Institute of Infectious Disease and Molecular Medicine

Cape Town, South Africa

Institute of Infectious Disease and Molecular Medicine

Cape Town, South Africa
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Cornell M.,Center for Infectious Disease | Johnson L.F.,Center for Infectious Disease | Schomaker M.,Center for Infectious Disease | Tanser F.,University of Cape Town | And 11 more authors.
The Lancet HIV | Year: 2015

Background As access to antiretroviral therapy (ART) expands, increasing numbers of older patients will start treatment and need specialised long-term care. However, the eff ect of age in ART programmes in resource-constrained settings is poorly understood. The HIV epidemic is ageing rapidly and South Africa has one of the highest HIV population prevalences worldwide. We explored the eff ect of age on mortality of patients on ART in South Africa and whether this eff ect is mediated by baseline immunological status. Methods In this retrospective cohort analysis, we studied HIV-positive patients aged 16-80 years who started ART for the fi rst time in six large South African cohorts of the International Epidemiologic Databases to Evaluate AIDSSouthern Africa collaboration, in KwaZulu-Natal, Gauteng, and Western Cape (two primary care clinics, three hospitals, and a large rural cohort). The primary outcome was mortality. We ascertained patients' vital status through linkage to the National Population Register. We used inverse probability weighting to correct mortality for loss to follow-up. We estimated mortality using Cox's proportional hazards and competing risks regression. We tested the interaction between baseline CD4 cell count and age. Findings Between Jan 1, 2004, and Dec 31, 2013, 84 078 eligible adults started ART. Of these, we followed up 83 566 patients for 174 640 patient-years. 8% (1817 of 23 258) of patients aged 16-29 years died compared with 19% (93 of 492) of patients aged 65 years or older. The age adjusted mortality hazard ratio was 2·52 (95% CI 2·01-3·17) for people aged 65 years or older compared with those 16-29 years of age. In patients starting ART with a CD4 count of less than 50 cells per μL, the adjusted mortality hazard ratio was 2·52 (2·04-3·11) for people aged 50 years or older compared with those 16-39 years old. Mortality was highest in patients with CD4 counts of less than 50 cells per μL, and 15% (1103 of 7295) of all patients aged 50 years or older starting ART were in this group. The proportion of patients aged 50 years or older enrolling in ART increased with successive years, from 6% (290 of 4999) in 2004 to 10% (961 of 9657) in 2012-13, comprising 9% of total enrolment (7295 of 83 566). At the end of the study, 6304 (14%) of 44 909 patients still alive and in care were aged 50 years or older. Interpretation Health services need reorientation towards HIV diagnosis and starting of ART in older individuals. Policies are needed for long-term care of older people with HIV. Funding National Institutes of Health (National Institute of Allergy and Infectious Diseases), US Agency for International Development, and South African Centre for Epidemiological Modelling and Analysis.

Korir P.K.,University College Cork | Geeleher P.,University of Chicago | Seoighe C.,University Road | Seoighe C.,Institute of Infectious Disease and Molecular Medicine
BMC Bioinformatics | Year: 2015

Background: Quantifying gene expression by RNA-Seq has several advantages over microarrays, including greater dynamic range and gene expression estimates on an absolute, rather than a relative scale. Nevertheless, microarrays remain in widespread use, demonstrated by the ever-growing numbers of samples deposited in public repositories. Results: We propose a novel approach to microarray analysis that attains many of the advantages of RNA-Seq. This method, called Machine Learning of Transcript Expression (MaLTE), leverages samples for which both microarray and RNA-Seq data are available, using a Random Forest to learn the relationship between the fluorescence intensity of sets of microarray probes and RNA-Seq transcript expression estimates. We trained MaLTE on data from the Genotype-Tissue Expression (GTEx) project, consisting of Affymetrix gene arrays and RNA-Seq from over 700 samples across a broad range of human tissues. Conclusion: This approach can be used to accurately estimate absolute expression levels from microarray data, at both gene and transcript level, which has not previously been possible. This methodology will facilitate re-analysis of archived microarray data and broaden the utility of the vast quantities of data still being generated. © 2015 Korir et al.

