammatory (TNF-α) tolerance to subsequent LPS stimulation; however, pre-treatment of PBMC with HIV single-stranded RNA40, could enhance TLR4-mediated LPS responsiveness in vitro. Conclusions/Significance Thus, dysregulation of endotoxin tolerance by HIV-1 RNA may exacerbate HIV chronic immune activation and pathogenesis.
Evaluation of a Quantitative Real-Time PCR Assay to Measure HIV-Specific Mucosal CD8+ T Cell Responses in the Cervix
Duncan Chege,Yijie Chai,Sanja Huibner,Lyle McKinnon,Charles Wachihi,Makubo Kimani,Walter Jaoko,Joshua Kimani,T. Blake Ball,Francis A. Plummer,Rupert Kaul,Anuradha Rebbapragada
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0013077
Abstract: Several candidate HIV vaccines aim to induce virus-specific cellular immunity particularly in the genital tract, typically the initial site of HIV acquisition. However, standardized and sensitive methods for evaluating HIV-specific immune responses at the genital level are lacking. Therefore we evaluated real-time quantitative PCR (qPCR) as a potential platform to measure these responses. β-Actin and GAPDH were identified as the most stable housekeeping reference genes in peripheral blood mononuclear cells (PBMCs) and cervical mononuclear cells (CMCs) respectively and were used for normalizing transcript mRNA expression. HIV-specific cellular T cell immune responses to a pool of optimized CD8+ HIV epitopes (HIV epitope pool) and Staphylococcal enterotoxin B (SEB) superantigen control were assayed in HIV infected PBMC by qPCR, with parallel assessment of cytokine protein production. Peak HIV-specific mRNA expression of IFNγ, IL-2 and TNFα occurred after 3, 5 and 12 hours respectively. PBMCs were titrated to cervical appropriate cell numbers to determine minimum required assay input cell numbers; qPCR retained sensitivity with input of at least 2.5×104 PBMCs. This optimized qPCR assay was then used to assess HIV-specific cellular T cell responses in cytobrush-derived cervical T cells from HIV positive individuals. SEB induced IFNγ mRNA transcription was detected in CMCs and correlated positively with IFNγ protein production. However, qPCR was unable to detect HIV-induced cytokine mRNA production in the cervix of HIV-infected women despite robust detection of gene induction in PBMCs. In conclusion, although qPCR can be used to measure ex vivo cellular immune responses to HIV in blood, HIV-specific responses in the cervix may fall below the threshold of qPCR detection. Nonetheless, this platform may have a potential role in measuring mitogen-induced immune responses in the genital tract.
A prospective study of vaginal trichomoniasis and HIV-1 shedding in women on antiretroviral therapy
Linnet N Masese, Susan M Graham, Ruth Gitau, Nobert Peshu, Walter Jaoko, Jeckoniah O Ndinya-Achola, Kishorchandra Mandaliya, Barbra A Richardson, Julie Overbaugh, R McClelland
BMC Infectious Diseases , 2011, DOI: 10.1186/1471-2334-11-307
Abstract: We conducted a prospective cohort study including monthly follow-up of 147 women receiving ART in Mombasa, Kenya. Those with T. vaginalis infection, defined by the presence of motile trichomonads on vaginal saline wet mount, received treatment with single dose metronidazole (2 g). Test of cure was performed at the next monthly visit. Using the pre-infection visit as the reference category, we compared detection of vaginal HIV-1 RNA before versus during and after infection using generalized estimating equations. A cut-off of 100 HIV-1 RNA copies/swab was used as the lower limit for linear quantitation.Among 31 women treated for trichomoniasis, the concentration of vaginal HIV-1 RNA was above the limit for quantitation before, during, and after T. vaginalis infection in 4 (13% [95% CI 4% - 30%]), 4 (13% [95% CI 4% - 30%]), and 5 (16% [95% confidence interval {CI} 5% - 34%]) women respectively. After adjusting for potential confounding factors, we could detect no difference in the likelihood of detecting vaginal HIV-1 RNA before versus during infection (odds ratio [OR] 1.41, 95% CI 0.23 - 8.79, p = 0.7). In addition, detection of HIV-1 RNA was similar before infection versus after successful treatment (OR 0.68, 95% CI (0.13 - 3.45), p = 0.6).Detection of vaginal HIV-1 RNA during ART was uncommon at visits before, during and after T. vaginalis infection.In sub-Saharan Africa, transmission of HIV-1 is predominantly heterosexual [1]. The risk of transmission is likely related to the concentration of virus in genital mucosal secretions, suggesting that reducing genital HIV-1 shedding may reduce infectivity in seropositive individuals [2,3]. Clinical studies provide strong evidence that antiretroviral therapy (ART) leads to rapid and sustained suppression of genital HIV-1 shedding [3,4]. However, this suppression is incomplete [4,5], and persistent genital HIV-1 replication may reflect ongoing risk of transmitting the virus even in individuals on treatment [3].Trichomonas v
Interferon Regulatory Factor 1 Polymorphisms Previously Associated with Reduced HIV Susceptibility Have No Effect on HIV Disease Progression
Aida Sivro, Lyle R. McKinnon, Hezhao Ji, Joshua Kimani, Walter Jaoko, Francis A. Plummer, Ruey-Chyi Su, T. Blake Ball
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0066253
Abstract: Introduction Interferon regulatory factor 1 (IRF1) is induced by HIV early in the infection process and serves two functions: transactivation of the HIV-1 genome and thus replication, and eliciting antiviral innate immune responses. We previously described three IRF1 polymorphisms that correlate with reduced IRF1 expression and reduced HIV susceptibility. Objective To determine whether IRF1 polymorphisms previously associated with reduced HIV susceptibility play a role in HIV pathogenesis and disease progression in HIV-infected ART-na?ve individuals. Methods IRF1 genotyping for polymorphisms (619, MS and 6516) was performed by PCR in 847 HIV positive participants from a sex worker cohort in Nairobi, Kenya. Rates of CD4+ T cell decline and viral loads (VL) were analyzed using linear mixed models. Results Three polymorphisms in the IRF1, located at 619, microsatellite region and 6516 of the gene, previously associated with decreased susceptibility to HIV infection show no effect on disease progression, either measured by HIV-1 RNA levels or the slopes of CD4 decline before treatment initiation. Conclusion Whereas these three polymorphisms in the IRF1 gene protect against HIV-1 acquisition, they appear to exert no discernable effects once infection is established.
