98 research outputs found
Progress with retroviral gene vectors
No full textRetroviral vectors have become a standard tool for gene transfer technology. Compared with other gene transfer systems, retroviral vectors have several advantages, including their ability to transduce a variety of cell types, to integrate efficiently into the genomic DNA of the recipient cells and to express the transduced gene at high levels. The relatively well understood biology of retroviruses has made possible the development of packaging cell lines which provide in trans all the viral proteins required for viral particle formation. The design of different types of packaging cells has evolved to reduce the possibility of helper virus production. The host range of retroviruses has been expanded by pseudotyping the vectors with heterologous viral glycoproteins and receptor-specific ligands. The development of lentivirus vectors has allowed efficient gene transfer to quiescent cells. This review describes different strategies adopted for developing vectors to be used in gene therapy ..
Discovery and characterization of novel Nef-like infectivity factor
No full textThe SERINC family is a highly conserved group of genes which in the human genome comprises 5 members, encoding five homologous multipass transmembrane proteins. SERINC5, and to a lesser extent SERINC3, are powerful inhibitors of Human immunodeficiency virus 1 (HIV-1). SERINC5, expressed in virus-producing cells, is incorporated into the envelope of newly formed retroviral particles and inhibits an early stage of the virus infection process of the target cell, by preventing the delivery of the retroviral core into the target cell cytoplasm. Nef, an accessory protein of HIV-1, counteracts the antiretroviral activity of SERINC5 by promoting its endocytosis, which results in its removal from the cell surface, preventing its incorporation into retroviral particles. SERINC5 inhibits not only HIV-1, but also other divergent retroviruses, such as Murine leukemia virus (MLV). During my Ph.D. studies I demonstrated that the S2 auxiliary protein from Equine infectious anemia virus (EIAV) functionally resembles Nef and MLV glycoGag and counteracts SERINC5 with a similar mechanism.
While the inhibitory effect of SERINC5 has been established on retroviruses, nothing is yet known about its effect on other viruses. Here I describe evidence which indicates the possible inhibitory activity of the SERINC gene family against other RNA viruses
The cellular and molecular basis of the Nef requirement for HIV-1 infectivity
No full textNef is an HIV -1 accessory protein with a fundamental role for virus replication in vivo and for the development of AIDS. Among its several activities, Nef is essential for full HIV-1 infectivity, a function highly prominent in lymphoid cells. So far, the mechanism by which Nef promotes HIV-1 infectivity has remained elusive. Over the course of 3 years, my PhD research activity has led to the identification of the host transmembrane protein SERINC5, and to a lesser extent SERINC3, as potent inhibitors of HIV-1 infectivity counteracted by the viral protein Nef [Rosa et al., 2015]. SERINC5 is predominantly localized on the plasma membrane where it is efficiently incorporated into budding HIV-1 virions and impairs subsequent virion penetration of susceptible target cells. Nef relocalizes SERINC5 to an endosomal compartment preventing its incorporation into HIV-1 particles. The ability to counteract SERINC5 is conserved in Nef proteins encoded by different primate immunodeficiency viruses, as well as in the structurally unrelated glycosylated Gag from murine leukaemia virus (MLV). These examples of functional conservation and convergent evolution emphasize the fundamental importance of SERINC5 in the interaction of the host with retroviral pathogens. Remarkably, SERINC5 potently inhibits HIV-1 even in the presence of Nef in a dose-dependent manner, suggesting that this cellular factor might be exploited as an anti-HIV-1 therapeutic gene
Trends and symptoms of SARS-CoV-2 infection: a longitudinal study on an Alpine population representative sample
