Search

The hallmark of HIV-1 and SIV infections is [CD4.sup.+] T cell depletion. Both direct cell killing and indirect mechanisms related to immune activation have been suggested to cause the depletion of T cells. We have now identified a mechanism by which immune activation-induced fibrosis of lymphoid tissues leads to depletion of naive T cells in HIV-1 infected patients and SIV-infected rhesus macaques. The T regulatory cell response to immune activation increased procollagen production and subsequent deposition as fibrils via the TGF-β1 signaling pathway and chitinase 3-like-1 activity in fibroblasts in lymphoid tissues from patients infected with HIV-1. Collagen deposition restricted T cell access to the survival factor IL-7 on the fibroblastic reticular cell (FRC) network, resulting in apoptosis and depletion of T cells, which, in turn, removed a major source of lymphotoxin-β, a survival factor for FRCs during SIV infection in rhesus macaques. The resulting loss of FRCs and the loss of IL-7 produced by FRCs may thus perpetuate a vicious cycle of depletion of T cells and the FRC network. Because this process is cumulative, early treatment and antifibrotic therapies may offer approaches to moderate T cell depletion and improve immune reconstitution during HIV-1 infection., Introduction Depletion of [CD4.sup.+] T cells, the defining characteristic for which the immunodeficiency viruses HIV-1 and SIV were named, has been attributed to direct mechanisms of infection and cell killing [...]

Natural SIV infection of sooty mangabeys (SMs) is nonprogressive despite chronic virus replication. Strikingly, it is characterized by low levels of immune activation, while pathogenic SIV infection of rhesus macaques (RMs) is associated with chronic immune activation. To elucidate the mechanisms underlying this intriguing phenotype, we used high-density oligonucleotide microarrays to longitudinally assess host gene expression in SIV-infected SMs and RMs. We found that acute SIV infection of SMs was consistently associated with a robust innate immune response, including widespread upregulation of IFN-stimulated genes (ISGs) in blood and lymph nodes. While SMs exhibited a rapid resolution of ISG expression and immune activation, both responses were observed chronically in RMs. Systems biology analysis indicated that expression of the lymphocyte inhibitory receptor LAG3, a marker of T cell exhaustion, correlated with immune activation in SIV-infected RMs but not SMs. Our findings suggest that active immune regulatory mechanisms, rather than intrinsically attenuated innate immune responses, underlie the low levels of immune activation characteristic of SMs chronically infected with SIV., Introduction HIV infection is characterized by progressive depletion of [CD4.sup.+] T cells that eventually results in clinically significant immunodeficiency. Although development of AIDS occurs years after primary HIV infection, it [...]

Although there has been great progress in treating human immunodeficienry virns 1 (HIV-1) infection (1), preventing transmission has thus far proven an elusive goal. Indeed, recent trials of a candidate vaccine and microbicide have been disappointing, both for want of efficacy and concerns about increased rates of transmission (2-4). Nonetheless, studies of vaginal transmission in the simian immunodeficienry virus (SIV)-rhesus macaque (Macacca mulatta) model point to opportunities at the earliest stages of infection in which a vaccine or microbicide might be protective, by limiting the expansion of infected founder populations at the portal of entrys (5-6). Here we show in this SIV-macaque model, that an outside-in endocervical mucosal signalling system, involving MIP-3 α (also known as CCL20), plasmarytoid dendritic cells and [CCR5.sup.+] cell-attracting chemokines produced by these cells, in combination with the innate immune and inflammatory responses to infection in both cervix and vagina, recrnits [CD4.sup.+] T cells to fuel this obligate expansion. We then show that glycerol monolaurate--a widely used antimicrobial compound (7) with inhibitory activity against the production of MIP-3α and other proinflammatory cytokines (8)--can inhibit mucosal signalling and the innate and inflammatory response to HIV-1 and SIV in vitro, and in vivo it can protect rhesus macaques from acute infection despite repeated intra-vaginal exposure to high doses of SIV. This new approach, plausibly linked to interfering with innate host responses that recruit the target cells necessary to establish systemic infection, opens a promising new avenue for the development of effective interventions to block HIV-1 mucosal transmission., To understand how SIV infection in a small founder population of cells at the portal of entry transitions in less than two weeks to systemic infection, with massive levels of [...]

