Kloverpris H.N.,University of KwaZulu - Natal |
Kloverpris H.N.,Copenhagen University |
Kazer S.W.,Massachusetts General Hospital |
Kazer S.W.,Massachusetts Institute of Technology |
And 38 more authors.
Immunity | Year: 2016
Innate lymphoid cells (ILCs) play a central role in the response to infection by secreting cytokines crucial for immune regulation, tissue homeostasis, and repair. Although dysregulation of these systems is central to pathology, the impact of HIV-on ILCs remains unknown. We found that human blood ILCs were severely depleted during acute viremic HIV-infection and that ILC numbers did not recover after resolution of peak viremia. ILC numbers were preserved by antiretroviral therapy (ART), but only if initiated during acute infection. Transcriptional profiling during the acute phase revealed upregulation of genes associated with cell death, temporally linked with a strong IFN acute-phase response and evidence of gut barrier breakdown. We found no evidence of tissue redistribution in chronic disease and remaining circulating ILCs were activated but not apoptotic. These data provide a potential mechanistic link between acute HIV-infection, lymphoid tissue breakdown, and persistent immune dysfunction. © 2016 Elsevier Inc.
Xu G.J.,Harvard University |
Xu G.J.,Harvard Massachusetts Institute of Technology Division of Health Sciences and Technology |
Xu G.J.,Howard Hughes Medical Institute |
Kula T.,Howard Hughes Medical Institute |
And 21 more authors.
Science | Year: 2015
The human virome plays important roles in health and immunity. However, current methods for detecting viral infections and antiviral responses have limited throughput and coverage. Here, we present VirScan, a high-throughput method to comprehensively analyze antiviral antibodies using immunoprecipitation and massively parallel DNA sequencing of a bacteriophage library displaying proteome-wide peptides from all human viruses. We assayed over 108 antibody-peptide interactions in 569 humans across four continents, nearly doubling the number of previously established viral epitopes. We detected antibodies to an average of 10 viral species per person and 84 species in at least two individuals. Although rates of specific virus exposure were heterogeneous across populations, antibody responses targeted strongly conserved "public epitopes" for each virus, suggesting that they may elicit highly similar antibodies. VirScan is a powerful approach for studying interactions between the virome and the immune system.
PubMed | Inkosi Albert Luthuli Hospital, Karolinska Institutet, Doris Duke Medical Research Institute, Copenhagen University and 10 more.
Type: Journal Article | Journal: Immunity | Year: 2016
Innate lymphoid cells (ILCs) play a central role in the response to infection by secreting cytokines crucial for immune regulation, tissue homeostasis, and repair. Although dysregulation of these systems is central to pathology, the impact of HIV-1 on ILCs remains unknown. We found that human blood ILCs were severely depleted during acute viremic HIV-1 infection and that ILC numbers did not recover after resolution of peak viremia. ILC numbers were preserved by antiretroviral therapy (ART), but only if initiated during acute infection. Transcriptional profiling during the acute phase revealed upregulation of genes associated with cell death, temporally linked with a strong IFN acute-phase response and evidence of gut barrier breakdown. We found no evidence of tissue redistribution in chronic disease and remaining circulating ILCs were activated but not apoptotic. These data provide a potential mechanistic link between acute HIV-1 infection, lymphoid tissue breakdown, and persistent immune dysfunction.
Gurdasani D.,Wellcome Trust Sanger Institute |
Gurdasani D.,University of Cambridge |
Iles L.,Wellcome Trust Sanger Institute |
Iles L.,University of Cambridge |
And 15 more authors.
AIDS | Year: 2014
The study of individuals at opposite ends of the HIV clinical spectrum can provide invaluable insights into HIV biology. Heterogeneity in criteria used to define these individuals can introduce inconsistencies in results from research and make it difficult to identify biological mechanisms underlying these phenotypes. In this systematic review, we formally quantified the heterogeneity in definitions used for terms referring to extreme phenotypes in the literature, and identified common definitions and components used to describe these phenotypes. We assessed 714 definitions of HIV extreme phenotypes in 501 eligible studies published between 1 January 2000 and 15 March 2012, and identified substantial variation among these. This heterogeneity in definitions may represent important differences in biological endophenotypes and clinical progression profiles of individuals selected by these, suggesting the need for harmonized definitions. In this context, we were able to identify common components in existing definitions that may provide a framework for developing consensus definitions for these phenotypes in HIV infection. © 2014 Wolters Kluwer Health.
