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At least 37 records · Page 2
All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

405 nm violet-blue light inactivates hepatitis C cell culture virus (HCVcc) in ex vivo human platelet concentrates and plasma

Abstract Added safety measures coupled with the development and use of pathogen reduction technologies (PRT) significantly reduces the risk of transfusion-transmitted infections (TTIs) from blood products. Current approved PRTs utilize chemical and/or UV-light based inactivation methods. While the effectiveness of these PRTs in reducing pathogens are well documented, these can cause tolerable yet unintended consequences on the quality and efficacy of the transfusion products. As an alternative to UV-based approaches, we have previously demonstrated that 405 nm violet-blue light exposure successfully inactivates a variety of pathogens, including bacteria, parasites, and viruses, in both platelet concentrates (PCs) and plasma. Herein, we show that 405 nm light treatment effectively inactivates hepatitis C cell culture virus (HCVcc) by up to ~ 3.8 log10 in small volumes of a variety of matrices, such as cell culture media, PBS, plasma, and PCs with 27 J/cm 2 of light exposure, and total inactivation of HCVcc after 162 J/cm 2 light exposure. Furthermore, we demonstrate that carry-over of media supplemented with fetal bovine serum enhances the production of reactive oxygen species (ROS), providing mechanistic insights to 405 nm light-mediated viral inactivation. Overall, 405 nm light successfully inactivates HCVcc, further strengthening this method as a novel PRT for platelets and plasma.

Science & Technology - Other Topics↗
DOE OSTI2020

HIV influences clustering and intracellular replication of hepatitis C virus

We report HCV and HIV coinfection is common and HIV leads to increased HCV viraemia and accelerated disease progression. However, the biological basis of this interaction remains poorly understood and little is known about the impact of HIV on HCV replication at the cellular level. We analysed HCV RNA, based on single-cell laser-capture microdissection, in liver biopsies from monoinfected (n = 4) and HCV/HIV-coinfected (n = 5) participants. HCV RNA was assayed in 3200 hepatocytes with information of spatial position. We compared HCV RNA levels and clustering properties of infection between mono- and coinfected participants, and developed a mathematical model of infection. Although the median plasma HCV RNA level and the fraction of infected cells were comparable in monoinfected (7.0 log 10 IU/mL and ~ 30%) and coinfected (7.3 log 10 IU/mL and ~ 40%) participants, the median HCV RNA per infected hepatocyte in monoinfected (2.8IU) was significantly lower than in coinfected (8.2IU) participants (p = .03). Clustering of infected cells was more prominent in monoinfected participants (91% of samples) than in coinfected participants (~48%), p = .0045, suggesting that spatial spread may be influenced by HIV coinfection. Interestingly, when clustering does occur, the size of clusters is similar in both types of infection. A mathematical model of infection suggested that HIV allows higher intracellular accumulation of HCV RNA by impeding the export of HCV RNA. Our observations show that HIV coinfection impacts intracellular accumulation of HCV RNA and the clustering of HCV-infected cells, but to a less extent the fraction of HCV-infected cells.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Mechanistic modelling of SARS-CoV-2 and other infectious diseases and the effects of therapeutics

Modern viral kinetic modeling and its application to therapeutics is a field that attracted the attention of the medical, pharmaceutical and modeling communities during the early days of the AIDS epidemic. Its successes lead to applications of modeling methods not only to HIV but a plethora of other viruses, such as hepatitis C virus (HCV), hepatitis B virus (HBV) and cytomegalovirus (CMV), which along with HIV cause chronic diseases, and viruses such as influenza, respiratory syncytial virus (RSV), West Nile virus (WNV), Zika virus, and SAR-CoV-2, which generally cause acute infections. Here we first review the historical development of mathematical models to understand HIV and HCV infections and the effects of treatment by fitting the models to clinical data. Furthermore, we then focus on recent efforts and contributions of applying these models towards understanding SARS-CoV-2 infection and highlight outstanding questions where modeling can provide crucial insights and help to optimize non-pharmaceutical and pharmaceutical interventions of the COVID-19 pandemic. The review is written from our personal perspective emphasizing the power of simple target cell limited models that provided important insights and then their evolution into more complex models that captured more of the virology and immunology. To quote Albert Einstein “Everything should be made as simple as possible, but not simpler”, and this idea underlies the modeling we describe below.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Association of human T-cell leukemia virus type 1 with prevalent rheumatoid arthritis among atomic bomb survivors: A cross-sectional study

