暂无摘要。

Access to Hepatis C treatment in Sub-Saharan Africa is a clinical, public health and ethical concern. The multi-country open-label trial TAC ANRS 12311 allowed assessing the feasibility, safety, efficacy of a specific care model of HCV treatment and retreatment in patients with hepatitis C in Sub Saharan Africa. Between November 2015 and March 2017, with follow-up until mid 2019, treatment-naïve patients with HCV without decompensated cirrhosis or liver cancer were recruited to receive 12 week-treatment with either sofosbuvir + ribavirin (HCV genotype 2) or sofosbuvir + ledipasvir (genotype 1 or 4) and retreatment with sofosbuvir + velpatasvir + voxilaprevir in case of virological failure. The primary outcome was sustained virological response at 12 weeks after end of treatment (SVR12). Secondary outcomes included treatment adherence, safety and SVR12 in patients who were retreated due to non-response to first-line treatment. The model of care relied on both viral load assessment and educational sessions to increase patient awareness, adherence and health literacy. The study recruited 120 participants, 36 HIV-co-infected, and 14 cirrhotic. Only one patient discontinued treatment because of return to home country. Neither death nor severe adverse event occurred. SVR12 was reached in 107 patients (89%): (90%) in genotype 1 or 2, and 88% in GT-4. All retreated patients (n = 13) reached SVR12. HCV treatment is highly acceptable, safe and effective under this model of care. Implementation research is now needed to scale up point-of-care HCV testing and SVR assessment, along with community involvement in patient education, to achieve HCV elimination in Sub-Saharan Africa.

OBJECTIVE: The COVID-19 pandemic remains a significant public health concern for the global population; the development and characterization of therapeutics, especially ones that are broadly effective, will continue to be essential as severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) variants emerge. Neutralizing monoclonal antibodies remain an effective therapeutic strategy to prevent virus infection and spread so long as they recognize and interact with circulating variants. The epitope and binding specificity of a neutralizing anti-SARS-CoV-2 Spike receptor-binding domain antibody clone against many SARS-CoV-2 variants of concern were characterized by generating antibody-resistant virions coupled with cryo-EM structural analysis and VSV-spike neutralization studies. This workflow can serve to predict the efficacy of antibody therapeutics against emerging variants and inform the design of therapeutics and vaccines.

We report spike protein-based lineage and AZD7442 (tixagevimab/cilgavimab) neutralizing activity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants identified from breakthrough infections in the PROVENT preexposure prophylaxis trial.
Variants identified from PROVENT participants with reverse-transcription polymerase chain reaction-positive symptomatic illness were phenotypically assessed to determine neutralization susceptibility of variant-specific pseudotyped virus-like particles.
At completion of 6 months\' follow-up, no AZD7442-resistant variants were observed in breakthrough coronavirus disease 2019 (COVID-19) cases. SARS-CoV-2 neutralizing antibody titers were similar in breakthrough and nonbreakthrough cases.
Symptomatic COVID-19 breakthrough cases in PROVENT were not due to resistance-associated substitutions in AZD7442 binding sites or lack of AZD7442 exposure.
NCT04625725.

Potato (Solanum tuberosum L.) is an important vegetable crop that plays a pivotal role in the world, especially given its potential to feed the world population and to act as the major staple food in many developing countries. Every year, significant crop loss is caused by viral diseases due to a lack of effective agrochemical treatments, since only transmission by insect vectors can be combated with the use of insecticides, and this has been an important factor hindering potato production. With the rapid development of molecular biology and plant genetic engineering technology, transgenic approaches and non-transgenic techniques (RNA interference and CRISPR-cas9) have been effectively employed to improve potato protection against devastating viruses. Moreover, the availability of viral sequences, potato genome sequences, and host immune mechanisms has remarkably facilitated potato genetic engineering. In this study, we summarize the progress of antiviral strategies applied in potato through engineering either virus-derived or plant-derived genes. These recent molecular insights into engineering approaches provide the necessary framework to develop viral resistance in potato in order to provide durable and broad-spectrum protection against important viral diseases of solanaceous crops.

UNASSIGNED: Rapid switching from second-line to third-line antiretroviral therapy (TLART) is crucial for achieving viral suppression and reducing illness related to ART failure.
UNASSIGNED: This retrospective cohort study quantified the waiting periods for TLART initiation after virological failure on second-line therapy was detected, assessed factors associated with delays and assessed the outcomes of patients started on TLART.
UNASSIGNED: Data were abstracted from records of individuals eligible for TLART, and the time to TLART initiation was calculated. Reasons for delays were categorised according to patient, clinician and administrative processes.
UNASSIGNED: Fifty-four patients were eligible for TLART. The median delay from the date of first viral load > 1000 copies/mL on second-line therapy to the start of TLART was 640 days (interquartile range [IQR]: 451-983 days). Of the patients that failed second-line and had an application for TLART, 41 (75.6%) were eventually initiated on TLART, and 11 (20.4%) died while waiting. Delays were primarily due to non-response to the first unsuppressed viral load while on second-line ART: 467 days (IQR: 232-803 days).
UNASSIGNED: This study showed a prolonged waiting period for TLART initiation mainly between detected high viral load to requesting of resistance tests; many factors could have contributed, including clinicians\' delayed responses to elevated viral loads. Mortality was high before TLART could be initiated. The process of TLART initiation needs to be made more efficient. Healthcare services should be strengthened to (1) recognise and manage virological failure early and identify those eligible for resistance testing, (2) ensure access to resistance testing and appropriately skilled clinicians, and (3) streamline approvals and delivery of TLART.

