Journal of Virus Eradication最新文献

Viral infections occupy an essential place in modern medicine, particularly a large group of diseases caused by the influenza viruses. They are rapidly transmitted and mutate quickly, which can lead to significant socio-economic consequences. Silver nanoparticles (AgNPs) are considered to be an effective antimicrobial agent. This study shows that they have strong antiviral properties against the influenza A virus infection. Their absence of cytotoxicity at inhibitory concentrations demonstrates that they could be an effective antiviral agent against this virus. As AgNPs inhibit the influenza A virus replication and spread, they could also be successfully used as a post-infection virostatic agent.

Introduction

The recent outbreak of SARS-CoV-2 has significantly increased the need to find inhibitors that target the essential enzymes for viral replication in host cells. This systematic review was conducted to identify potential inhibitors of SARS-CoV, MERS-CoV, and SARS-CoV-2 helicases that have been tested by in vitro methods. Their inhibitory mechanisms are discussed in this review, in addition to their cytotoxic and protective properties.

Methods

The databases PUBMED/MEDLINE, EMBASE, SCOPUS, and Web of Science were searched using different combinations of the keywords “helicase”, “nsp13”, “inhibitors”, “coronaviridae”, “coronaviruses”, “virus replication”, “replication”, and “antagonists and inhibitors".

Results

A total of 6854 articles were identified. Thirty-one were included into this review. These studies reported on the inhibitory effects of 309 compounds on SARS-CoV, MERS-CoV, and SARS-CoV-2 helicase activities measured by in vitro methods. Helicase inhibitors were categorized according to the type of coronavirus and tested enzymatic activity, nature, approval, inhibition level, cytotoxicity, and viral infection protective effects. These inhibitors are classified according to the site of their interaction with coronavirus helicases into four types: zinc-binding site inhibitors, nucleic acid-binding site inhibitors, nucleotide-binding site inhibitors, and inhibitors with no clear interaction site.

Conclusion

Evidence from in vitro studies suggests that helicase inhibitors have a high potential as antiviral agents. Several show good antiviral activity while maintaining moderate cytotoxicity. These inhibitors should be clinically investigated to determine their efficacy in treating coronavirus infections, particularly SARS-CoV-2.

Quantification of intact proviruses is a critical measurement in HIV cure studies both in vitro and in vivo. The widely adopted ‘intact proviral DNA assay’ (IPDA), designed to discriminate and quantify genetically intact HIV proviruses based on detection of two HIV sequence-specific targets, was originally validated using Bio-Rad's droplet digital PCR technology (ddPCR). Despite its advantages, ddPCR is limited in multiplexing capability (two-channel) and is both labor- and time intensive. To overcome some of these limitations, we utilized a nanowell-based digital PCR platform (dPCR, QIAcuity from Qiagen) which is a fully automated system that partitions samples into nanowells rather than droplets. In this study we adapted the IPDA assay to the QIAcuity platform and assessed its performance relative to ddPCR. The dPCR could differentiate between intact, 5’ defective and 3’ defective proviruses and was sensitive to single HIV copy input. We found the intra-assay and inter-assay variability was within acceptable ranges (with coefficient of variation at or below 10%). When comparing the performance of the IPDA in ex vivo CD4⁺ T cells from people with HIV on antiretroviral therapy, there was a strong correlation in the quantification of intact (rs = 0.93; p < 0.001) and 3’ defective proviruses (rs = 0.96; p < 0.001) with a significant but less strong correlation for 5’ defective proviruses (rs = 0.7; p = 0.04). We demonstrate that the dPCR platform enables sensitive and accurate quantification of genetically intact and defective proviruses similar to the ddPCR system but with greater speed and efficiency. This flexible system can be further optimized in the future, to detect up to 5 targets, enabling a more precise detection of intact and potentially replication-competent proviruses.

Antigen-experienced memory CD4⁺ T cells are the major target of HIV infection and support both productive and latent infections, thus playing a key role in HIV dissemination and persistence, respectively. Here, we reviewed studies that have shown direct association between HIV infection and antigen specificity. During untreated infection, some HIV-specific cells host productive infection, while other pathogen-specific cells such as cytomegalovirus (CMV) and Mycobacterium tuberculosis also contribute to viral persistence on antiretroviral therapy (ART). These patterns could be explained by phenotypic features differing between these pathogen-specific cells. Mechanisms involved in these preferential infection and selection processes include HIV entry and restriction, cell exhaustion, survival, self-renewal and immune escape. For instance, MIP-1β expressing cells such as CMV-specific memory cells were shown to resist infection by HIV CCR5 coreceptor downregulation/inhibition. Conversely, HIV-infected CMV-specific cells undergo clonal expansion during ART. We have identified several research areas that need further focus such as the role of other pathogens, viral genome intactness, inducibility and phenotypic features. However, given the sheer diversity of both the CD4⁺ T cell repertoire and antigenic history of each individual, studying HIV-infected, antigen-experienced cells still imposes numerous challenges.