Marillier R.G.,Institute of Infectious Disease and Molecular Medicine | Brombacher T.M.,Institute of Infectious Disease and Molecular Medicine | Dewals B.,Institute of Infectious Disease and Molecular Medicine | Leeto M.,Institute of Infectious Disease and Molecular Medicine | And 4 more authors.
American Journal of Physiology - Gastrointestinal and Liver Physiology | Year: 2010

Interleukin-(IL)-4 and IL-13 signal through heterodimeric receptors containing a common IL-4 receptor-α (IL-4Rα) subunit, which is important for protection against helminth infections, including schistosomiasis. Previous studies demonstrated important roles for IL-4Rα-responsive hematopoietic cells, including T cells and macrophages in schistosomiasis. In this study, we examined the role of IL-4Rα responsiveness by nonhematopoietic smooth muscle cells during experimental acute murine schistosomiasis. Comparative Schistosoma mansoni infection studies with smooth muscle cell-specific IL-4Rα-deficient (SM-MHCcreIL- 4Rα-/flox) mice, heterozygous control (IL-4Rα -/flox) mice, and global IL-4Rα-deficient (IL-4Rα -/-) mice were conducted. S. mansoni-infected SM-MHC creIL-4Rα-/flox mice showed increased weight loss and earlier mortalities compared with IL-4Rα-/flox mice, despite comparable TH2/type 2 immune responses. In contrast to highly susceptible IL-4Rα-deficient mice, increased susceptibility in SMMHC creIL-4Rα-/flox mice was not accompanied by intestinal tissue damage and subsequent sepsis. However, both susceptible mutant mouse strains failed to efficiently expel eggs, demonstrated by egg reduction in the feces compared with control mice. Reduced egg expulsion was accompanied by impaired IL-4/IL-13-mediated hypercontractile intestinal responses, which was present in the more resistant control mice. Together, we conclude that IL-4Rα responsiveness by smooth muscle cells and subsequent IL-4- and IL-13-mediated hypercontractility are required for host protection during acute schistosomiasis to efficiently expel S. mansoni eggs and to prevent premature mortality. Copyright © 2010 the American Physiological Society.

McIlleron H.M.,Institute of Infectious Disease and Molecular Medicine | Schomaker M.,Center for Infectious Disease Epidemiology and Research | Nuttall J.J.C.,University of Cape Town | Nuttall J.J.C.,Red Cross | And 8 more authors.
AIDS | Year: 2013

Objectives: An efavirenz-based antiretroviral therapy (ART) regimen is preferred for children more than 3 years of age with tuberculosis. However, rifampin, a key component of antituberculosis therapy, induces CYP2B6. An increased dose of efavirenz is recommended in adults weighing more than 50 kg who require rifampin, but there is scant information in children being treated for tuberculosis. Design: Plasma efavirenz concentrations were compared in 40 children during concomitant treatment for tuberculosis and HIV-1, after stopping rifampicin, and in a control group of children without tuberculosis. Associations with antituberculosis treatment, metabolizer genotype (based on CYP2B6 516G→T, 983T→C, and 15582C→T), weight, and time after dose were evaluated. Results: Compared to children with extensive metabolizer genotypes, efavirenz concentrations were increased 1.42-fold (95% confidence interval, CI 0.94-2.15) and 2.85-fold (95% CI 1.80-4.52) in children with intermediate and slow metabolizer genotypes, respectively. Concomitant antituberculosis treatment increased efavirenz concentrations 1.49-fold (95% CI 1.10-2.01) in children with slow metabolizer genotypes, but did not affect efavirenz concentrations in extensive or intermediatemetabolizer genotypes. After adjustment for dose/kg, each kilogram of weight was associated with a 2.8% (95% CI 0.9-4.7) decrease in efavirenz concentrations. Despite higher milligram per kilogram doses, a higher proportion of children in the lowest weight band (10-13.9 kg) had efavirenz concentrations less than 1.0 mg/l than larger children. Conclusion: Antituberculosis treatment was not associated with reduced efavirenz concentrations in children, which does not support increased efavirenz doses. Children with slow metabolizer genotype have increased efavirenz concentrations during antituberculosis treatment, likely due to isoniazid inhibiting enzymes involved in accessory metabolic pathways for efavirenz. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Jindani A.,St George's, University of London | Harrison T.S.,St George's, University of London | Nunn A.J.,University College London | Phillips P.P.J.,University College London | And 17 more authors.
New England Journal of Medicine | Year: 2014