In the early stages of viral infection, outcomes depend on a race between expansion of infection and the immune response generated to contain it. We combined in situ tetramer staining with in situ hybridization to visualize, map, and quantify relationships between immune effector cells and their targets in tissues. In simian immunodeficiency virus infections in macaques and lymphocytic choriomeningitis virus infections in mice, the magnitude and timing of the establishment of an excess of effector ceils versus targets were found to correlate with the extent of control and the infection outcome (i.e., control and clearance versus partial or poor control and persistent infection). This method highlights the importance of the location, timing, and magnitude of the immune response needed for a vaccine to be effective against agents of persistent infection, such as HIV-1.

The ranging patterns of female chimpanzees were observed over eighteen years at Gombe National Park in Tanzania. It was found that there is considerable variety among female ranging patterns but in general female ranging patterns supported the male-bonded model of chimpanzee social systems.

Abstract Background Visualizing 3-dimensional (3-D) datasets is an important part of modern neuroimaging research. Many tools address this problem; however, they often fail to address specific needs and flexibility, such as the ability to work with different data formats, to control how and what data are displayed, to interact with values, and to undo mistakes. Results iiV, an interactive software program for displaying 3-D brain images, is described. This tool was programmed to solve basic problems in 3-D data visualization. It is written in Java so it is extensible, is platform independent, and can display images within web pages. iiV displays 3-D images as 2-dimensional (2-D) slices with each slice being an independent object with independent features such as location, zoom, colors, labels, etc. Feature manipulation becomes easier by having a full set of editing capabilities including the following: undo or redo changes; drag, copy, delete and paste objects; and save objects with their features to a file for future editing. It can read multiple standard positron emission tomography (PET) and magnetic resonance imaging (MRI) file formats like ECAT, ECAT7, ANALYZE, NIfTI-1 and DICOM. We present sample applications to illustrate some of the features and capabilities. Conclusion iiV is an image display tool with many useful features. It is highly extensible, platform independent, and web-compatible. This report summarizes its features and applications, while illustrating iiV's usefulness to the biomedical imaging community.

Background: Oral cancer survival rates increase significantly when it is detected and treated early. Unfortunately, clinicians now lack tests which easily and reliably distinguish pre-malignant oral lesions from those already transitioned to malignancy. A test for proteins, ones found in non-invasively-collected whole saliva and whose abundances distinguish these lesion types, would meet this critical need. Methodology/Principal Findings: To discover such proteins, in a first-of-its-kind study we used advanced mass spectrometry-based quantitative proteomics analysis of the pooled soluble fraction of whole saliva from four subjects with pre-malignant lesions and four with malignant lesions. We prioritized candidate biomarkers via bioinformatics and validated selected proteins by western blotting. Bioinformatic analysis of differentially abundant proteins and initial western blotting revealed increased abundance of myosin and actin in patients with malignant lesions. We validated those results by additional western blotting of individual whole saliva samples from twelve other subjects with pre-malignant oral lesions and twelve with malignant oral lesions. Sensitivity/specificity values for distinguishing between different lesion types were 100%/75% (p = 0.002) for actin, and 67%/83% (p<0.00001) for myosin in soluble saliva. Exfoliated epithelial cells from subjects' saliva also showed increased myosin and actin abundance in those with malignant lesions, linking our observations in soluble saliva to abundance differences between pre-malignant and malignant cells. Conclusions/Significance: Salivary actin and myosin abundances distinguish oral lesion types with sensitivity and specificity rivaling other non-invasive oral cancer tests. Our findings provide a promising starting point for the development of noninvasive and inexpensive salivary tests to reliably detect oral cancer early. [ABSTRACT FROM AUTHOR]

Summary: RIPPER is a framework for mass-spectrometry-based label-free relative quantification for proteomics and metabolomics studies. RIPPER combines a series of previously described algorithms for pre-processing, analyte quantification, retention time alignment, and analyte grouping across runs. It is also the first software framework to implement proximity-based intensity normalization. RIPPER produces lists of analyte signals with their unnormalized and normalized intensities that can serve as input to statistical and directed mass spectrometry (MS) methods for detecting quantitative differences between biological samples using MS. Availability and implementation: http://www.z.umn.edu/ripper. [ABSTRACT FROM AUTHOR]