Previous studies have suggested that human T-cell leukemia virus type 1 (HTLV-1) might act as a pathogen in rheumatoid arthritis (RA), but epidemiological evidence of an association is scarce. We measured anti-HTLV-1 antibodies among Nagasaki atomic bomb survivors to determine whether HTLV-1 is related to RA and whether radiation exposure is associated with HTLV-1 and RA prevalence. This is a cross-sectional study among atomic bomb survivors who participated in biennial health examinations from 2006 to 2010. Serum levels of anti-HTLV-1 antibodies were measured using a chemiluminescent enzyme immunoassay and confirmed by Western blotting. Association between HTLV-1 and RA was analyzed by a logistic regression model. Of 2091 participants (women 61.5%; median age, 73 years), 215 (10.3%) had anti-HTLV-1 antibodies. HTLV-1 prevalence was higher among women (13.1% vs 5.8%; P<.001). Twenty-two participants (1.1%) were diagnosed with RA. HTLV-1 prevalence among RA participants was significantly higher than that among non-RA participants (27.3% vs 10.1%; P=.020). After adjustment for age, sex, and hepatitis C virus infection, HTLV-1 was significantly associated with prevalent RA (odds ratio, 2.89; 95% confidence interval, 1.06, 7.03). There was no association between radiation dose and either the prevalence of HTLV-1 or RA. This study, among a well-defined group of atomic bomb survivors, suggests that HTLV-1 is associated with RA. Abbreviations: AHS = Adult Health Study, ATL/ATLL = adult T cell leukemia/lymphoma, bioDMARDs = biological disease modifying antirheumatic drugs, CCP = cyclic citrullinated peptide, CI = confidence interval, CLEIA = chemiluminescent enzyme immunoassay, CRP = C-reactive protein, csDMARDs = conventional synthetic disease modifying antirheumatic drugs, Gy = gray, HCV = hepatitis C virus, HTLV-1 = human T-cell leukemia virus type 1, IF = immunofluorescent, RA = rheumatoid arthritis, RERF = Radiation Effects Research Foundation, RF = rheumatoid factor, SS = Sjogren syndrome.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Computational identification of HCV neutralizing antibodies with a common HCDR3 disulfide bond motif in the antibody repertoires of infected individuals

Despite recent success in hepatitis C virus (HCV) treatment using antivirals, an HCV vaccine is still needed to prevent reinfections in treated patients, to avert the emergence of drug-resistant strains, and to provide protection for people with no access to the antiviral therapeutics. The early production of broadly neutralizing antibodies (bNAbs) associates with HCV clearance. Several potent bNAbs bind a conserved HCV glycoprotein E2 epitope using an unusual heavy chain complementarity determining region 3 (HCDR3) containing an intra-loop disulfide bond. Isolation of additional structurally-homologous bNAbs would facilitate the recognition of key determinants of such bNAbs and guide rational vaccine design. Here we report the identification of new antibodies containing an HCDR3 disulfide bond motif using computational screening with the Rosetta software. Using the newly-discovered and already-known members of this antibody family, we review the required HCDR3 amino acid composition and propose determinants for the bent versus straight HCDR3 loop conformation observed in these antibodies.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Analysis of antibodies from HCV elite neutralizers identifies genetic determinants of broad neutralization

The high genetic diversity of hepatitis C virus (HCV) complicates effective vaccine development. We screened a cohort of 435 HCV-infected individuals and found that 2%–5% demonstrated outstanding HCV-neutralizing activity. From four of these patients, we isolated 310 HCV antibodies, including neutralizing antibodies with exceptional breadth and potency. High neutralizing activity was enabled by the use of the VH1-69 heavy-chain gene segment, somatic mutations within CDRH1, and CDRH2 hydrophobicity. Structural and mutational analyses revealed an important role for mutations replacing the serines at positions 30 and 31, as well as the presence of neutral and hydrophobic residues at the tip of the CDRH3. Based on these characteristics, we computationally created a de novo antibody with a fully synthetic VH1-69 heavy chain that efficiently neutralized multiple HCV genotypes. Finally, our findings provide a deep understanding of the generation of broadly HCV-neutralizing antibodies that can guide the design of effective vaccine candidates.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Mathematical modeling of plus-strand RNA virus replication to identify broad-spectrum antiviral treatment strategies

