Hepatitis C virus (HCV) is a hepatotropic positive-sense RNA virus of the Flaviviridae virus family and is a major cause of chronic liver disease worldwide. Like all obligate parasites, HCV relies on host pathways to enable its pathogenesis. HCV, in particular, has a clear link with hepatic lipid metabolism, promoting a lipid-rich environment for its proliferation. This manifests as liver steatosis in many patients harboring chronic HCV infection. Based on our recent findings regarding an immunometabolic and HCV antiviral microRNA (miRNA), miRNA-185 targeting and down regulating serine hydrolases (SH) involved in lipid and endocannabinoid metabolism, here we investigate HCV and its dependency on certain metabolic serine hydrolases involved in lipid and endocannabinoid metabolism. Serine hydrolases are one of the largest and most diverse enzyme families. This enzyme family has emerged as a center of therapeutic potential due to its implications in many metabolic roles. Here, we demonstrate that pharmacological inhibition of metabolic serine hydrolases alpha-beta hydrolyzing domain 6 (ABHD6), carboxylesterase 1 (CES1), and monoacylglycerol lipase (MGLL), enzymes involved in the hydrolysis of the endogenous cannabinoid receptor 1 (CB1) agonist 2-arachidonoyl glycerol (2-AG) are potently antiviral against HCV. Serine hydrolase inhibition with the MGLL inhibitor MJN110 paired with endocannabinoid signaling antagonization led to additive antiviral effects against HCV and has revealed modulation of the viral pathogenic phenotype to be its key course of action. MGLL inhibitor MJN110 transcriptomic characterization revealed modulations in humoral immunity and phagocytosis and acts antiviraly against HCV independent of CB1 antagonization. This provides an avenue for future investigation, assessing the viability of CB1 antagonization, and MGLL as a key host targeted antiviral factor in affecting HCV viral life cycle.

Sammanfattning Introduktion: Hepatit C är en inflammation av levern orsakad av hepatit C-viruset. Runt 71 miljoner människor världen över är drabbade av den kroniska formen. Effektiva läkemedel finns för att bota sjukdomen, men dessa är dyra och således behövs ett vaccin. Problemet med viruset är den stora variationen av genotyper och subtyper, vilket försvårar vaccinutvecklingen eftersom vaccinet framför allt kommer vara effektivt för en viss grupp smittade. En rad prekliniska studier har gjorts på olika djurslag, där fokus oftast ligger på att generera både antikroppar och att framkalla effektiva T-celler. Tyvärr har dock ingen större framgång gällande vaccinutvecklingen setts till ännu.  Syfte: Litteraturstudiens syfte gick ut på att analysera olika hepatit C-vacciners effekter med avsikten att försöka få en insikt i hur dessa kommer att tillverkas i framtiden för att de ska ge en fullgod effekt hos människor och förhindra smittspridning.   Material och metod: Databasen PubMed användes för att hitta fem olika vetenskapliga artiklar att analysera. Sökorden som användes för att hitta samtliga av dessa studier var ”vaccines hepatitis c”. Endast prekliniska studier valdes ut för analys.  Resultat: Över lag sågs kraftiga responser från immunförsvarets sida till följd av stimulering med olika typer av vacciner. Responserna förmedlades av antikroppar samt cytotoxiska T-celler och T-hjälparceller, ofta genom en produktion av interferon gamma respektive tumörnekrosfaktor alfa. I processen skapades även minnesceller som snabbt kunde reagera vid återexponering av samma antigen.   Slutsats: Fler prekliniska experiment kommer att behöva genomföras innan vaccinen kan ta sig vidare till klinisk fas. Exakt när i framtiden ett vaccin kommer hittas, och om det kommer hittas, är svårt att förutspå. Under tiden finns antivirala läkemedel att tillgå i brist på en mer effektiv lösning. / ABSTRACT Background: Hepatitis C is an inflammation of the liver caused by the hepatitis C virus. Around 71 million people worldwide are affected by the chronic form of the infection. Effective drugs are available to cure the disease, but these are expensive and thus a vaccine is needed. The problem with the virus is the wide variety of genotypes and subtypes, which complicates vaccine development since the vaccine will be especially effective for a particular group of infected individuals. A number of preclinical studies have been conducted on different animal species, where the focus is usually on generating both antibodies and producing efficient T lymphocytes. Unfortunately, no major success regarding vaccine development has yet been seen.  Aim: The purpose of this literature study was to analyze the effects of various hepatitis C vaccines with the intention of trying to gain an insight into how these will be manufactured in the future in order to generate an adequate effect in humans and prevent the spread of infection. Materials and methods: The database PubMed was used to find five different scientific articles to analyze. The keywords used to find each of these studies were "vaccines hepatitis c". Only preclinical studies were selected for evaluation. Results: Overall, strong responses were seen from the immune system as a result of stimulation with different types of vaccines. Responses were mediated by antibodies as well as cytotoxic T cells and T helper cells, often through the production of interferon gamma and tumor necrosis factor alpha. In the process, memory cells were also generated that could react rapidly upon re-exposure of the same antigen. Conclusion: More preclinical experiments will need to be carried out before the vaccines can move forward to clinical trials. Exactly when in the future a vaccine will be found, and if it will be found, is difficult to predict. Meanwhile, antiviral drugs are available in the absence of a more effective solution.

