RESUMEN
PD-1 as an immune checkpoint molecule down-regulates T cell activity during immune responses in order to prevent autoimmune tissue damage. In chronic infections or tumors, lasting antigen-exposure leads to permanent PD-1 expression that can limit immune-mediated clearance of pathogens or degenerated cells. Blocking PD-1 can enhance T cell function; in cancer treatment PD-1 blockade is already used as a successful therapy. However, the role of PD-1 expression and blocking in the context of acute and chronic infections is less defined. Building on its success in cancer therapy leads to the hypothesis that blocking PD-1 in infectious diseases is also beneficial in acute or chronic infections. This review will focus on the role of PD-1 expression in acute and chronic infections with virus, bacteria, and parasites, with a particular focus on recent studies regarding PD-1 blockade in infectious diseases.
Asunto(s)
Infecciones/inmunología , Receptor de Muerte Celular Programada 1/fisiología , Animales , Antígenos Virales/inmunología , Autoantígenos/inmunología , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/inmunología , Humanos , Tolerancia Inmunológica , Activación de Linfocitos , Subgrupos Linfocitarios/inmunología , Ratones Transgénicos , Polimorfismo de Nucleótido Simple , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/deficiencia , Receptor de Muerte Celular Programada 1/genética , Infecciones por Protozoos/tratamiento farmacológico , Infecciones por Protozoos/inmunología , Sepsis/inmunología , Virosis/tratamiento farmacológico , Virosis/inmunologíaRESUMEN
Selenof (15-kDa selenoprotein; Sep15) is an endoplasmic reticulum (ER)-resident thioredoxin-like oxidoreductase that occurs in a complex with UDP-glucose:glycoprotein glucosyltransferase. We found that Selenof deficiency in mice leads to elevated levels of non-functional circulating plasma immunoglobulins and increased secretion of IgM during in vitro splenic B cell differentiation. However, Selenof knockout animals show neither enhanced bacterial killing capacity nor antigen-induced systemic IgM activity, suggesting that excess immunoglobulins are not functional. In addition, ER-to-Golgi transport of a target glycoprotein was delayed in Selenof knockout embryonic fibroblasts, and proteomic analyses revealed that Selenof deficiency is primarily associated with antigen presentation and ER-to-Golgi transport. Together, the data suggest that Selenof functions as a gatekeeper of immunoglobulins and, likely, other client proteins that exit the ER, thereby supporting redox quality control of these proteins.
Asunto(s)
Presentación de Antígeno , Linfocitos B/inmunología , Retículo Endoplásmico/inmunología , Aparato de Golgi/inmunología , Inmunoglobulina M/inmunología , Selenoproteínas/inmunología , Animales , Linfocitos B/citología , Línea Celular , Retículo Endoplásmico/genética , Fibroblastos/citología , Fibroblastos/inmunología , Aparato de Golgi/genética , Inmunoglobulina M/genética , Ratones , Ratones Noqueados , Selenoproteínas/genética , Bazo/citología , Bazo/inmunologíaRESUMEN
BACKGROUND: There is an international epidemic of hepatitis C virus (HCV) infection among HIV-infected men who have sex with men. We previously showed that adding telaprevir to pegylated interferon (IFN) and ribavirin (RBV) both shortened treatment and increased the cure rate of early HCV in these men. Whether shortening treatment of early HCV using IFN-free regimens would be similarly successful has not yet been demonstrated. METHODS: We performed a pilot study of treatment with sofosbuvir (SOF) + RBV for 12 weeks in early genotype 1 HCV infection in HIV-infected men. The primary endpoint was SVR 12. RESULTS: Twelve men were treated with 12 weeks SOF + RBV and 11 (92%) achieved SVR 12. Most (63%) were actively using recreational drugs, mostly methamphetamine. The one man who failed had laboratory results more characteristic of chronic than of early HCV infection. The overall safety profile was similar to that known for SOF + RBV. CONCLUSIONS: The success of this short-duration IFN-free treatment in early HCV infection is proof in principle that enhanced treatment responsiveness is an inherent characteristic of early HCV infection and not a function of IFN treatment itself. Future studies should now be done with more potent regimens to try to further shorten therapy. In the mean time, in clinical practice early HCV infection should be treated immediately after detection to take advantage of short-duration treatments, as well as to decrease further HCV transmission among HIV-infected MSM.