PubMed | Howard Hughes Medical Institute, Doris Duke Medical Research Institute, University of KwaZulu - Natal, Johns Hopkins University and 2 more.
Type: Journal Article | Journal: The Journal of infectious diseases | Year: 2015
Improved biomarkers are needed for tuberculosis. To develop tests based on products secreted by tubercle bacilli that are strictly associated with viability, we evaluated 3 bacterial-derived, species-specific, small molecules as biomarkers: 2 mycobactin siderophores and tuberculosinyladenosine. Using liquid chromatography-tandem mass spectrometry, we demonstrated the presence of 1 or both mycobactins and/or tuberculosinyladenosine in serum and whole lung tissues from infected mice and sputum, cerebrospinal fluid (CSF), or lymph nodes from infected patients but not uninfected controls. Detection of the target molecules distinguished host infection status in 100% of mice with both serum and lung as the target sample. In human subjects, we evaluated detection of the bacterial small molecules (BSMs) in multiple body compartments in 3 patient cohorts corresponding to different forms of tuberculosis. We detected at least 1 of the 3 molecules in 90%, 71%, and 40% of tuberculosis patients sputum, CSF, and lymph node samples, respectively. In paucibacillary forms of human tuberculosis, which are difficult to diagnose even with culture, detection of 1 or more BSM was rapid and compared favorably to polymerase chain reaction-based detection. Secreted BSMs, detectable in serum, warrant further investigation as a means for diagnosis and therapeutic monitoring in patients with tuberculosis.
Upfold M.,Doris Duke Medical Research Institute |
Upfold M.,University of KwaZulu - Natal |
Grobler A.,Doris Duke Medical Research Institute |
Suleman F.,University of KwaZulu - Natal |
And 2 more authors.
AIDS and Behavior | Year: 2016
Accurate and objective measurement of adherence is critical in microbicide trials. We compared two applicator tests: visual inspection of returned empty tenofovir gel applicators (VIREA) and ultraviolet light (UVL) assessment in terms of sensitivity and specificity, and for concordance. Sensitivity and specificity analysis of 24 control applicators (12 known-inserted and 12 sham-inserted) at 4-months after receipt was 75.0 and 66.7 % for VIREA and 83.3 and 91.7 % for UVL, respectively. After an additional 3 months of storage sensitivity and specificity was 100 and 58.3 % for VIREA and 100 and 66.7 % for UVL, respectively. In January 2015, 1316 empty applicators were returned as used by 115 participants enrolled at one site in a randomized controlled trial. Assessment outcomes showed 78.8 % agreement between the techniques. Methods concurred that 22.0 % of the returned empty applicators appeared unused. By UVL assessment, 40.0 % of returned empty applicators had no evidence of vaginal insertion, translating to a potential 28.0 % less product used as compared to that returned as used by women. UVL assessment may be considered a more accurate and less subjective measure of adherence as compared to VIREA. © 2016 Springer Science+Business Media New York
Roider J.M.,University of Oxford |
Roider J.M.,Doris Duke Medical Research Institute |
Roider J.M.,University of KwaZulu - Natal |
Muenchhoff M.,University of Oxford |
And 3 more authors.
Current Opinion in HIV and AIDS | Year: 2016
Purpose of review The paediatric HIV epidemic is changing. Over the past decade, new infections have substantially reduced, whereas access to antiretroviral therapy (ART) has increased. Overall this success means that numbers of children living with HIV are climbing. In addition, the problems observed in adult infection resulting from chronic inflammation triggered by persistent immune activation even following ART mediated suppression of viral replication are magnified in children infected from birth. Recent findings Features of immune ontogeny favour low immune activation in early life, whereas specific aspects of paediatric HIV infection tend to increase it. A subset of ART-naïve nonprogressing children exists in whom normal CD4 + cell counts are maintained in the setting of persistent high viremia and yet in the context of low immune activation. This sooty mangabey-like phenotype contrasts with nonprogressing adult infection which is characterized by the expression of protective HLA class I molecules and low viral load. The particular factors contributing to raised or lowered immune activation in paediatric infection, which ultimately influence disease outcome, are discussed. Summary Novel strategies to circumvent the unwanted long-term consequences of HIV infection may be possible in children in whom natural immune ontogeny in early life militates against immune activation. Defining the mechanisms underlying low immune activation in natural HIV infection would have applications beyond paediatric HIV. © Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved.
