Systemic inhibition of myeloid dendritic cells by circulating HLA class I molecules in HIV-1 infection

<p>Abstract</p> <p>Background</p> <p>HIV-1 infection is associated with profound dysfunction of myeloid dendritic cells, for reasons that remain ill-defined. Soluble HLA class I molecules can have important inhibitory effects on T cells and NK cells, but may also contribute to reduced functional properties of professional antigen-presenting cells. Here, we investigated the expression of soluble HLA class I isoforms during HIV-1 infection and assessed their functional impact on antigen-presenting characteristics of dendritic cells.</p> <p>Results</p> <p>Soluble HLA class I molecules were highly upregulated in progressive HIV-1 infection as determined by quantitative Western blots. This was associated with strong increases of intracellular expression of HLA class I isoforms in dendritic cells and monocytes. Using mixed lymphocyte reactions, we found that soluble HLA class I molecules effectively inhibited the antigen-presenting properties of dendritic cells, however, there was no significant influence of HLA class I molecules on the cytokine-secretion properties of these cells. The immunomodulatory effects of soluble HLA class I molecules were mediated by interactions with inhibitory myelomonocytic MHC class I receptors from the Leukocyte Immunoglobulin Like Receptor (LILR) family.</p> <p>Conclusions</p> <p>During progressive HIV-1 infection, soluble HLA class I molecules can contribute to systemic immune dysfunction by inhibiting the antigen-presenting properties of myeloid dendritic cells through interactions with inhibitory myelomonocytic HLA class I receptors.</p

Human properdin modulates macrophage: Mycobacterium bovis BCG interaction via thrombospondin repeats (TSR) 4 and 5

Mycobacterium tuberculosis can proficiently enter macrophages and diminish complement activation on its cell surface. Within macrophages, the mycobacterium can suppress macrophage apoptosis and survive within the intracellular environment. Previously, we have shown that complement regulatory proteins such as factor H may interfere with pathogen–macrophage interactions during tuberculosis infection. In this study, we show that Mycobacterium bovis BCG binds properdin, an upregulator of the complement alternative pathway. TSR4+5, a recombinant form of thrombospondin repeats 4 and 5 of human properdin expressed in tandem, which is an inhibitor of the alternative pathway, was also able to bind to M. bovis BCG. Properdin and TSR4+5 were found to inhibit uptake of M. bovis BCG by THP-1 macrophage cells in a dose-dependent manner. Quantitative real-time PCR revealed elevated pro-inflammatory responses (TNF-α, IL-1β, and IL-6) in the presence of properdin or TSR4+5, which gradually decreased over 6 h. Correspondingly, anti-inflammatory responses (IL-10 and TGF-β) showed suppressed levels of expression in the presence of properdin, which gradually increased over 6 h. Multiplex cytokine array analysis also revealed that properdin and TSR4+5 significantly enhanced the pro-inflammatory response (TNF-α, IL-1β, and IL-1α) at 24 h, which declined at 48 h, whereas the anti-inflammatory response (IL-10) was suppressed. Our results suggest that properdin may interfere with mycobacterial entry into macrophages via TSR4 and TSR5, particularly during the initial stages of infection, thus affecting the extracellular survival of the pathogen. This study offers novel insights into the non-complement related functions of properdin during host–pathogen interactions in tuberculosis.MA-A has been supported by the Ministry of Higher Education, Malaysia and the Universiti Sains Malaysia

HIV-Care Outcome in Saudi Arabia; a Longitudinal Cohort

Background: Clinical characteristics of HIV-1 infection in people inhabiting Western, Sub-Saharan African, and South-East Asian countries are well recognized. However, very little information is available with regard to HIV-1 infection and treatment outcome in MENA countries including the Gulf Cooperation Council (GCC) states. Methods: Clinical, demographic and epidemiologic characteristics of 602 HIV-1 infected patients followed in the adult Infectious Diseases Clinic of King Faisal Specialist Hospital and Research Centre, in Riyadh, Kingdom of Saudi Arabia a tertiary referral center were longitudinally collected from 1989 to 2010. Results: Of the 602 HIV-1 infected patients in this observation period, 70% were male. The major mode of HIV-1 transmission was heterosexual contact (55%). At diagnosis, opportunistic infections were found in 49% of patients, most commonly being pneumocysitis. AIDS associated neoplasia was also noted in 6% of patients. A hundred and forty-seven patients (24%) died from the cohort by the end of the observation period. The mortality rate peaked in 1992 at 90 deaths per 1000 person-year, whereas the mortality rate gradually decreased to <1% from 1993-2010. In 2010, 71% of the patients were receiving highly active retroviral therapy. Conclusions: These data describe the clinical characteristic of HIV-1-infected patients at a major tertiary referral hospital in KSA over a 20-year period. Initiation of antiretroviral therapy resulted in a significant reduction in both morbidity and mortality. Future studies are needed in the design and implementation of targeted treatment and prevention strategies for HIV-1 infection in KSA