I det patientnära arbetet exponeras sjuksköterskor dagligen för kroppsvätskor. Det medför en risk för överföring av blodburna smittor såsom humant immunbristvirus (HIV), acquired immunodeficiency syndrome (AIDS), hepatit B och hepatit C (HBV och HCV). Tidigare forskning påvisar att sjuksköterskans vilja att vårda patienter med blodburen smitta skiljer sig från patienter utan en blodburen smitta. Syftet med litteraturöversikten är att belysa faktorer som påverkar sjuksköterskans vilja att vårda patienter med blodburen smitta. I litteraturöversikten inkluderas åtta kvantitativa artiklar och en kvalitativ artikel. I artikelgranskningen analyseras likheter respektive skillnader enligt Fribergs analysmetod (2017 ss. 141-152). I resultatet identifieras 10 faktorer i 4 kategorier som inverkar på sjuksköterskans vilja att vårda patienter med blodburen. I kategorin Känsla av oro och rädsla att själv bli smittad uttrycker sjuksköterskor en underliggande oro och rädsla av att själv bli smittad. Kategorin Kunskapsnivå, utbildning och yrkeserfarenhet belyser att en hög kunskapsnivå inom området påverkar sjuksköterskans vilja att vårda patienter med blodburen smitta. Kategorin Ålder, civilstatus och familjestatus visar att äldre sjuksköterskor har en större motvilja att vårda denna patientgrupp jämfört med yngre sjuksköterskor. Den sista kategorin, Patientens smittväg och typ av blodburen smitta visar att en del sjuksköterskor har en motvillighet att vårda de patienter som har blivit smittade genom ett intravenöst missbruk. Litteraturöversikten visar att det land sjuksköterskan befinner sig i har en inverkan i deras vilja att vårda patienter med blodburen smitta.

This thesis was undertaken to assess the characteristics of individuals who smoke crack cocaine and to examine the health-related risks and healthcare needs of this population. A literature review of 147 published articles was conducted to synthesize evidence regarding behaviours associated with crack use and to assess the risks of disease transmission through crack smoking behaviours. Qualitative interviews were subsequently conducted with thirty Ottawa residents who smoke crack to learn about their experiences with healthcare and harm reduction services. Results identified barriers related to accessing primary healthcare and drug treatment programming among people who smoke crack and gaps within existing harm reduction services. Individuals who smoke crack represent a marginalized population who are often missed through traditional health promotion and harm reduction programming. There is a need for increased coverage of current programming and a reduction of factors which currently hinder the delivery and effectiveness of crack-specific harm reduction programs.

RUNX1 overlapping RNA (RUNXOR) is a long non-coding RNA and plays a pivotal role in the differentiation of myeloid cells via targeting runt-related transcription factor 1 (RUNX1). We and others have previously reported that myeloid-derived suppressor cells (MDSCs) expand and inhibit host immune responses during chronic viral infections; however, the mechanisms responsible for MDSC differentiation and suppressive functions, in particular the role of RUNXOR-RUNX1, remain unclear. Here, we demonstrated that RUNXOR and RUNX1 expressions are significantly upregulated and associated with elevated levels of immunosuppressive molecules, such as arginase 1 (Arg1), inducible nitric oxide synthase (iNOS), signal transducer and activator of transcription 3 (STAT3), and reactive oxygen species (ROS) in MDSCs during chronic hepatitis C virus (HCV) infection. Mechanistically, we discovered that HCV-associated exosomes (HCV-Exo) can induce the expressions of RUNXOR and RUNX1, which in turn regulates miR-124 expression via STAT3 signaling, thereby promoting MDSC differentiation and suppressive functions. Importantly, overexpression of RUNXOR in healthy CD33+ myeloid cells promoted differentiation and suppressive functions of MDSCs. Conversely, silencing RUNXOR or RUNX1 expression in HCV-derived CD33+ myeloid cells significantly inhibited their differentiation and expressions of suppressive molecules and improved the function of co-cultured autologous CD4 T cells. Taken together, these results indicate that the RUNXOR-RUNX1-STAT3-miR124 axis enhances the differentiation and suppressive functions of MDSCs and could be a potential target for immunomodulation in conjunction with antiviral therapy during chronic HCV infection.

Given the shared risk factors for transmission, co-infection of hepatitis B virus (HBV) with hepatitis C virus (HCV) and/or human immunodeficiency virus (HIV) is quite common, and may lead to increases in morbidity and mortality. As such, HBV vaccine is recommended as the primary means to prevent HBV super-infection in HCV- and/or HIV-infected individuals. However, vaccine response (sero-conversion with a hepatitis B surface antibody titer >10 IU/L) in this setting is often blunted, with poor response rates to standard HBV vaccinations in virally infected individuals when compared with the healthy subjects. This phenomenon also occurs to other vaccines in adults, such as pneumococcal and influenza vaccines, in other immunocompromised hosts who are really at risk for opportunistic infections, such as individuals with hemodialysis, transplant, and malignancy. In this review, we summarize the underlying mechanisms involving vaccine failure in these conditions, focusing on immune exhaustion and immune senescence - two distinct signaling pathways regulating cell function and fate. We raise the possibility that blocking these negative signaling pathways might improve success rates of immunizations in the setting of chronic viral infection.