The enteropathic manifestations of the human immunodeficiency virus (HIV) and the simian immunodeficiency virus (SIV) in late infection are usually due to infection by other microbes, but in early infection the viruses themselves cause an enteropathy by heretofore undetermined mechanisms. Here we report that SIV induces massive apoptosis of intestinal epithelial cells lining the small and large bowel, thus identifying apoptosis as the driving force behind the regenerative pathology of early infection. We found that apoptosis of gut epithelium paralleled the previously documented apoptosis and massive depletion of CD4 T cells in gut lamina propria, triggered by established mechanisms of gut epithelial cell apoptosis and, at peak, possibly by virus interactions with GPR15/Bob, an intestinal epithelial cell-associated alternative coreceptor for SIV and HIV-1. Apoptosis in early SIV infection is thus the common theme of the pathological processes that quickly afflict the innate as well as adaptive arms of the gut immune system. [ABSTRACT FROM AUTHOR]

Background: Visualizing 3-dimensional (3-D) datasets is an important part of modern neuroimaging research. Many tools address this problem; however, they often fail to address specific needs and flexibility, such as the ability to work with different data formats, to control how and what data are displayed, to interact with values, and to undo mistakes. Results: iiV, an interactive software program for displaying 3-D brain images, is described. This tool was programmed to solve basic problems in 3-D data visualization. It is written in Java so it is extensible, is platform independent, and can display images within web pages. iiV displays 3-D images as 2-dimensional (2-D) slices with each slice being an independent object with independent features such as location, zoom, colors, labels, etc. Feature manipulation becomes easier by having a full set of editing capabilities including the following: undo or redo changes; drag, copy, delete and paste objects; and save objects with their features to a file for future editing. It can read multiple standard positron emission tomography (PET) and magnetic resonance imaging (MRI) file formats like ECAT, ECAT7, ANALYZE, NIfTI-1 and DICOM. We present sample applications to illustrate some of the features and capabilities. Conclusion: iiV is an image display tool with many useful features. It is highly extensible, platform independent, and web-compatible. This report summarizes its features and applications, while illustrating iiV's usefulness to the biomedical imaging community. [ABSTRACT FROM AUTHOR]

Discusses factors affecting a successful interdisciplinary scientific database research. Importance of collaboration between computer scientist and biologist; Advances in computing system; Advances in specific data capture technology.

Focuses on the knowledge of engineers to use expert system shells to develop production-rule-based expert system applications. Problems explored on the use of data-based management; Identification of the features of this system; Examination of basic syntactic components in relation to this topic; Exploration of similarities and differences in syntax in relation to this topic. INSET: Related work..

Live attenuated vaccines such as SIV with a deleted nef gene have provided the most robust protection against subsequent vaginal challenge with wild-type (WT) SIV in the SIV-rhesus macaque model of HIV-1 transmission to women. Hence, identifying correlates of this protection could enable design of an effective HIV-1 vaccine. One such prechallenge correlate of protection from vaginal challenge has recently been identified as a system with three components: 1) IgG Abs reacting with the viral envelope glycoprotein trimeric gp41; 2) produced by plasma cells in the submucosa and ectopic tertiary lymphoid follicles in the ectocervix and vagina; and 3) concentrated on the path of virus entry by the neonatal FcR in the overlying epithelium. We now examine the mucosal production of the Ab component of this system after vaginal challenge. We show that vaginal challenge immediately elicits striking increases in plasma cells not only in the female reproductive tract but also at other mucosal sites, and that these increases correlate with low but persistent replication at mucosal sites. We describe vaginal ectopic follicles that are structurally and functionally organized similar to follicles in secondary lymphoid organs, and we provide inferential evidence for a key role of the female reproductive tract epithelium in facilitating Ab production, affinity maturation, and class switch recombination. Vaccination thus accesses an epithelial-immune system axis in the female reproductive tract to respond to exposure to mucosal pathogens. Designing strategies to mimic this system could advance development of an effective HIV-1 vaccine. [ABSTRACT FROM AUTHOR]