Surfactant protein D inhibits HIV-1 infection of target cells via interference with gp120-CD4 interaction and modulates pro-inflammatory cytokine production

© 2014 Pandit et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Surfactant Protein SP-D, a member of the collectin family, is a pattern recognition protein, secreted by mucosal epithelial cells and has an important role in innate immunity against various pathogens. In this study, we confirm that native human SP-D and a recombinant fragment of human SP-D (rhSP-D) bind to gp120 of HIV-1 and significantly inhibit viral replication in vitro in a calcium and dose-dependent manner. We show, for the first time, that SP-D and rhSP-D act as potent inhibitors of HIV-1 entry in to target cells and block the interaction between CD4 and gp120 in a dose-dependent manner. The rhSP-D-mediated inhibition of viral replication was examined using three clinical isolates of HIV-1 and three target cells: Jurkat T cells, U937 monocytic cells and PBMCs. HIV-1 induced cytokine storm in the three target cells was significantly suppressed by rhSP-D. Phosphorylation of key kinases p38, Erk1/2 and AKT, which contribute to HIV-1 induced immune activation, was significantly reduced in vitro in the presence of rhSP-D. Notably, anti-HIV-1 activity of rhSP-D was retained in the presence of biological fluids such as cervico-vaginal lavage and seminal plasma. Our study illustrates the multi-faceted role of human SPD against HIV-1 and potential of rhSP-D for immunotherapy to inhibit viral entry and immune activation in acute HIV infection. © 2014 Pandit et al.The work (Project no. 2011-16850) was supported by Medical Innovation Fund of Indian Council of Medical Research, New Delhi, India (www.icmr.nic.in/)

Epstein-Barr virus BART gene products

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Personalized medicine: Is it time for infectious diseases?

[No Abstract Available

Macromolecular Structure Underlying Recognition in Innate Immunity

Immune molecules have evolved to distinguish “self “molecules from “non-self”, “altered self” and “danger” molecules. Recognition is mediated via interactions between pattern recognition receptor molecules (PPRs) and their ligands, which include hydrophobic and electrostatic interactions between amino acid residues on the PPRs and uncharged or charged groups on amino acid residues, sugar rings or DNA/RNA molecules. Recognition in innate immunity range from cases (C1q, mannin-binding protein etc) where recognition is orchestrated by interaction between many ligands with one receptor molecule, and density of interaction is necessary for strong specific recognition, distinct from weak non-specific binding, and cases such as TLRs and NLRs where recognition involves complexation of single receptor and ligand, followed by oligomerisation of the receptor molecule. The majority of PPR molecules bind and recognise a wide variety of ligands, e.g TLR4 recognises LPS (gram negative bacteria), Lipotechoic acid (gram positive bacteria), heat shock protein hsp60, respiratory syncytial virus fusion protein etc, molecules that are structurally dissimilar to each other. This indicates considerable flexibility in their binding domains (amino acid residue variations) and modes (hydrophobic and charged, direct or mediated via an adaptor molecule). However, in many cases there is a dearth of structural and molecular data available, required to delineate the mechanism of ligand binding underlining recognition in pathogen receptors in innate immunity. Insights into requirements of conformation, charge, surface etc in the recognition and function of innate immunity receptors and their activation pathways, based on current data can suggest valuable avenues for future work

Antiretroviral resistance in HIV-1 patients at a tertiary medical institute in Saudi Arabia: a retrospective study and analysis

