Electrical properties of thin metal films

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A compartmentalized type I interferon response in the gut during chronic HIV-1 infection is associated with immunopathogenesis.

OBJECTIVE(S):Type I interferon (IFN-I) responses confer both protective and pathogenic effects in persistent virus infections. IFN-I diversity, stage of infection and tissue compartment may account for this dichotomy. The gut is a major site of early HIV-1 replication and microbial translocation, but the nature of the IFN-I response in this compartment remains unclear. DESIGN:Samples were obtained from two IRB-approved cross-sectional studies. The first study included individuals with chronic, untreated HIV-1 infection (n = 24) and age/sex-balanced uninfected controls (n = 14). The second study included antiretroviral-treated, HIV-1-infected individuals (n = 15) and uninfected controls (n = 15). METHODS:The expression of 12 IFNα subtypes, IFNβ and antiviral IFN-stimulated genes (ISGs) were quantified in peripheral blood mononuclear cells (PBMCs) and colon biopsies using real-time PCR and next-generation sequencing. In untreated HIV-1-infected individuals, associations between IFN-I responses and gut HIV-1 RNA levels as well as previously established measures of colonic and systemic immunological indices were determined. RESULTS:IFNα1, IFNα2, IFNα4, IFNα5 and IFNα8 were upregulated in PBMCs during untreated chronic HIV-1 infection, but IFNβ was undetectable. By contrast, IFNβ was upregulated and all IFNα subtypes were downregulated in gut tissue. Gut ISG levels positively correlated with gut HIV-1 RNA and immune activation, microbial translocation and inflammation markers. Gut IFN-I responses were not significantly different between HIV-1-infected individuals on antiretroviral treatment and uninfected controls. CONCLUSION:The IFN-I response is compartmentalized during chronic untreated HIV-1 infection, with IFNβ being more predominant in the gut. Gut IFN-I responses are associated with immunopathogenesis, and viral replication is likely a major driver of this response

A compositional look at the human gastrointestinal microbiome and immune activation parameters in HIV infected subjects.

HIV progression is characterized by immune activation and microbial translocation. One factor that may be contributing to HIV progression could be a dysbiotic microbiome. We therefore hypothesized that the GI mucosal microbiome is altered in HIV patients and this alteration correlates with immune activation in HIV. 121 specimens were collected from 21 HIV positive and 22 control human subjects during colonoscopy. The composition of the lower gastrointestinal tract mucosal and luminal bacterial microbiome was characterized using 16S rDNA pyrosequencing and was correlated to clinical parameters as well as immune activation and circulating bacterial products in HIV patients on ART. The composition of the HIV microbiome was significantly different than that of controls; it was less diverse in the right colon and terminal ileum, and was characterized by loss of bacterial taxa that are typically considered commensals. In HIV samples, there was a gain of some pathogenic bacterial taxa. This is the first report characterizing the terminal ileal and colonic mucosal microbiome in HIV patients with next generation sequencing. Limitations include use of HIV-infected subjects on HAART therapy

Stacked histogram of bacterial composition in all samples by disease and site, to the family level of taxonomic resolution.

<p>Each column represents bacterial composition in one single sample (n = 121 for all samples; n = 65 for controls; n = 56 for HIV). Y- axis denotes abundance of bacterial taxa as a percentage within the sample, with each column totaling 100%. X-axis shows samples from healthy subjects to the left of the graph, and samples from HIV subjects to the right of the graph. TI = samples from terminal ileum; RC = samples from right colon; LC = samples from left colon; F = fecal samples. While all identified families are shown on the graph, sample coloring is grouped by phylogeny. Among the colors used, Bacteroidales are shown in brown tones, Bacilli are shown in orange tones, Clostridia are shown in red tones, Alphaproteobacteria are shown in green tones, Betaproteobacteria are shown in yellow tones, Gammaproteobacteria are shown in blue tones. Major differences between control and HIV samples are visually apparent based on difference in coloring of the samples.</p

PerMANOVA summary results.

<p>*Mean F reflects the mean result of 1000 observed F values after 1000 subsamplings, each with 4999 randomizations.</p

Sample diversity assessed by diversity indices in HIV cases versus controls by sample site.

<p>HIV cases have decreased diversity compared to controls. HIV samples are in red; Control samples are in blue. Diversity indices shown are OTU richness (panels (a–d)), Chao1 index (panels (e–h)), and Phylogenetic Diversity (PD) Whole Tree metric (panels (i–l)). Samples from ileum are shown in panels (a),(e),(i); samples from right colon are shown in panels (b),(f),(j) ; samples from left colon are shown in panels (c),(g),(k); and fecal samples are shown in panels (d),(h),(l).</p

Beta diversity measures in HIV versus controls.

<p>HIV samples appear separated from control samples in beta diversity analyses. HIV samples are in red; Control samples are in blue. Panel (a) shows nonmetric multidimensional scaling (NMDS) of all the samples using the Bray-Curtis similarity at the OTU level. Panel (b) shows principal coordinates analysis of all of the samples using the Unifrac metric at the OTU level. Panels (c–f) show principal coordinates analysis using the Unifrac metric, by sample site. Panels: (c) For samples from ileum; (d) For samples from right colon; (e) For samples from left colon; (f) For fecal samples.</p

Scatterplots of bacterial taxa indicative of HIV samples.

<p>Y-axis shows percent abundance in rarified sequences for each sample. Control samples are shown as black dots and HIV samples are shown as upward black triangles. Horizontal lines denote mean value in each group. P-values shown are results from indicator species analysis. Genera and those unclassified bacterial members of families that not able to be classified down to a particular genus, that also have indicator values >15 and p<0.05 are shown.</p