Principles to guide design of an effective vaccine against HIV are greatly needed, particularly to protect women in the pandemic’s epicenter in Africa. We have been seeking these principles by identifying correlates of the robust protection associated with SIVmac239Δnef vaccination in the SIV-rhesus macaque animal model of HIV-1 transmission to women. We identified one correlate of SIVmac239Δnef protection against vaginal challenge as a resident mucosal system for SIV-gp41 trimer Ab production and neonatal FcR-mediated concentration of these Abs on the path of virus entry to inhibit establishment of infected founder populations at the portal of entry. In this study, we identify blocking CD4+ T cell recruitment to thereby inhibit local expansion of infected founder populations as a second correlate of protection. Virus-specific immune complex interactions with the inhibitory FcγRIIb receptor in the epithelium lining the cervix initiate expression of genes that block recruitment of target cells to fuel local expansion. Immune complex–FcγRIIb receptor interactions at mucosal frontlines to dampen the innate immune response to vaginal challenge could be a potentially general mechanism for the mucosal immune system to sense and modulate the response to a previously encountered pathogen. Designing vaccines to provide protection without eliciting these transmission-promoting innate responses could contribute to developing an effective HIV-1 vaccine. [ABSTRACT FROM AUTHOR]

We sought design principles for a vaccine to prevent HIV transmission to women by identifying correlates of protection conferred by a highly effective live attenuated SIV vaccine in the rhesus macaque animal model. We show that SIVmac239Δnef vaccination recruits plasma cells and induces ectopic lymphoid follicle formation beneath the mucosal epithelium in the rhesus macaque female reproductive tract. The plasma cells and ectopic follicles produce IgG Abs reactive with viral envelope glycoprotein gp41 trimers, and these Abs are concentrated on the path of virus entry by the neonatal FcR in cervical reserve epithelium and in vaginal epithelium. This local Ab production and delivery system correlated spatially and temporally with the maturation of local protection against high-dose pathogenic SIV vaginal challenge. Thus, designing vaccines to elicit production and concentration of Abs at mucosal frontlines could aid in the development of an effective vaccine to protect women against HIV-1. [ABSTRACT FROM AUTHOR]

The hallmark of HIV-1 and SIV infections is CD4(+) T cell depletion. Both direct cell killing and indirect mechanisms related to immune activation have been suggested to cause the depletion of T cells. We have now identified a mechanism by which immune activation-induced fibrosis of lymphoid tissues leads to depletion of naive T cells in HIV-1 infected patients and SIV-infected rhesus macaques. The T regulatory cell response to immune activation increased procollagen production and subsequent deposition as fibrils via the TGF-β1 signaling pathway and chitinase 3-like-1 activity in fibroblasts in lymphoid tissues from patients infected with HIV-1. Collagen deposition restricted T cell access to the survival factor IL-7 on the fibroblastic reticular cell (FRC) network, resulting in apoptosis and depletion of T cells, which, in turn, removed a major source of lymphotoxin-β, a survival factor for FRCs during SIV infection in rhesus macaques. The resulting loss of FRCs and the loss of IL-7 produced by FRCs may thus perpetuate a vicious cycle of depletion of T cells and the FRC network. Because this process is cumulative, early treatment and antifibrotic therapies may offer approaches to moderate T cell depletion and improve immune reconstitution during HIV-1 infection. [ABSTRACT FROM AUTHOR]

In the early stages of viral infection, outcomes depend on a race between expansion of infection and the immune response generated to contain it. We combined in situ tetramer staining with in situ hybridization to visualize, map, and quantify relationships between immune effector cells and their targets in tissues. In simian immunodeficiency virus infections in macaques and lymphocytic choriomeningitis virus infections in mice, the magnitude and timing of the establishment of ah excess of effector cells versus targets were found to correlate with the extent of control and the infection outcome (i.e., control and clearance versus partial or poor control and persistent infection). This method highlights the importance of the location, timing, and magnitude of the immune response needed for a vaccine to be effective against agents of persistent infection, such as HIV-1. [ABSTRACT FROM AUTHOR]