Abstract Background Since the early 90’s antiretroviral drugs have been available at King Faisal Specialist Hospital and Research Centre (KFSH&RC), a referral hospital in Riyadh, Saudi Arabia, for the treatment of both adults and children infected with HIV-1. However, up to date, there are no genetic profiling data for the resistance-causing mutations in HIV-1 virus in patients on antiretroviral drugs therapy. This paper presents an initial report and a profiling survey of drug resistance-associated mutations of 103 HIV-1 patients seen at KFSH&RC. Methods This is a retrospective study on Patients treated at KFSH&RC since 2003 up to 2016. The analysis was done on the drug resistance mutations profiles of 103 patients who were undergoing highly active antiretroviral therapy protocols. Results Our analysis shows that the drug resistance mutations reported in our treatment cohort of HIV-infected adults patients is similar what is internationally reported to some extent. Additionally, we have identified novel drug resistance causing mutations. Furthermore, different profile of drug resistance causing mutations was also observed. Conclusion Patients showed both similar and new drug resistant causing mutations, early identification of these mutations is crucial to guide and avoid failure future therapy

Cell cycle disruption and apoptotic activity of 3-aminothiazolo[3,2-a]benzimidazole-2-carbonitrile and its homologues

3-aminothiazolo[3,2-a]benzimidazole-2-carbonitrile (2) was prepared and upon hydrolysis using concentrated sulfuric acid or phosphoric acid resulted in the corresponding 3-aminothiazolo[3,2-a]benzimidazole-2-carboxamide derivative (3). Cyclization of the 2 using acetic anhydride or formic acid gave the corresponding pyrimido[4',5':4,5]thiazolo[3,2-a]benzimidazol-4(3H)-one (5) in good yields. Acetylation of 2 with acetic anhydride in pyridine afforded N-acetylaminothiazolo[3,2-a]benzimidazole-2-carbonitrile (6). In vitro antiproliferative activities of synthesized compounds were investigated at The National Cancer Institute (NCI), USA, according to their applied protocol. Compound 6 revealed significant antiproliferative activity, however, weak activity was shown by the other derivatives. Cell cycle disruption and apoptotic activity of 6 were studied, interestingly, 6 has the ability to arrest G2/M phase and it can induce apoptosis in time dependent manner. Copyright (c) 2010 Elsevier Masson SAS. All rights reserve

Molecular epidemiology and genotyping of TT virus isolated from Saudi blood donors and hepatitis patients

<b>Background: </b> In Saudi Arabia, the epidemiology and clinical signifi-nance of Torque Teno virus (TTV) infection alone and in patients with hepatitis virus infections have not been determined in a single study. In this paper, we molecularly investigated the rate and genotypes of TTV in-fection among Saudi Arabian blood donors and patients with viral hepa-titis. The effect of TTV coinfection on viral hepatitis was also examined. <b> Subjects and Methods: </b> DNA was extracted from the sera of 200 healthy blood volunteers, 45 hepatitis B virus patients, 100 hepatitis C virus patients, 19 hepatitis G virus patients, and 56 non-A-G hepatitis patients. TTV DNA was amplified using primers derived from the ORF1 and 5&#x2032;UTR regions. The alanine aminotransferase (ALT) level was deter-mined for each specimen. Sequencing of ORF1 amplicons was carried out to investigate TTV genotypes. <b> Results: </b> Using primers derived from ORF1 and 5&#x2032;UTR, TTV DNA was detected in 5.5&#x0025; and 50.5&#x0025;, respectively, of healthy blood donors, in 2.2&#x0025; and 88.8&#x0025; in hepatitis B patients, in 2.0&#x0025; and 70&#x0025; of hepatitis C patients, in 15.8&#x0025; and 100&#x0025; of hepatitis G patients, in 5.4&#x0025; and 12.5&#x0025; of non-A-G hepatitis patients and in 4.8&#x0025; and 56.4&#x0025; overall. No detrimental effect of TTV coinfection in viral hepatitis patients was noted. An overall prevalence of 4.8&#x0025; and 56.4&#x0025; was established. Phylogenetic analysis indicated that the most common genotype of TTV among Saudis is 2c. <b> Conclusion: </b> The rate of TTV infection among Saudi Arabians seems to be lower than that stated in previous reports on Saudi Arabia and in some other countries. The virus does not seem to worsen the status of those who are suffering from viral hepatitis infection