Karim S.S.A.,Doris Duke Medical Research Institute |
Karim S.S.A.,University of KwaZulu - Natal |
Karim S.S.A.,Columbia University |
Karim Q.A.,Doris Duke Medical Research Institute |
And 10 more authors.
New England Journal of Medicine | Year: 2015
Background Globally, herpes simplex virus type 2 (HSV-2) infection is the most common cause of genital ulcer disease. Effective prevention strategies for HSV-2 infection are needed to achieve the goals of the World Health Organization global strategy for the prevention and control of sexually transmitted infections. METHODS We assessed the effectiveness of pericoital tenofovir gel, an antiviral microbicide, in preventing HSV-2 acquisition in a subgroup of 422 HSV-2-negative women enrolled in the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 study, a double-blind, randomized, placebo-controlled trial. Incident HSV-2 cases were identified by evidence of seroconversion on an HSV-2 IgG enzyme-linked immunosorbent assay between study enrollment and exit. A confirmatory analysis was performed by Western blot testing. RESULTS The HSV-2 incidence rate was 10.2 cases per 100 person-years (95% confidence interval [CI], 6.8 to 14.7) among 202 women assigned to tenofovir gel, as compared with 21.0 cases per 100 person-years (95% CI, 16.0 to 27.2) among 222 women assigned to placebo gel (incidence rate ratio, 0.49; 95% CI, 0.30 to 0.77; P = 0.003). The HSV-2 incidence rate among the 25 women with vaginal tenofovir concentrations of 10,000 ng per milliliter or more was 5.7 cases per 100 person-years, as compared with 15.5 cases per 100 person-years among the 103 women with no detectable vaginal tenofovir (incidence rate ratio, 0.37; 95% CI, 0.04 to 1.51; P = 0.14). As confirmed by Western blot testing, there were 16 HSV-2 seroconversions among women assigned to tenofovir gel as compared with 36 among those assigned to the placebo gel (incidence rate ratio, 0.45; 95% CI, 0.23 to 0.82; P = 0.005). CONCLUSIONS In this study in South Africa, pericoital application of tenofovir gel reduced HSV-2 acquisition in women. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
Kasprowicz V.O.,Harvard University |
Kasprowicz V.O.,Kwazulu Natal Research Institute for Tuberculosis and HIV K RITH |
Kasprowicz V.O.,Doris Duke Medical Research Institute |
Halliday J.S.,University of Oxford |
And 3 more authors.
Biomarkers in Medicine | Year: 2012
IFN-γ release by antigen-specific T cells can be used to track immune responses to infections and vaccines. In recent years, there have been substantial advances in the techniques available to measure IFN-γ release and a generation of such assays are now available for clinical use, as well as in a research setting. Interferon release leads to subsequent release of interferon-responsive chemokines such as MIG and IP-10, thus amplifying the original signal. A number of investigators have assessed whether measurement of these chemokines might provide a sensitive platform for detection of infection and antigen-specific T-cell responses. In this article, we assess the potential of these new approaches. We have termed the new antigen-specific T-cell assays monokine-amplified IFN-γ release assays (MIGRAs). Overall, it seems likely that improvements in the detection threshold could be made by analysis of antigen-triggered chemokines and potentially of other molecules in the future, although whether MIGRAs will provide additional clinical utility still remains to be determined. © 2012 Future Medicine Ltd.
Chelule P.K.,Doris Duke Medical Research Institute |
Mbongwa H.P.,Doris Duke Medical Research Institute |
Carries S.,Doris Duke Medical Research Institute |
Gqaleni N.,Doris Duke Medical Research Institute
Food Chemistry | Year: 2010
The ability of traditional amahewu fermentation to increase protein digestibility and detoxify mycotoxins commonly contaminating maize in southern Africa was investigated. Commercial maize meal, with or without a range of added ingredients, was fermented, following the traditional way, and the levels of proteins and amino acids assessed. Traditional amahewu samples (and the maize meal used to prepare them) were also collected from a neighbouring rural village. Mycotoxin levels (aflatoxin B1, fumonisin B1 and zearalenone) in maize meal and amahewu were analysed and compared in the two sets of samples. Increased levels of protein were observed in amahewu, especially in the samples with added yeast and bread flour (up to 149%), in comparison to the levels in starter maize. In addition, the mycotoxins detected in maize samples were drastically reduced, by 76.5-100%, following fermentation. This observation shows that traditional amahewu fermentation may improve the nutritional quality of maize-based foods and reduce the levels of toxic/carcinogenic mycotoxins. © 2010 Elsevier Ltd. All rights reserved.