Adrian J. Puren

Interleukin-18 (IFNgamma-inducing factor) induces IL-8 and IL-1beta via TNFalpha production from non-CD14+ human blood mononuclear cells.

IL-18 is synthesized as a precursor molecule without a signal peptide but requires the IL-1beta converting enzyme (ICE, caspase-1) for cleavage into a mature peptide. Human precursor IL-18 was expressed, purified, and cleaved by ICE into a 18-kD mature form. Mature IL-18 induced IL-8, macrophage inflammatory protein-1alpha, and monocyte chemotactic protein-1 in human peripheral blood mononuclear cells in the absence of any co-stimuli. Blocking IL-1 with IL-1 receptor antagonist resulted in a 50% reduction in IL-8. Neutralization of TNF with TNF binding protein resulted in a 66% reduction in IL-1beta, an 80% reduction of IL-8, and an 88% reduction in mean TNFalpha mRNA. In purified CD14+ cells but not CD3+/CD4+, IL-18 induced gene expression and synthesis of IL-8 and IL-1beta. TNFalpha production was induced in the non-CD14+ population and there was no induction of TNFbeta by IL-18. In purified natural killer cells, IL-18 induced IL-8 that was also inhibited by TNF binding protein. IL-18 did not induce antiinflammatory cytokines, IL-1Ra, or IL-10, although IL-18 induction of TNFalpha was inhibited by IL-10. In the presence of IFNgamma, IL-18-induced TNFalpha was enhanced and there was an increase in the mature form of IL-1beta. We conclude that IL-18 possesses proinflammatory properties by direct stimulation of gene expression and synthesis of TNFalpha from CD3+/CD4+ and natural killer cells with subsequent production of IL-1beta and IL-8 from the CD14+ population.

Overview of interleukin-18: more than an interferon-gamma inducing factor.

Initially described in 1989 as interferon‐γ (IFN‐γ) inducing factor (IGIF), interleukin‐18 (IL‐18) is a novel proinflammatory cytokine that is clearly more than an inducer of IFN‐γ The cytokine possesses several biological properties such as activation of nuclear factor‐κB (NF‐κB), Fas ligand expression, the induction of both CC and CXC chemokines, and increased production of competent human immunodeficiency virus. Most activities are due to a receptor complex that recruits the IL‐1 receptor‐activating kinase (IRAK), leading to translocation of NF‐κB. This property and others support the concept that IL‐18 is related to the IL‐1 family. Indeed, one of the IL‐18 receptor chains is the IL‐1 receptor‐related protein, a member of the IL‐1R family. In addition, IL‐18 is structurally similar to IL‐1β and like IL‐1β is first synthesized as a leaderless precursor requiring the IL‐1β converting enzyme for cleavage into an active molecule. The biology of IL‐18 is reviewed in the overview and the implication for a role for this cytokine in disease is presented. J. Leukoc. Biol. 63: 658–664; 1998.

Interleukin-18 Enhances Lipopolysaccharide-Induced Interferon-γ Production in Human Whole Blood Cultures

Interleukin-18 (IL-18) is a newly described cytokine, formerly called interferon-gamma (IFN-gamma)-inducing factor. In a simple 24-h human whole blood culture, IFN-gamma was produced by the combination of lipopolysaccharide (LPS) plus IL-18. To liberate cytokines in the leukocyte and red cell compartments, the detergent Triton X-100 was added to the entire blood culture. The combination of low concentrations of LPS plus IL-18 induced a 3- to 5-fold greater production of IFN-gamma than did either stimulant alone. Tumor necrosis factor-alpha (TNF-alpha), IL-6, and IL-8 were also produced. The presence of IL-10 completely suppressed the production of IFN-gamma and reduced that of TNF-alpha, IL-6, and IL-8. Thus, IFN-gamma, TNF-alpha, IL-8, and IL-6 are produced in a single whole blood culture, making correlations in the synthesis of a T helper type 1 cytokine and proinflammatory cytokines with disease activity possible in a single culture.

