Inhibitory Killer Immunoglobulin-like receptors to self HLA-B and HLA-C ligands contribute differentially to Natural Killer cell functional potential in HIV infected Slow Progressors

Ce manuscrit est une pré-publication d'un article paru dans Clinical Immunology 2012; 143(3): 246-255 url: http://www.journals.elsevier.com/clinical-immunology/IRSC et FRSQ - Réseau SIDA et maladies infectieuse

Longitudinal changes in HIV-specific IFN-γ secretion in subjects who received Remune™ vaccination prior to treatment interruption

BACKGROUND: Despite the benefits of highly active antitretroviral therapy (HAART) for suppressing viral replication in HIV infection, virus persists and rebounds during treatment interruption (TI). This study explored whether HAART intensification with Remune™ vaccination before TI can boost HIV-1-specific immunity, leading to improved control of viremia off HAART. METHODS: Ten chronically HIV-infected adults were enrolled in this proof of concept study. After a 6-month HAART intensification phase with didanosine, hydroxyurea, granulocyte-macrophage colony-stimulating factor, (GM-CSF), and a first dose of Remune™ (HIV-1 Immunogen), HAART was discontinued. Patients continued to receive Remune™ every 3 months until the end of study. HAART was restarted if viral load did not fall below 50,000 copies/ml of plasma within 3 months or if CD4+ counts decreased to <200 cells/mm(3). HIV-specific immunity was monitored with the interferon-γ (IFN-γ) ELISPOT assay. RESULTS: All subjects experienced viral rebound during TIs. Although the magnitude and breadth of HIV-specific responses to HLA-restricted optimal peptide panels and Gag p55 peptide pools increased and viral load decreased by 0.44 log(10 )units from TI#1 to TI#2, no significant correlations between these parameters were observed. The patients spent 50.4% of their 36 months follow up off HAART. CONCLUSION: Stopping HAART in this vaccinated population induced immune responses that persisted after therapy was restarted. Induction of HIV-specific immunity beyond IFN-γ secretion may be contributing to better control of viremia during subsequent TIs allowing for long periods off HAART

Mechanisms of Transcranial Doppler Ultrasound phenotypes in paediatric cerebral malaria remain elusive.

BACKGROUND: Cerebral malaria (CM) results in significant paediatric death and neurodisability in sub-Saharan Africa. Several different alterations to typical Transcranial Doppler Ultrasound (TCD) flow velocities and waveforms in CM have been described, but mechanistic contributors to these abnormalities are unknown. If identified, targeted, TCD-guided adjunctive therapy in CM may improve outcomes. METHODS: This was a prospective, observational study of children 6 months to 12 years with CM in Blantyre, Malawi recruited between January 2018 and June 2021. Medical history, physical examination, laboratory analysis, electroencephalogram, and magnetic resonance imaging were undertaken on presentation. Admission TCD results determined phenotypic grouping following a priori definitions. Evaluation of the relationship between haemodynamic, metabolic, or intracranial perturbations that lead to these observed phenotypes in other diseases was undertaken. Neurological outcomes at hospital discharge were evaluated using the Paediatric Cerebral Performance Categorization (PCPC) score. RESULTS: One hundred seventy-four patients were enrolled. Seven (4%) had a normal TCD examination, 57 (33%) met criteria for hyperaemia, 50 (29%) for low flow, 14 (8%) for microvascular obstruction, 11 (6%) for vasospasm, and 35 (20%) for isolated posterior circulation high flow. A lower cardiac index (CI) and higher systemic vascular resistive index (SVRI) were present in those with low flow than other groups (p \u3c 0.003), though these values are normal for age (CI 4.4 [3.7,5] l/min/m2, SVRI 1552 [1197,1961] dscm-5m2). Other parameters were largely not significantly different between phenotypes. Overall, 118 children (68%) had a good neurological outcome. Twenty-three (13%) died, and 33 (19%) had neurological deficits. Outcomes were best for participants with hyperaemia and isolated posterior high flow (PCPC 1-2 in 77 and 89% respectively). Participants with low flow had the least likelihood of a good outcome (PCPC 1-2 in 42%) (p \u3c 0.001). Cerebral autoregulation was significantly better in children with good outcome (transient hyperemic response ratio (THRR) 1.12 [1.04,1.2]) compared to a poor outcome (THRR 1.05 [0.98,1.02], p = 0.05). CONCLUSIONS: Common pathophysiological mechanisms leading to TCD phenotypes in non-malarial illness are not causative in children with CM. Alternative mechanistic contributors, including mechanical factors of the cerebrovasculature and biologically active regulators of vascular tone should be explored