Plus-strand RNA viruses are the largest group of viruses. Many are human pathogens that inflict a socio-economic burden. Interestingly, plus-strand RNA viruses share remarkable similarities in their replication. A hallmark of plus-strand RNA viruses is the remodeling of intracellular membranes to establish replication organelles (so-called “replication factories”), which provide a protected environment for the replicase complex, consisting of the viral genome and proteins necessary for viral RNA synthesis. In the current study, we investigate pan-viral similarities and virus-specific differences in the life cycle of this highly relevant group of viruses. We first measured the kinetics of viral RNA, viral protein, and infectious virus particle production of hepatitis C virus (HCV), dengue virus (DENV), and coxsackievirus B3 (CVB3) in the immuno-compromised Huh7 cell line and thus without perturbations by an intrinsic immune response. Based on these measurements, we developed a detailed mathematical model of the replication of HCV, DENV, and CVB3 and showed that only small virus-specific changes in the model were necessary to describe the in vitro dynamics of the different viruses. Our model correctly predicted virus-specific mechanisms such as host cell translation shut off and different kinetics of replication organelles. Further, our model suggests that the ability to suppress or shut down host cell mRNA translation may be a key factor for in vitro replication efficiency, which may determine acute self-limited or chronic infection. We further analyzed potential broad-spectrum antiviral treatment options in silico and found that targeting viral RNA translation, such as polyprotein cleavage and viral RNA synthesis, may be the most promising drug targets for all plus-strand RNA viruses. Moreover, we found that targeting only the formation of replicase complexes did not stop the in vitro viral replication early in infection, while inhibiting intracellular trafficking processes may even lead to amplified viral growth.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Spatial inequities in access to medications for treatment of opioid use disorder highlight scarcity of methadone providers under counterfactual scenarios

Access to treatment and medication for opioid use disorder (MOUD) is essential in reducing opioid use and associated behavioral risks, such as syringe sharing among persons who inject drugs (PWID). Syringe sharing among PWID carries high risk of transmission of serious infections such as hepatitis C and HIV. MOUD resources, such as methadone provider clinics, however, are often unavailable to PWID due to barriers like long travel distance to the nearest methadone provider and the required frequency of clinic visits. The goal of this study is to examine the uncertainty in the effects of travel distance in initiating and continuing methadone treatment and how these interact with different spatial distributions of methadone providers to impact co-injection (syringe sharing) risks. A baseline scenario of spatial access was established using the existing locations of methadone providers in a geographical area of metropolitan Chicago, Illinois, USA. Next, different counterfactual scenarios redistributed the locations of methadone providers in this geographic area according to the densities of both the general adult population and according to the PWID population per zip code. We define different reasonable methadone access assumptions as the combinations of short, medium, and long travel distance preferences combined with three urban/suburban travel distance preference. Our modeling results show that when there is a low travel distance preference for accessing methadone providers, distributing providers near areas that have the greatest need (defined by density of PWID) is best at reducing syringe sharing behaviors. However, this strategy also decreases access across suburban locales, posing even greater difficulty in regions with fewer transit options and providers. As such, without an adequate number of providers to give equitable coverage across the region, spatial distribution cannot be optimized to provide equitable access to all PWID. Our study has important implications for increasing interest in methadone as a resurgent treatment for MOUD in the United States and for guiding policy toward improving access to MOUD among PWID.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2026

Bemnifosbuvir: An HCV NS5B Inhibitor With Multiple Modes of Action

Bemnifosbuvir (BEM) is a potent, pan-genotypic inhibitor targeting the hepatitis C virus (HCV) NS5B polymerase. Its antiviral activity was evaluated in an ascending dose phase I clinical trial involving 30 patients treated once a day for 7 days. After treatment initiation, plasma HCV RNA declined in a biphasic manner with a mean reduction of 2.3 log 10 IU/mL after 24 hours and 4.4 log10 IU/mL by day 7 for the highest dose. Alanine aminotransferase (ALT) also normalized in most patients. We employed a multiscale mathematical model fitted to the HCV RNA and ALT dynamics to quantify the antiviral activity and evaluate the modes of action of BEM. We found that models in which BEM only acted as a typical HCV RNA polymerase inhibitor and reduced the intracellular production of HCV RNA did not fit the data as well as models in which BEM had multiple modes of action, including suppressing viral assembly and secretion and enhancing intracellular HCV RNA degradation. BEM's effectiveness in inhibiting intracellular HCV RNA production increased with dose (150 mg/day: 88.2%, 300 mg/day: 98.8%, 600 mg/day: 99.5%), while inhibition of viral assembly and release was ~95% effective regardless of dose. We observed a dose-dependent enhancement in the degradation of intracellular HCV RNA, with degradation rates 1.5-fold higher in patients receiving 300 mg/day and 2.7-fold higher in those receiving 600 mg/day than in patients receiving 150 mg/day. No significant differences in antiviral activity were detected between HCV genotypes 1b and 3 or between patients with and without compensated cirrhosis.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