Does Tuberculosis Increase HIV Load

BACKGROUNDnThe effect that tuberculosis (TB) has on human immunodeficiency virus (HIV) disease progression is not clearly understood.nnnMETHODSnIn an observational cohort study of HIV-infected adults in South Africa, baseline and final HIV load were compared between individuals who experienced an episode of TB (n=30) during follow-up and control subjects (n=56) matched by baseline CD4 cell count and follow-up time; linear regression modeling was used to control for confounding.nnnRESULTSnMean HIV load was higher in the TB group than in the non-TB control group for both baseline (4.73 vs. 4.24 log(10) copies/mL; P=.003) and final values (5.02 vs. 4.34 log(10) copies/mL; P<.001). After adjustment for baseline HIV load and World Health Organization HIV stage, the difference in final HIV load was 0.24 log(10) copies/mL (95% confidence interval, -0.01 to 0.50 log(10) copies/mL; P=.06).nnnCONCLUSIONSnPoor prognosis for HIV-infected individuals after TB may be due to preexisting high HIV load rather than to the TB event itself. An episode of TB was associated with a small adjusted increase in HIV load at the end of the study--an increase that would not be regarded as clinically significant in an individual but could have some effect on HIV disease progression or HIV transmission at the population level. Prevention of TB is important for the reduction of HIV-related morbidity and mortality; however, antiretroviral therapy is required to have a major effect on survival in individuals with HIV disease.

The interleukin 1 receptor

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Studies on IL-1 receptors on D10S T-helper cells: Demonstration of two molecularly and antigenically distinct IL-1 binding proteins

Receptor binding studies were performed on the interleukin-1 (IL-1) sensitive T-helper cell line D10S, a stable line which proliferates to subfemtomolar concentrations of IL-1 in the absence of mitogens. IL-1 binds in a specific and saturable manner and Scatchard analysis at 4 degrees C reveals one class of binding affinity. On D10S cells, the Kd for IL-1 is 227 pM +/- 80, with 11,000 (range 3,300 to 23,800) sites per cell. EL4.6.1 cells, which are less sensitive to IL-1, bind with a single class of high affinity sites (55 pM; 4,000 sites). D10S cells incubated 18 h with IL-1 display reduced IL-1 receptor (IL-1R) numbers and affinities, consistent with reduced (75%, p less than 0.005) proliferation to subsequent IL-1; preincubation with IL-4 increases the number of IL-1R which is associated with increased (200%, p less than 0.001) proliferation to IL-1. The molecular mass of the major (80 kD) IL-1R binding [125I]IL-1 alpha on D10S cells was consistently observed at 73 kD as compared to the 80 kD molecule on the EL4 cells. On the other hand, crosslinking studies with [125I]IL-1 beta on D10S cells revealed a novel 46 kD band on gradient SDS-PAGE corresponding to a binding protein of 29 to 30 kD, which is antigenically distinct from the 80 kD IL-1R. Crosslinking of D10S or EL4 cells at 4 degrees C in the presence of phytohemagglutinin (PHA) and labeled IL-1 enhanced the appearance of the 30 kD IL-1 binding protein. The findings are consistent with a two-chain model for the IL-1R, although Scatchard analysis did not consistently indicate two classes of affinities. IL-1 binding to the 80 kD protein may form a heteroduplex with the 30 kD IL-1R which could account for the presence of the 120 to 130 kD IL-1 crosslinked proteins observed by several investigators.

Investigation of HIV in Amniotic Fluid from HIV-Infected Pregnant Women at Full Term

BACKGROUNDnIn the absence of interventions and breast-feeding, the in utero transmission rate of human immunodeficiency virus (HIV) is estimated to be 10%-15%, and the role that amniotic fluid (AF) plays in this is unclear.nnnOBJECTIVESnLevels of cytomegalovirus (CMV) in AF and levels of HIV-1 in AF, maternal blood, and fetal cord blood were assessed.Study design. We enrolled 23 HIV-1-positive women with healthy, singleton pregnancies who underwent elective cesarean section (CS) at full term. The Roche Amplicor HIV-1 Monitor test (version 1.5) was used for determination of maternal plasma VLs. The NASBA Nuclisens assay was used for determination of VLs in other samples. To determine the feasibility of detecting viral infections in AF, CMV polymerase chain reaction DNA extraction was performed on the AF samples by use of the QIAamp DNA kit.nnnRESULTSnHIV-1 RNA was not detected in either AF or fetal cord blood. CMV was detected in 4 AF samples. Maternal CD4(+) T cell counts were 158-654 cells/mL (mean, 405 cells/mL). The maternal plasma VLs ranged from below detectable limits to 169,990 copies/mL (mean, 33,700 copies/mL).nnnCONCLUSIONSnIn the absence of medical complications and before labor, AF collected during elective CS from women who had received either zidovudine or nevirapine during late-stage pregnancy was free of HIV.