METHODS We randomly assigned patients with newly diagnosed, smear-positive, drug-sensitive tuberculosis to one of three regimens: a control regimen that included 2 months of ethambutol, isoniazid, rifampicin, and pyrazinamide administered daily followed by 4 months of daily isoniazid and rifampicin; a 4-month regimen in which the isoniazid in the control regimen was replaced by moxifloxacin administered daily for 2 months followed by moxifloxacin and 900 mg of rifapentine administered twice weekly for 2 months; or a 6-month regimen in which isoniazid was replaced by daily moxifloxacin for 2 months followed by one weekly dose of both moxifloxacin and 1200 mg of rifapentine for 4 months. Sputum specimens were examined on microscopy and after culture at regular intervals. The primary end point was a composite treatment failure and relapse, with noninferiority based on a margin of 6 percentage points and 90% confidence intervals.RESULTS We enrolled a total of 827 patients from South Africa, Zimbabwe, Botswana, and Zambia; 28% of patients were coinfected with the human immunodefiency virus. In the per-protocol analysis, the proportion of patients with an unfavorable response was 4.9% in the control group, 3.2% in the 6-month group (adjusted difference from control, -1.8 percentage points; 90% confidence interval [CI], -6.1 to 2.4), and 18.2% in the 4-month group (adjusted difference from control, 13.6 percentage points; 90% CI, 8.1 to 19.1). In the modified intention-to-treat analysis these proportions were 14.4% in the control group, 13.7% in the 6-month group (adjusted difference from control, 0.4 percentage points; 90% CI, -4.7 to 5.6), and 26.9% in the 4-month group (adjusted difference from control, 13.1 percentage points; 90% CI, 6.8 to 19.4).CONCLUSIONS The 6-month regimen that included weekly administration of high-dose rifapentine and moxifloxacin was as effective as the control regimen. The 4-month regimen was not noninferior to the control regimen. (Funded by the European and Developing Countries Clinical Trials Partnership and the Wellcome Trust; RIFAQUIN Current Controlled Trials number, ISRCTN44153044.).BACKGROUND Tuberculosis regimens that are shorter and simpler than the current 6-month daily regimen are needed. Copyright © 2014 Massachusetts Medical Society. All rights reserved.

PubMed | Leiden University, National Institute For Infectious Diseases L Spallanzani, Tuberculosis and Hepatitis Programme, Institute of Infectious Disease and Molecular Medicine and San Raffaele Scientific Institute
Type: Review | Journal: The European respiratory journal | Year: 2016

New approaches to control the spread of tuberculosis (TB) are needed, including tools to predict development of active TB from latent TB infection (LTBI). Recent studies have described potential correlates of risk, in order to inform the development of prognostic tests for TB disease progression. These efforts have included unbiased approaches employing omics technologies, as well as more directed, hypothesis-driven approaches assessing a small set or even individual selected markers as candidate correlates of TB risk. Unbiased high-throughput screening of blood RNAseq profiles identified signatures of active TB risk in individuals with LTBI, 1year before diagnosis. A recent infant vaccination study identified enhanced expression of T-cell activation markers as a correlate of risk prior to developing TB; conversely, high levels of Ag85A antibodies and high frequencies of interferon (IFN)- specific T-cells were associated with reduced risk of disease. Others have described CD27

Govindasamy D.,Institute of Infectious Disease and Molecular Medicine | Govindasamy D.,University of Cape Town | Van Schaik N.,Institute of Infectious Disease and Molecular Medicine | Kranzer K.,Institute of Infectious Disease and Molecular Medicine | And 7 more authors.
Journal of Acquired Immune Deficiency Syndromes | Year: 2011

Background: The linkage and barriers of linkage to facility-based HIV care from a mobile HIV testing unit have not previously been described. Methods: A stratified random sample (N = 192) was drawn of all eligible, newly diagnosed, HIV-infected individuals with a laboratory CD4 count result on a mobile unit between August 2008 and December 2009. All individuals with CD4 counts ≤350 cells per microliter and 30% of individuals with CD4 counts >350 cells per microliter were sampled. Linkage to care was assessed during April to June 2010 in those who received their CD4 count result. A participant who accessed HIV care at least once after testing was regarded as having linked to care. Binomial regression models were used to identify clinical and socio-demographic factors associated with receiving a CD4 count result and linking to care. Results: Forty-three (27%) individuals did not receive their CD4 count result. A lower CD4 count, being female, and the availability of a phone number increased the likelihood of receiving this result. Follow-up was attempted in the remaining 145 individuals. Ten refused to participate, and contact was unsuccessful in 42.4%. Linkage was 100% in patients with CD4 counts ≤200 cells per microliter, 66.7% in individuals with CD4 counts 201-350 cells per microliter, and 36.4% in those with CD4 counts >350 cells per microliter. A lower CD4 count, disclosure, symptoms of tuberculosis, and unemployment increased the likelihood of linking to care. Conclusion: Linkage to care was best among those eligible for antiretroviral therapy. Interventions designed at improving linkage among employed individuals are urgently warranted. © 2011 Lippincott Williams & Wilkins.