A structured RNA motif locks Argonaute2:miR-122 onto the 5’ end of the HCV genome

microRNAs (miRNAs) form regulatory networks in metazoans. Viruses engage miRNA networks in numerous ways, with Flaviviridae members exploiting direct interactions of their RNA genomes with host miRNAs. For hepatitis C virus (HCV), binding of liver-abundant miR-122 stabilizes the viral RNA and regulates viral translation. Here, we investigate the structural basis for these activities, taking into consideration that miRNAs function in complex with Argonaute (Ago) proteins. The crystal structure of the Ago2:miR-122:HCV complex reveals a structured RNA motif that traps Ago2 on the viral RNA, masking its 5’ end from enzymatic attack. The trapped Ago2 can recruit host factor PCBP2, implicated in viral translation, while binding of a second Ago2:miR-122 competes with PCBP2, creating a potential molecular switch for translational control. Combined results reveal a viral RNA structure that modulates Ago2:miR-122 dynamics and repurposes host proteins to generate a functional analog of the mRNA cap-binding complex.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Covalent narlaprevir- and boceprevir-derived hybrid inhibitors of SARS-CoV-2 main protease

Emerging SARS-CoV-2 variants continue to threaten the effectiveness of COVID-19 vaccines, and small-molecule antivirals can provide an important therapeutic treatment option. The viral main protease (Mpro) is critical for virus replication and thus is considered an attractive drug target. We performed the design and characterization of three covalent hybrid inhibitors BBH-1, BBH-2 and NBH-2 created by splicing components of hepatitis C protease inhibitors boceprevir and narlaprevir, and known SARS-CoV-1 protease inhibitors. A joint X-ray/neutron structure of the M pro /BBH-1 complex demonstrates that a Cys145 thiolate reaction with the inhibitor’s keto-warhead creates a negatively charged oxyanion. Protonation states of the ionizable residues in the M pro active site adapt to the inhibitor, which appears to be an intrinsic property of M pro . Structural comparisons of the hybrid inhibitors with PF-07321332 reveal unconventional F···O interactions of PF-07321332 with Mpro which may explain its more favorable enthalpy of binding. BBH-1, BBH-2 and NBH-2 exhibit comparable antiviral properties in vitro relative to PF-07321332, making them good candidates for further design of improved antivirals.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations

Inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M pro ) such as nirmatrelvir (NTV) and ensitrelvir (ETV) have proven effective in reducing the severity of COVID-19, but the presence of resistance-conferring mutations in sequenced viral genomes raises concerns about future drug resistance. Second-generation oral drugs that retain function against these mutants are thus urgently needed. We hypothesized that the covalent hepatitis C virus protease inhibitor boceprevir (BPV) could serve as the basis for orally bioavailable drugs that inhibit SARS-CoV-2 M pro more efficiently than existing drugs. Performing structure-guided modifications of BPV, we developed a picomolar-affinity inhibitor, ML2006a4, with antiviral activity, oral pharmacokinetics, and therapeutic efficacy similar or superior to those of NTV. A crucial feature of ML2006a4 is a derivatization of the ketoamide reactive group that improves cell permeability and oral bioavailability. Last, ML2006a4 was found to be less sensitive to several mutations that cause resistance to NTV or ETV and occur in the natural SARS-CoV-2 population. Thus, anticipatory design can preemptively address potential resistance mechanisms to expand future treatment options against coronavirus variants.

Westberg, Michael↗
DOE OSTI2024

How robust are estimates of key parameters in standard viral dynamic models?

Mathematical models of viral infection have been developed, fitted to data, and provide insight into disease pathogenesis for multiple agents that cause chronic infection, including HIV, hepatitis C, and B virus. However, for agents that cause acute infections or during the acute stage of agents that cause chronic infections, viral load data are often collected after symptoms develop, usually around or after the peak viral load. Consequently, we frequently lack data in the initial phase of viral growth, i.e., when pre-symptomatic transmission events occur. Missing data may make estimating the time of infection, the infectious period, and parameters in viral dynamic models, such as the cell infection rate, difficult. However, having extra information, such as the average time to peak viral load, may improve the robustness of the estimation. Here, we evaluated the robustness of estimates of key model parameters when viral load data prior to the viral load peak is missing, when we know the values of some parameters and/or the time from infection to peak viral load. Although estimates of the time of infection are sensitive to the quality and amount of available data, particularly pre-peak, other parameters important in understanding disease pathogenesis, such as the loss rate of infected cells, are less sensitive. Viral infectivity and the viral production rate are key parameters affecting the robustness of data fits. Fixing their values to literature values can help estimate the remaining model parameters when pre-peak data is missing or limited. We find a lack of data in the pre-peak growth phase underestimates the time to peak viral load by several days, leading to a shorter predicted growth phase. On the other hand, knowing the time of infection (e.g., from epidemiological data) and fixing it results in good estimates of dynamical parameters even in the absence of early data. While we provide ways to approximate model parameters in the absence of early viral load data, our results also suggest that these data, when available, are needed to estimate model parameters more precisely.

59 BASIC BIOLOGICAL SCIENCES↗