Given the shared risk factors for transmission, co-infection of hepatitis B virus (HBV) with hepatitis C virus (HCV) and/or human immunodeficiency virus (HIV) is quite common, and may lead to increases in morbidity and mortality. As such, HBV vaccine is recommended as the primary means to prevent HBV super-infection in HCV- and/or HIV-infected individuals. However, vaccine response (sero-conversion with a hepatitis B surface antibody titer >10 IU/L) in this setting is often blunted, with poor response rates to standard HBV vaccinations in virally infected individuals when compared with the healthy subjects. This phenomenon also occurs to other vaccines in adults, such as pneumococcal and influenza vaccines, in other immunocompromised hosts who are really at risk for opportunistic infections, such as individuals with hemodialysis, transplant, and malignancy. In this review, we summarize the underlying mechanisms involving vaccine failure in these conditions, focusing on immune exhaustion and immune senescence - two distinct signaling pathways regulating cell function and fate. We raise the possibility that blocking these negative signaling pathways might improve success rates of immunizations in the setting of chronic viral infection.

T regulatory (TR) cells suppress T-cell responses that are critical in the development of chronic viral infection and associated malignancies. Programmed death-1 (PD-1) also has a pivotal role in regulation of T-cell functions during chronic viral infection. To examine the role of PD-1 pathway in regulating TR-cell functions that inhibit T-cell responses during virus-associated malignancy, TR cells were investigated in the setting of hepatitis C virus-associated lymphoma (HCV-L), non-HCV-associated lymphoma (non-HCV-L), HCV infection alone and healthy subjects (HS). Relatively high numbers of CD4+ CD25+ and CD8+CD25 + TR cells, as well as high levels of PD-1 expressions on these TR cells were found in the peripheral blood of subjects with HCV-L compared with those from non-HCV-L or HCV alone or HS. TR cells from the HCV-L subjects were capable of suppressing the autogeneic lymphocyte response, and depletion of TR cells in peripheral blood mononuclear cells from HCV-L improved T-cell proliferation. Additionally, the suppressed T-cell activation and proliferation in HCV-L was partially restored by blocking the PD-1 pathway ex vivo, resulting in both a reduction in TR-cell number and the ability of TR to suppress the activity of effector T cells. This study suggests that the PD-1 pathway is involved in regulating TR cells that suppress T-cell functions in the setting of HCV-associated B-cell lymphoma.

HCV infection is associated with immune dysregulation and B cell Non-Hodgkins lymphoma (HCV-NHL). We have previously shown in vitro that HCV core protein differentially regulates T and B cell functions through two negative signaling pathways, programmed death-1 (PD-1) and suppressor of cytokine signaling-1 (SOCS-1). In this report, we performed a detailed immunologic analysis of T and B cell functions in the setting of HCV-NHL. We observed that T cells isolated from patients with HCV-NHL exhibited an exhausted phenotype including decreased expression of viral-specific and non-specific activation markers; whereas B cells exhibited an activated phenotype including over-expression of cell activation markers and immunoglobulins compared to healthy subjects. Individuals with HCV alone or NHL alone exhibited abnormal T and B cell phenotypes, but to a lesser extent compared to HCV-NHL. This differential activation of T and B lymphocytes was inversely associated with the expression of PD-1 and SOCS-1. Interestingly, blocking PD-1 during TCR activation inhibited SOCS-1 gene expression, suggesting that these regulatory pathways are linked in T cells. Importantly, blocking PD-1 also restored the impaired T cell functions observed in the setting of HCV-NHL. These results support a coordinated mechanism by which HCV might cause immune dysregulation that is associated to HCV-NHL.

This study aimed to assess the prevalence of and factors associated with tobacco use among patients living with HIV/HCV co-infection. Patient reported outcomes (PROs) were analyzed of patients living with HIV/HCV co-infection (n = 313) who presented for clinical evaluation and treatment of HCV between 2013 and 2017 at a university-affiliated HIV/HCV Co-infection Clinic. The prevalence of tobacco use in patients living with HIV/HCV co-infection was 48%. Compared to non-smokers, a higher proportion of tobacco smokers had substance use disorders and concurrent alcohol and substance use. In the multivariate analysis, concurrent alcohol and substance use was positively associated with tobacco use. The findings suggest clinical interventions are urgently needed to reduce tobacco use among patients living with HIV/HCV co-infection—a doubly-vulnerable immunocompromised population. Otherwise, failed efforts to dedicate resources and targeted behavioral interventions for this respective population will inhibit survival—especially considering the recent and evolving COVID-19 pandemic.