The Grizzly, November 22, 1994

Pew Roundtable Discusses Priorities at Ursinus • Clinton Wavers on School Prayer • Letters to the Editor: Parent Shows Concern Over Alcohol • Man Arrested for Threatening Children • Class of \u2798 Update • Iraq Recognizes Kuwait • Final Exam Schedule • Berman Features Watercolor Exhibit • Lady Bears Preseason Outlook • Ursinus\u27 All-Centennial Conference Performershttps://digitalcommons.ursinus.edu/grizzlynews/1348/thumbnail.jp

Immune correlates of CD4 decline in HIV-infected patients experiencing virologic failure before undergoing treatment interruption

<p>Abstract</p> <p>Background</p> <p>The advantage of treatment interruptions (TIs) in salvage therapy remains controversial. Regardless, characterizations of the correlates of CD4 count fall during TI are important to identify since patients with virologic failure commonly stop antiretroviral (ARV) therapy. The objective of this study was to determine the predictive value of pre-TI proliferative capacity and cell surface markers for CD4 count change in HIV-infected patients experiencing virologic failure before undergoing TI.</p> <p>Methods</p> <p>Peripheral blood mononuclear cells (PBMCs) from 13 HIV-infected patients experiencing virologic failure at baseline time points before the TI were tested for proliferation using the 5,6-carboxyfluorescein diacetate succinimidyl ester (CFSE) dilution assay and a Gag p55 peptide pool, staphylococcus enterotoxin B (SEB), cytomegalovirus (CMV) recall antigen, and anti-CD3 antibody as stimuli. CD28 and CD57 expression on CD4+ and CD8+ T-cells was measured.</p> <p>Results</p> <p>The median changes in the CD4+ T-cell count and viral load from baseline to the TI time point corresponding to the CD4 count nadir were -44 cells/mm³{Interquartile range (IQR) -17, -104} and +85,332 copies/mL (IQR +11,198, +283,327), respectively. CD4+ T-cell proliferation to CMV, pre-TI CD4+ T-cell count, and percent CD4+CD57+ cells correlated negatively with CD4 count change during TI (r = -0.59, p = 0.045, r = -0.61, p = 0.030 and r = -0.69, p = 0.0095, respectively; Spearman correlation). The presence of HIV-specific proliferative responses was not associated with a reduced decline in CD4 count during TI.</p> <p>Conclusion</p> <p>The use of pre-TI immune proliferative responses and cell surface markers may have predictive value for CD4 count decline during TI.</p

Host-like carbohydrates promote bloodstream survival of Vibrio vulnificus in vivo

Sialic acids are found on all vertebrate cell surfaces and are part of a larger class of molecules known as nonulosonic acids. Many bacterial pathogens synthesize related nine-carbon backbone sugars; however, the role(s) of these non-sialic acid molecules in host-pathogen interactions is poorly understood. Vibrio vulnificus is the leading cause of seafood-related death in the United States due to its ability to quickly access the host bloodstream, which it can accomplish through gastrointestinal or wound infection. However, little is known about how this organism persists systemically. Here we demonstrate that sialic acid-like molecules are present on the lipopolysaccharide of V. vulnificus, are required for full motility and biofilm formation, and also contribute to the organism's natural resistance to polymyxin B. Further experiments in a murine model of intravenous V. vulnificus infection demonstrated that expression of nonulosonic acids had a striking benefit for bacterial survival during bloodstream infection and dissemination to other tissues in vivo. In fact, levels of bacterial persistence in the blood corresponded to the overall levels of these molecules expressed by V. vulnificus isolates. Taken together, these results suggest that molecules similar to sialic acids evolved to facilitate the aquatic lifestyle of V. vulnificus but that their emergence also resulted in a gain of function with life-threatening potential in the human host

vitro and ex vivo testing of tenofovir shows it is effective as an HIV-1 microbicide

Abstract Background: Tenofovir gel has entered into clinical trials for use as a topical microbicide to prevent HIV-1 infection but has no published data regarding pre-clinical testing using in vitro and ex vivo models. To validate our findings with on-going clinical trial results, we evaluated topical tenofovir gel for safety and efficacy. We also modeled systemic application of tenofovir for efficacy