Loss to Follow-Up as a Competing Risk in an Observational Study of HIV-1 Incidence
Susan M. Graham, Janet Raboud, R. Scott McClelland, Walter Jaoko, Jeckoniah Ndinya-Achola, Kishor Mandaliya, Julie Overbaugh, Ahmed M. Bayoumi
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0059480
Abstract: Objective Conventional survival estimates may be biased if loss to follow-up (LTF) is associated with the outcome of interest. Our goal was to assess whether the association between sexual risk behavior and HIV-1 acquisition changed after accounting for LTF with competing risks regression. Methods HIV-1-seronegative women who enrolled in a Kenyan sex worker cohort from 1993–2007 were followed prospectively and tested for HIV at monthly clinic visits. Our primary predictor was self-reported sexual risk behavior in the past week, analyzed as a time-dependent covariate. Outcomes included HIV-1 acquisition and LTF. We analyzed the data using Cox proportional hazards regression and competing risks regression, in which LTF was treated as a competing event. Results A total of 1,513 women contributed 4,150 person-years (py), during which 198 (13.1%) acquired HIV-1 infection (incidence, 4.5 per 100 py) and 969 (64.0%) were LTF (incidence, 23.4 per 100 py). After adjusting for potential confounders, women reporting unprotected sex with multiple partners were less likely to be lost to follow-up (adjusted sub-hazard ratio (aSHR) 0.50, 95% confidence interval (CI) 0.32–0.76, relative to no sexual activity). The risk of HIV-1 acquisition after reporting unprotected sex with multiple partners was similar with Cox regression (adjusted hazard ratio (aHR) 2.41, 95% CI 1.36–4.27) and competing risks regression (aSHR 2.47, 95% CI 1.33–4.58). Conclusions Unprotected sex with multiple partners was associated with higher HIV-1 acquisition risk, but lower attrition. This differential attrition did not substantially bias Cox regression estimates when compared to competing risks regression results.
More precise model of α-helix and transmembrane α-helical peptide backbone structure  [PDF]
Walter F. Schmidt, Clayton G. Thomas
Journal of Biophysical Chemistry (JBPC) , 2012, DOI: 10.4236/jbpc.2012.34036
Abstract: The 3-D structure of the β-adrenergic receptor with a molecular weight of 55,000 daltons is available from crystallographic data. Within one of the seven transmembrane ion channel helices in the β2-receptor, one loop of a helix ACADL has previously been proposed as the site that explains β2 activity (fights acute bronchitis) whereas ASADL in the β1-receptor at the corresponding site explains β1-activity (cardiac stimulation). The α-agonist responsible for this selective reaction is only 0.5% of the receptor molecular weight, and only 1.5% of the weight of the trans-membrane portion of the receptor. The understanding of the mechanism by which a small molecule on binding to a site on one single loop of a helix produces a specific agonist activity on an entire transmembrane ion channel is uncertain. A model of an α-helix is presented in which of pitch occurs at angles both smaller and larger than 180° n. Consequently, atomic coordinates in a peptide backbone α-helix match the data points of individual atom (and atom types) in the backbone. More precisely, eleven atoms in peptide backbone routinely equal one loop of a helix, instead of eleven amino acid residues equaling three loops of a helix; therefore, an α-helix can begin (or end) at any specific atom in a peptide backbone, not just at any specific amino acid. Wavefront Topology System and Finite Element Methods calculate this specific helical shape based only upon circumference, pitch, and phase. Only external forces which specifically affect circumference, pitch and/or phase (e.g. from agonist binding) can/will alter the shape of an α-helix.
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