Major and Minor Group Rhinoviruses Elicit Differential Signaling and Cytokine Responses as a Function of Receptor-Mediated Signal Transduction

Major- and minor-group human rhinoviruses (HRV) enter their host by binding to the cell surface molecules ICAM-1 and LDL-R, respectively, which are present on both macrophages and epithelial cells. Although epithelial cells are the primary site of productive HRV infection, previous studies have implicated macrophages in establishing the cytokine dysregulation that occurs during rhinovirus-induced asthma exacerbations. Analysis of the transcriptome of primary human macrophages exposed to major- and minor-group HRV demonstrated differential gene expression. Alterations in gene expression were traced to differential mitochondrial activity and signaling pathway activation between two rhinovirus serotypes, HRV16 (major-group) and HRV1A (minor-group), upon initial HRV binding. Variances in phosphorylation of kinases (p38, JNK, ERK5) and transcription factors (ATF-2, CREB, CEBP-alpha) were observed between the major- and minor-group HRV treatments. Differential activation of signaling pathways led to changes in the production of the asthma-relevant cytokines CCL20, CCL2, and IL-10. This is the first report of genetically similar viruses eliciting dissimilar cytokine release, transcription factor phosphorylation, and MAPK activation from macrophages, suggesting that receptor use is a mechanism for establishing the inflammatory microenvironment in the human airway upon exposure to rhinovirus

The role of thrombospondins in wound healing, ischemia, and the foreign body reaction

Thrombospondin (TSP) 1 and TSP2 have been implicated in the regulation of several processes during tissue repair. Due to their matricellular nature, these proteins are thought to modulate cell-matrix interactions through a variety of mechanisms specific to the spatio-temporal context of their expression. Most notably, TSP1 and TSP2 appear to play distinct, non-overlapping roles in the healing of skin wounds. In contrast, both proteins have been implicated as regulators of ischemia-induced angiogenesis. Moreover, TSP2 has been shown to be a critical regulator of angiogenesis in the foreign body response (FBR). In this review, we discuss the role of TSPs in tissue repair and examine the mechanistic data regarding the ability of the thrombospondins to modulate cell-matrix interactions in this context

HIV-2 Integrase Variation in Integrase Inhibitor-Naïve Adults in Senegal, West Africa

Antiretroviral therapy for HIV-2 infection is hampered by intrinsic resistance to many of the drugs used to treat HIV-1. Limited studies suggest that the integrase inhibitors (INIs) raltegravir and elvitegravir have potent activity against HIV-2 in culture and in infected patients. There is a paucity of data on genotypic variation in HIV-2 integrase that might confer intrinsic or transmitted INI resistance.We PCR amplified and analyzed 122 HIV-2 integrase consensus sequences from 39 HIV-2-infected, INI-naive adults in Senegal, West Africa. We assessed genetic variation and canonical mutations known to confer INI-resistance in HIV-1.No amino acid-altering mutations were detected at sites known to be pivotal for INI resistance in HIV-1 (integrase positions 143, 148 and 155). Polymorphisms at several other HIV-1 INI resistance-associated sites were detected at positions 72, 95, 125, 154, 165, 201, 203, and 263 of the HIV-2 integrase protein.Emerging genotypic and phenotypic data suggest that HIV-2 is susceptible to the new class of HIV integrase inhibitors. We hypothesize that intrinsic HIV-2 integrase variation at "secondary" HIV-1 INI-resistance sites may affect the genetic barrier to HIV-2 INI resistance. Further studies will be needed to assess INI efficacy as part of combination antiretroviral therapy in HIV-2-infected patients

Characterization of thrombospondin synthesis, secretion and cell surface expression by human tumor cells

Previous studies have shown that thrombospondin (TSP) is an adhesion factor for some human tumor cells. The previous studies have shown further that tumor cells which utilize TSP as an adhesion factor also synthesize it. This study continues the effort to understand how TSP production and expression are regulated in human tumor cells and the consequences of this for the cells. It is shown that differences among cell lines in their capacity to biosynthesize TSP are associated with differences in TSP specific mRNA levels. This indicates that biosynthesis is regulated at the transcriptional level. There is also a direct relationship between TSP biosynthesis and secretion into the culture medium and expression at the cell surface. The cells which are the most biosynthetically active secrete amounts of TSP into the culture medium that are sufficient to elicit a detectable response in the cell-substrate adhesion assay. The kinetics of TSP secretion by these cells are in accord with the kinetics of attachment and spreading of the same cells in the absence of exogenous adhesion factors. These data are consistent with the idea that endogenously produced TSP promotes the adhesion of the cells which synthesize it in an autocrine manner.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42595/1/10585_2005_Article_BF01753679.pd

PLoS One

Introduction The long-term prognosis of HIV-2-infected patients receiving antiretroviral therapy (ART) is still challenging, due to the intrinsic resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI) and the suboptimal response to some protease inhibitors (PI). The objective was to describe the 5-years outcomes among HIV-2 patients harboring drug-resistant viruses. Methods A clinic-based cohort of HIV-2-patients experiencing virologic failure, with at least one drug resistance mutation was followed from January 2012 to August 2017 in Côte d’Ivoire. Follow-up data included death, lost to follow-up (LTFU), immuno-virological responses. The Kaplan-Meier curve was used to estimate survival rates. Results A total of 31 HIV-2 patients with virologic failure and with at least one drug resistance mutation were included. Two-third of them were men, 28(90.3%) were on PI-based ART-regimen at enrolment and the median age was 50 years (IQR = 46–54). The median baseline CD4 count and viral load were 456 cells/mm3 and 3.7 log10 c/mL respectively, and the participants have been followed-up in median 57 months (IQR = 24–60). During this period, 21 (67.7%) patients switched at least one antiretroviral drug, including two (6.5%) and three (9.7%) who switched to a PI-based and an integrase inhibitor-based regimen respectively. A total of 10(32.3%) patients died and 4(12.9%) were LTFU. The 36 and 60-months survival rates were 68.5% and 64.9%, respectively. Among the 17 patients remaining in care, six(35.3%) had an undetectable viral load (2. Conclusions The 36-months survival rate among ART-experienced HIV-2 patients with drug-resistant viruses is below 70%,lower than in HIV-1. There is urgent need to improve access to second-line ART for patients living with HIV-2 in West Afric