Asunto(s)
Antivirales/uso terapéutico , Coinfección , Infecciones por VIH/virología , Hepacivirus , Hepatitis C/tratamiento farmacológico , Hepatitis C/virología , Sofosbuvir/uso terapéutico , Adulto , Terapia Antirretroviral Altamente Activa , Antivirales/administración & dosificación , Antivirales/efectos adversos , Recuento de Linfocito CD4 , Quimioterapia Combinada , Genotipo , Infecciones por VIH/diagnóstico , Infecciones por VIH/tratamiento farmacológico , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Humanos , Interferones , Interleucinas/genética , Masculino , Persona de Mediana Edad , Mutación , Proyectos Piloto , Ribavirina/uso terapéutico , Sofosbuvir/administración & dosificación , Sofosbuvir/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Carga ViralRESUMEN
Background. The epidemic of sexually transmitted hepatitis C virus (HCV) infection among human immunodeficiency virus (HIV)-infected men who have sex with men (MSM) has been documented for over a decade. Despite this, there is no consensus as to the risk factors for sexual acquisition of HCV in these men. Methods. We obtained paired semen and blood samples at 2-week intervals from HIV-infected MSM with recent and chronic HCV infection and quantified HCV in semen. Results. Hepatitis C virus was quantified in 59 semen specimens from 33 men. Hepatitis C virus was shed in 16 (27%) of semen specimens from 11 (33%) of the men. Median HCV viral load (VL) in semen was 1.49 log10 IU/mL. Hepatitis C virus VL in blood was significantly higher at the time of HCV shedding in semen than when HCV shedding in semen was not detected (P = .002). Furthermore, there was a significant correlation between the HCV VL in blood and semen overall (rs = 0.41; P = .001), and in the subgroup with recent HCV infection (rs = 0.37; P = .02), but not in the subgroup with chronic HCV infection (rs = 0.34; P = .1). Conclusions. One third of HIV-infected MSM coinfected with HCV shed HCV into their semen. Based on the HCV VL in semen in this study, an average ejaculate would deliver up to 6630 IU of virus into the rectum of the receptive partner. Therefore, our data strongly support that condoms should be used during anal intercourse among MSM to prevent transmission of HCV.
RESUMEN
The modified base 8-oxo-7,8-dihydro-2'-deoxyguanosine (oxoG) is a common DNA adduct produced by the oxidation of DNA by reactive oxygen species. Kinetic data reveal that DNA polymerase X (pol X) from the African swine fever virus incorporates adenine (dATP) opposite to oxoG with higher efficiency than the non-damaged G:C basepair. To help interpret the kinetic data, we perform molecular dynamics simulations of pol X/DNA complexes, in which the template base opposite to the incoming dNTP (dCTP, dATP, dGTP) is oxoG. Our results suggest that pol X accommodates the oxoGsyn:A mispair by sampling closed active conformations that mirror those observed in traditional Watson-Crick complexes. Moreover, for both the oxoGsyn:A and oxoG:C ternary complexes, conformational sampling of the polymerase follows previously described large subdomain movements, local residue motions, and active site reorganization. Interestingly, the oxoGsyn:A system exhibits superior active site geometry in comparison to the oxoG:C system. Simulations for the other mismatch basepair complexes reveal large protein subdomain movement for all systems, except for oxoG:G, which samples conformations close to the open state. In addition, active site geometry and basepairing of the template base with the incoming nucleotide, reveal distortions and misalignments that range from moderate (i.e., oxoG:Asyn) to extreme (i.e., oxoGanti/syn:G). These results agree with the available kinetic data for pol X and provide structural insights regarding the mechanism by which this polymerase can accommodate incoming nucleotides opposite oxoG. Our simulations also support the notion that α-helix E is involved both in DNA binding and active site stabilization. Our proposed mechanism by which pol X can preferentially accommodate dATP opposite template oxoG further underscores the role that enzyme dynamics and conformational sampling operate in polymerase fidelity and function.
Asunto(s)
ADN Polimerasa Dirigida por ADN/química , ADN/química , Nucleótidos de Desoxiadenina/química , Guanina/análogos & derivados , Simulación de Dinámica Molecular , Secuencia de Aminoácidos , Secuencia de Bases , ADN/metabolismo , ADN Polimerasa Dirigida por ADN/metabolismo , Nucleótidos de Desoxiadenina/metabolismo , Guanina/química , Guanina/metabolismo , Simulación del Acoplamiento Molecular , Datos de Secuencia Molecular , Unión Proteica , Especificidad por SustratoRESUMEN
Intercellular adhesion molecule 1 (ICAM-1) is a membrane-bound glycoprotein expressed on endothelial cells and cells of the immune system. Human ICAM-1 mediates adhesion and migration of leucocytes, and is implicated in inflammatory pathologies, autoimmune diseases and in many cancer processes. Additionally, ICAM-1 acts as receptor for pathogens like human rhinovirus and Plasmodium falciparum malaria parasites. A group of related P. falciparum erythrocyte membrane protein 1 (PfEMP1) domains, the DBLß, mediates ICAM-1 binding of P. falciparum-infected erythrocytes. This ICAM1-binding phenotype has been suggested to be involved in the development of cerebral malaria. However, more studies identifying cross-reactive antibody and ICAM-1-binding epitopes and the establishment of a clinical link between DBLß expression and e.g. cerebral malaria are needed before the DBLß domains can be put forward as vaccine candidates and go into clinical trials. Such studies require availability of functional recombinant ICAM-1 in large quantities. In this study, we compared recombinant ICAM-1 expressed in HEK293 and COS-7 cells with mouse myeloma NS0 ICAM-1 purchased from a commercial vendor in terms of protein purity, yield, fold, ability to bind DBLß, and relative cost. We present a HEK293 cell-based, high-yield expression and purification scheme for producing inexpensive, functional ICAM1. ICAM-1 expressed in HEK293 is applicable to malaria research and can also be useful in other research fields.