Natural resistance to infection is an overlooked outcome after hepatitis C virus (HCV) exposure. Between 1977 and 1979, 1,200 Rhesus D-negative Irish women were exposed to HCV-contaminated anti-D immunoglobulin. Here, we investigate why some individuals appear to resist infection despite exposure (exposed seronegative [ESN]). We screen HCV-resistant and -susceptible donors for anti-HCV adaptive immune responses using ELISpots and VirScan to profile antibodies against all know human viruses. We perform standardized ex vivo whole blood stimulation (TruCulture) assays with antiviral ligands and assess antiviral responses using NanoString transcriptomics and Luminex proteomics. We describe an enhanced TLR3-type I interferon response in ESNs compared with seropositive women. We also identify increased inflammatory cytokine production in response to polyIC in ESNs compared with seropositive women. These enhanced responses may have contributed to innate immune protection against HCV infection in our cohort.

Despite their incredible contribution to fighting viral infections, antiviral viral resistance is an increasing concern and often arises due to unfavorable physicochemical and biopharmaceutical properties. To address this kind of issue, lipid nanocapsules (LNC) are developed in this study, using efavirenz (EFV) as a drug model. EFV solubility was assessed in water, Labrafac Lipophile and medium chain triglycerides oil (MCT oil). EFV turned out to be more soluble in the two latter dissolving media (solubility > 250 mg/mL); hence, given its affordability, MCT oil was used for LNC formulation. LNC were prepared using a low-energy method named phase inversion, and following a design of experiments process. This one resulted in polynomial models that predicted LNC particle size, polydispersity index and zeta potential that were, respectively, around 50 nm, below 0.2 and below −33 mV, for the optimized formulations. Once synthesized, we were able to achieve an encapsulation efficacy of 87%. On the other hand, high EFV release from the LNC carrier was obtained in neutral medium as compared to acid milieu (pH 4) with, respectively, 42 and 27% EFV release within 74 h. Other characterization techniques were applied and further supported the successful encapsulation of EFV in LNCs in an amorphous form. Stability studies revealed that the developed LNC were quite stable over the period of 28 days. Ultimately, LNCs have been demonstrated to improve the biopharmaceutical properties of EFV and could therefore be used to fight against antiviral resistance.

Wheat streak mosaic virus (WSMV) is an economically important viral pathogen that threatens global wheat production, particularly in the Great Plains of the United States. The Wsm2 locus confers resistance to WSMV and has been widely deployed in common wheat varieties adapted to this region. Characterizing the underlying causative genetic variant would contribute to our understanding of viral resistance mechanisms in wheat and aid the development of perfect markers for breeding. In this study, linkage mapping in a doubled-haploid (DH) mapping population confirmed Wsm2 as a major locus conferring WSMV resistance in wheat. The Wsm2 flanking markers were mapped to a 4.0 Mbp region at the distal end of chromosome 3BS containing 142 candidate genes. Eight haplotypes were identified from seventeen wheat genotypes collected from different agroecological zones, indicating that Wsm2 lies in a dynamic region of the genome with extensive structural variation and that it is likely a rare allele in most available genome assemblies of common wheat varieties. Exome sequencing of the variety \"Snowmass\", which carries Wsm2, revealed several loss-of-function mutations and copy number variants in the 142 candidate genes within the Wsm2 interval. Six of these genes are differentially expressed in \"Snowmass\" compared to \"Antero,\" a variety lacking Wsm2, including a gene that encodes a nucleotide-binding site leucine-rich repeat (NBS-LRR) type protein with homology to RPM1. A de novo assembly of unmapped RNA-seq reads identified nine transcripts expressed only in \"Snowmass,\" three of which are also induced in response to WSMV inoculation. This study sheds light on the variation underlying Wsm2 and provides a list of candidate genes for subsequent validation.

Even though substantial progress has been made in the treatment of hepatitis C virus (HCV) infection, viral resistance and relapse still occur in some patients and additional therapeutic approaches may ultimately be needed should viral resistance become more prevalent. Microtubules play important roles in several HCV life cycle events, including cell attachment, entry, cellular transportation, morphogenesis and progeny secretion steps. Therefore, it was hypothesized that microtubular inhibition might be a novel approach for the treatment of HCV infection. Here, the inhibitory effects of our recently developed microtubule inhibitors were studied in the HCV replicon luciferase reporter system and the infectious system. In addition, the combination responses of microtubule inhibitors with daclatasvir, which is a clinically used HCV NS5A inhibitor, were also evaluated. Our results indicated that microtubule targeting had activity against HCV replication and showed synergistic effect with a current clinical drug.