Progress towards the UNAIDS 90–90-90 goals by age and gender in a rural area of KwaZulu-Natal, South Africa: a household-based community cross-sectional survey

BackgroundThe Joint United Nations Programme on HIV/AIDS (UNAIDS) has developed an ambitious strategy to end the AIDS epidemic. After eight years of antiretroviral therapy (ART) program we assessed progress towards the UNAIDS 90–90-90 targets in Mbongolwane and Eshowe, KwaZulu-Natal, South Africa.MethodsWe conducted a cross-sectional household-based community survey using a two-stage stratified cluster probability sampling strategy. Persons aged 15–59xa0years were eligible. We used face-to-face interviewer-administered questionnaires to collect information on history of HIV testing and care. Rapid HIV testing was performed on site and venous blood specimens collected from HIV-positive participants for antiretroviral drug presence test, CD4 count and viral load. At the time of the survey the CD4 threshold for ART initiation was 350 cells/μL. We calculated progression towards the 90–90-90 UNAIDS targets by estimating three proportions: HIV positive individuals who knew their status (first 90), those diagnosed who were on ART (second 90), and those on ART who were virally suppressed (third 90).ResultsWe included 5649/6688 (84.5%) individuals. Median age was 26xa0years (IQR: 19–40), 62.3% were women. HIV prevalence was 25.2% (95% CI: 23.6–26.9): 30.9% (95% CI: 29.0–32.9) in women; 15.9% (95% CI: 14.0–18.0) in men. Overall progress towards the 90–90-90 targets was as follows: 76.4% (95% CI: 74.1–78.6) knew their status, 69.9% (95% CI: 67.0–72.7) of those who knew their status were on ART and 93.1% (95% CI: 91.0–94.8) of those on ART were virally suppressed. By sex, progress towards the 90–90-90 targets was: 79%–71%–93% among women; and 68%–68%–92% among men (p-values of women and men comparisons were <u20090.001, 0.443 and 0.584 respectively). By age, progress was: 83%–75%–95% among individuals aged 30–59xa0years and 64%–58%–89% among those aged 15–29xa0years (p-values of age groups comparisons were <u20090.001, <u20090.001 and 0.011 respectively).ConclusionsIn this context of high HIV prevalence, significant progress has been achieved with regards to reaching the UNAIDS 90–90-90 targets. The third 90, viral suppression in people on ART, was achieved among women and men. However, gaps persist in HIV diagnosis and ART coverage particularly in men and individuals younger than 30xa0years. Achieving 90–90-90 is feasible but requires additional investment to reach youth and men.

Suppression of endotoxin-inducible cytokines in whole blood from human subjects following single dose of recombinant human interleukin-11

To determine whether a single injection of recombinant human interleukin-11 (rhIL-11) to human subjects would affect endotoxin-inducible cytokine production, 6 dialysis-dependent patients with renal failure and 4 healthy volunteers were subcutaneously injected with rhIL-11 (50 µg/kg). The circulating concentrations of rhIL-11 remained at a constant level of approximately 12 ng/ml for 0.25—6 h in healthy volunteers but were 2-fold higher in dialysis-dependent patients. Venous blood obtained before and after rhIL-11 was stimulated with 10 ng/ml of LPS for 24 h at 37°C and production of TNFα, IL-1β, and IL-8 determined. The maximum suppression of IL-1β, TNFα and IL-8 production (66%, 24% and 58%, respectively) was observed 1 h after rhIL-11 administration. After 24 h, when circulating concentration of rhIL-11 had decreased to near pre-injection levels, LPS-induced TNFα and IL-1β production remained suppressed (56 ± 17%, P < 0.05; 46 ± 4.7, P<0.01, respectively) but returned to baseline at 48 h. These findings suggest that there is a therapeutic benefit of single doses of rhIL-11 in reducing LPS-induced IL-1β and TNFα production.

South African HIV self-testing policy and guidance considerations

The gap in HIV testing remains significant and new modalities such as HIV self-testing (HIVST) have been recommended to reach key and under-tested populations. In December 2016, the World Health Organization (WHO) released the Guidelines on HIV Self-Testing and Partner Notification: A Supplement to the Consolidated Guidelines on HIV Testing Services (HTS) and urged member countries to develop HIVST policy and regulatory frameworks. In South Africa, HIVST was included as a supplementary strategy in the National HIV Testing Services Policy in 2016, and recently, guidelines for HIVST were included in the South African National Strategic Plan for HIV, sexually transmitted infections and tuberculosis 2017–2022. This document serves as an additional guidance for the National HIV Testing Services Policy 2016, with specific focus on HIVST. It is intended for policy advocates, clinical and non-clinical HTS providers, health facility managers and healthcare providers in private and public health facilities, non-governmental, community-based and faith-based organisations involved in HTS and outreach, device manufacturers, workplace programmes and institutes of higher education.