No full textObjectives The continuous monitoring of SARS-CoV-2 infection waves and the emergence of novel pathogens pose a challenge for effective public health surveillance strategies based on diagnostics. Longitudinal population representative studies on incident events and symptoms of SARS-CoV-2 infection are scarce. We aimed at describing the evolution of the COVID-19 pandemic during 2020 and 2021 through regular monitoring of self-reported symptoms in an Alpine community sample.Design To this purpose, we designed a longitudinal population representative study, the Cooperative Health Research in South Tyrol COVID-19 study.Participants and outcome measures A sample of 845 participants was retrospectively investigated for active and past infections with swab and blood tests, by August 2020, allowing adjusted cumulative incidence estimation. Of them, 700 participants without previous infection or vaccination were followed up monthly until July 2021 for first-time infection and symptom self-reporting: COVID-19 anamnesis, social contacts, lifestyle and sociodemographic data were assessed remotely through digital questionnaires. Temporal symptom trajectories and infection rates were modelled through longitudinal clustering and dynamic correlation analysis. Negative binomial regression and random forest analysis assessed the relative importance of symptoms.Results At baseline, the cumulative incidence of SARS-CoV-2 infection was 1.10% (95% CI 0.51%, 2.10%). Symptom trajectories mimicked both self-reported and confirmed cases of incident infections. Cluster analysis identified two groups of high-frequency and low-frequency symptoms. Symptoms like fever and loss of smell fell in the low-frequency cluster. Symptoms most discriminative of test positivity (loss of smell, fatigue and joint-muscle aches) confirmed prior evidence.Conclusions Regular symptom tracking from population representative samples is an effective screening tool auxiliary to laboratory diagnostics for novel pathogens at critical times, as manifested in this study of COVID-19 patterns. Integrated surveillance systems might benefit from more direct involvement of citizens’ active symptom tracking
L'esperienza del progetto SECAP: Strategie di Mitigazione e Adattamento. Volume 1. Mitigazione / Izkušnje projekta SECAP: Strategije blaženja in prilagajanja: 1. zvezek Blaženje
No full textStudio della riattivazione del Polyomavirus umano JC durante il trattamento con anticorpi monoclonali: analisi di fattori virali e dell'ospite.
No full textPolyomavirus JC (JCV) reactivation causing progressive multifocal leukoencephalopathy (PML) is a main concern during biological therapies. We investigated JCV reactivation in the blood (PBMC and plasma samples) and urine of immunomediated diseases and relapsing-remitting subtype of multiple sclerosis (RRMS) patients after a long-term treatment with infliximab and natalizumab, respectively. Although JCV DNAemia occurred transiently, an higher JCV prevalence was detected in PBMC of patients treated with both mAbs than that observed in the diseases and healthy control groups. However, the viral load in the positive samples was low and did not significantly differ among them. All the patients, treated and untreated, exhibited an high prevalence of JCV in urine samples, with a range of viral load higher than that in the blood, as commonly reported in the literature. In order to monitor the risk of the viral reactivation, influenced by these mAbs treatment, we studied the possible JCV non-coding control region (NCCR) evolution. All positive samples sequenced exhibited the NCCR archetype structure; of note, several infliximab samples showed few point mutations in some cellular transcriptional factor binding sites on the viral NCCR. Moreover, we focused on the viral-host factor interaction during JCV reactivation. In particular, we analysed the possible effect of the mAb therapy on features related to the immunity response by exploiting the viremia of persistent widespread Torquetenovirus (TTV) as marker of immune functional status. A positive correlation between TTV viral load and number of mAb infusions performed was observed. Finally, we investigated whether infliximab and natalizumab treatment exerted some effect on microRNAs (miRNAs) expression level. We examined the expression level of four main miRNAs miR146-a, miR-150, miR-155, miR-223, potential players of the innate and adaptive immunity. Collectively, our results confirmed that infliximab treatment led to a down-regulation of miRNAs highly expressed in rheumatic patients, with miRNA-146a levels under that of healthy controls. Instead, no significant variations were detected among patients treated or not with natalizumab. Although these results derived from relatively small groups of patients, the infliximab and natalizumab long-term treatment, did not seem to exert foremost effects on the possible JCV reactivation. Further investigations should be performed in order to assess the real risk of a long-term mAbs treatment, to identify the possible factor(s) and shed light on the mechanism(s) implicated in the JCV molecular evolution and PML development
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