Rybicki E.P.,Institute of Infectious Disease and Molecular Medicine | Rybicki E.P.,University of Cape Town | Martin D.P.,Institute of Infectious Disease and Molecular Medicine
Current Topics in Microbiology and Immunology | Year: 2014

Plant viruses with ssRNA genomes provide a unique opportunity for generating expression vehicles for biopharming in plants, as constructs containing only the replication origin, with the replication-associated protein (Rep) gene provided in cis or in trans, can be replicationally amplified in vivo by several orders of magnitude, with significant accompanying increases in transcription and expression of gene(s) of interest. Appropriate replicating vectors or replicons may be derived from several different generic geminiviruses (family Geminiviridae) or nanoviruses (family Nanoviridae), for potential expression of a wide range of single or even multiple products in a wide range of plant families. The use of vacuum or other infiltration of whole plants by Agrobacterium tumefaciens suspensions has allowed the development of a set of expression vectors that rival the deconstructed RNA virus vectors in their yield and application, with some potential advantages over the latter that still need to be explored. Several modern applications of ssDNA plant vectors and their future potential will be discussed. © Springer-Verlag Berlin Heidelberg 2014.

Fauconnier M.,University of Orléans | Bourigault M.-L.,University of Orléans | Meme S.,CNRS Center for Molecular Biophysics | Szeremeta F.,CNRS Center for Molecular Biophysics | And 9 more authors.
American Journal of Pathology | Year: 2011

Cerebral malaria is the most severe neurologic complication in children and young adults infected with Plasmodium falciparum. T-cell activation is required for development of Plasmodium berghei ANKA (PbA)-induced experimental cerebral malaria (CM). To characterize the T-cell activation pathway involved, the role of protein kinase C-theta (PKC-θ) in experimental CM development was examined. PKC-θ-deficient mice are resistant to CM development. In the absence of PKC-θ, no neurologic sign of CM developed after blood stage PbA infection. Resistance of PKC-θ-deficient mice correlated with unaltered cerebral microcirculation and absence of ischemia, as documented by magnetic resonance imaging and magnetic resonance angiography, whereas wild-type mice developed distinct microvascular pathology. Recruitment and activation of CD8 + T cells, and ICAM-1 and CD69 expression were reduced in the brain of resistant mice; however, the pulmonary inflammation and edema associated with PbA infection were still present in the absence of functional PKC-θ. Resistant PKC-θ-deficient mice developed high parasitemia, and died at 3 weeks with severe anemia. Therefore, PKC-θ signaling is crucial for recruitment of CD8 + T cells and development of brain microvascular pathology resulting in fatal experimental CM, and may represent a novel therapeutic target of CM. Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Ameur A.,Uppsala University | Meiring T.L.,Institute of Infectious Disease and Molecular Medicine | Bunikis I.,Uppsala University | Haggqvist S.,Uppsala University | And 8 more authors.
Scientific Reports | Year: 2014

Infections by HIV increase the risk of acquiring secondary viral and bacterial infections and methods are needed to determine the spectrum of co-infections for proper treatment. We used rolling circle amplification (RCA) and Ion Proton sequencing to investigate the vaginal microbiome of 20 HIV positive women from South Africa. A total of 46 different human papillomavirus (HPV) types were found, many of which are not detected by existing genotyping assays. Moreover, the complete genomes of two novel HPV types were determined. Abundance of HPV infections was highly correlated with real-time PCR estimates, indicating that the RCA-Proton method can be used for quantification of individual pathogens. We also identified a large number of other viral, bacterial and parasitic co-infections and the spectrum of these co-infections varied widely between individuals. Our method provides rapid detection of a broad range of pathogens and the ability to reconstruct complete genomes of novel infectious agents.

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