Mechanism of interferon stimulated gene induction in HIV-1 infected macrophages

Viruses manipulate the complex interferon and interferon stimulated gene (ISG) system in different ways. We have previously shown that HIV inhibits type I and III interferons in its key target cells but directly stimulates a subset of >20 ISGs in macrophages and dendritic cells many of which are antiviral. Here we examined the mechanism of induction of ISGs and showed this occurred in two phases. The first phase was transient (0-24hpi) induced mainly by extracellular vesicles, and one of its component proteins HSP90α, contained within the HIV inoculum. The second dominant and persistent phase (>48hpi) was induced via newly transcribed HIV RNA and sensed via RIGI, as shown by the reduction in ISG expression after the knock down of the RIGI adaptor, MAVS, by siRNA and the inhibition of both the initiation and elongation of HIV transcription, by shRNA transcriptional silencing. We further defined the induction pathway, showing sequential HIV RNA stimulation via Tat, RIGI, MAVS, IRF1 and IRF7 also identified by siRNA knockdown. IRF1 also plays a key role in the first phase. We also showed that the ISGs, IFITs 1-3 inhibited HIV production, measured as extracellular infectious virus. All induced antiviral ISGs probably lead to restriction of HIV replication in macrophages, contributing to a persistent, non-cytopathic infection while the inhibition of interferon facilitates spread to adjacent cells. Both may influence the size of macrophage HIV reservoirs in vivo. Elucidating the mechanisms of ISG induction may help devise immunotherapeutic strategies to limit the size of these reservoirs. IMPORTANCE HIV, like other viruses, manipulates the antiviral interferon and interferon stimulated gene (ISG) system to facilitate its initial infection and establishment of viral reservoirs. HIV specifically inhibits all type l and lll interferons in its target cells, including, macrophages, dendritic cells and T cells. It also induces a subset of over 20 ISGs of differing composition in each cell target. This occurs in two temporal phases in macrophages. Extracellular vesicles contained within the inoculum induced the first and transient phase of ISGs. Newly transcribed HIV RNA induced the second and dominant ISG phase and here the full induction pathway is defined. Therefore, HIV nucleic acids, which are potent inducers of interferon and ISGs, are initially concealed and antiviral ISGs are not fully induced until replication is well established. Theses antiviral ISGs may contribute to the persistent infection in macrophages and to the establishment of viral reservoirs in vivo.Najla Nasr, Abdullateef A. Alshehri, Thomas K. Wright, Maryam Shahid, Bonnie M. Heiner, Andrew N. Harman, Rachel A. Botting, Karla J. Helbig, Michael R. Beard, Kazuo Suzuki, Anthony D. Kelleher, Paul Hertzog, Anthony L. Cunningha

Delayed antibiotic prescribing for respiratory tract infections : Individual patient data meta-analysis

Altres ajuts: NIHR Research for Patient Benefit (RfPB, grant No PB-PG-0416-20005).AbstractObjective To assess the overall effect of delayed antibiotic prescribing on average symptom severity for patients with respiratory tract infections in the community, and to identify any factors modifying this effect. Design Systematic review and individual patient data meta-analysis. Data sources Cochrane Central Register of Controlled Trials, Ovid Medline, Ovid Embase, EBSCO CINAHL Plus, and Web of Science. Eligibility criteria for study selection Randomised controlled trials and observational cohort studies in a community setting that allowed comparison between delayed versus no antibiotic prescribing, and delayed versus immediate antibiotic prescribing. Main outcome measures The primary outcome was the average symptom severity two to four days after the initial consultation measured on a seven item scale (ranging from normal to as bad as could be). Secondary outcomes were duration of illness after the initial consultation, complications resulting in admission to hospital or death, reconsultation with the same or worsening illness, and patient satisfaction rated on a Likert scale. Results Data were obtained from nine randomised controlled trials and four observational studies, totalling 55 682 patients. No difference was found in follow-up symptom severity (seven point scale) for delayed versus immediate antibiotics (adjusted mean difference -0.003, 95% confidence interval -0.12 to 0.11) or delayed versus no antibiotics (0.02, -0.11 to 0.15). Symptom duration was slightly longer in those given delayed versus immediate antibiotics (11.4 v 10.9 days), but was similar for delayed versus no antibiotics. Complications resulting in hospital admission or death were lower with delayed versus no antibiotics (odds ratio 0.62, 95% confidence interval 0.30 to 1.27) and delayed versus immediate antibiotics (0.78, 0.53 to 1.13). A significant reduction in reconsultation rates (odds ratio 0.72, 95% confidence interval 0.60 to 0.87) and an increase in patient satisfaction (adjusted mean difference 0.09, 0.06 to 0.11) were observed in delayed versus no antibiotics. The effect of delayed versus immediate antibiotics and delayed versus no antibiotics was not modified by previous duration of illness, fever, comorbidity, or severity of symptoms. Children younger than 5 years had a slightly higher follow-up symptom severity with delayed antibiotics than with immediate antibiotics (adjusted mean difference 0.10, 95% confidence interval 0.03 to 0.18), but no increased severity was found in the older age group. Conclusions Delayed antibiotic prescribing is a safe and effective strategy for most patients, including those in higher risk subgroups. Delayed prescribing was associated with similar symptom duration as no antibiotic prescribing and is unlikely to lead to poorer symptom control than immediate antibiotic prescribing. Delayed prescribing could reduce reconsultation rates and is unlikely to be associated with an increase in symptoms or illness duration, except in young children. Study registration PROSPERO CRD42018079400