Early-phase HIV remission (“cure”) trials aim to test interventions developed to eradicate HIV or to sustainably control HIV without antiretroviral treatment (ART). Many remission trials include analytic treatment interruption (ATI) to evaluate interventions, which increases the risk to participants and their sexual partners. We conducted an online questionnaire of international HIV remission trial investigators and other study team members to assess their expectations regarding the time to achieve long-term control of HIV replication without treatment (functional cure) or complete eradication of replication-competent HIV virus (sterilizing cure); attitudes toward HIV remission research and the feasibility, acceptability, and efficacy of six HIV transmission risk mitigation strategies during trials with ATI of fixed duration.

Nearly half of respondents (47%) reported expecting a functional cure for HIV to be achieved in 5–10 years, and one-third (35%) reported 10–20 years for a sterilizing cure to be achieved. On a scale of −3 to 3, mean scores indicated greater respondent concern about the risk of HIV transmission to partners during ATI (Time to rebound Mean: 0.4 and Fixed duration Mean: 1.1), compared to participant health risks from ATI (Time to Rebound Mean: -.9 and Fixed duration Mean: 0.0). With regard to feasibility, acceptability, and efficacy respectively, mitigation efforts rated positively included: requiring counseling for potential participants (Means: 2.3; 2.1; and 1.1), providing partner referrals for PrEP (Means: 1.3; 1.3; 1.5), providing pre-exposure proxylaxis directly to partners (Means: 1.0; 1.5; 1.6), and monitoring participants for new sexually transmitted disease acquisition (Means: 1.9; 1.4; 1.0). Respondents were less positive about requiring that participants’ sexual partner(s) participate in risk counseling or limiting participation to those who commit to abstaining from sex during the entire ATI period.

Our study demonstrates that HIV remission trial investigators and study team members are concerned about the risk of transmission to sexual partners during ATI. Separating the assessment of risk mitigation strategies for transmission risk into feasibility, acceptability, and efficacy allows the discovery of strategies that may best achieve all three outcomes. Additional research is needed to compare these more fine-grained assessments with views held by other investigators, people living with HIV, and trial participants.

Heat shock proteins (HSPs), which have a variety of functions, are one of the stress protein families. In recent years, They have been reported to play a dual role in hepatitis B virus (HBV) which as persistent infection which is associated with, cirrhosis and liver cancer. In this article, we have summarized the regulatory mechanisms between HSPs and viruses, especially HBV and associated diseases based on HSP biological functions of in response to viral infections. In view of their potential as broad-spectrum antiviral targets, we have also discuss current progress and challenges in drug development based on HSPs, as well as the potential applications of agents that have been evaluated clinically in HBV treatment.

The International Workshop on HIV Persistence during Therapy provides a forum in which HIV/AIDS researchers gather to share the latest research findings related to viral reservoirs and cure. The Tenth Workshop, which was attended by over 400 delegates, extended over 4 days and comprised eight sessions covering topics from the basic science of viral persistence to therapeutic approaches to HIV cure. Furthermore, satellite sessions on the first day of the Conference featuring cure research endeavours being pursued by the Bill and Melinda Gates Foundation as well as those being coordinated under the National Institutes of Health Martin Delaney Collaboratory program, provided important updates on research advances being made in these initiatives. As with previous conferences, the International Workshop on HIV Persistence during Therapy is primarily abstract-driven with only one invited talk for each of the sessions. This format, therefore, increases the number of presentations from early-stage investigators. Furthermore, presentations by Community representatives illustrated approaches to creating cure research literacy with effective messaging for the Community. The following article offers a synopsis of the meeting sessions. Due to space constraints, some presentations may have only been briefly discussed. Nevertheless, the Workshop abstracts can be found online (https://www/sciencedirect.com/journal/journal-of-virus-eradication/vol/8/suppl/S).