Rapid Viral Clearance Research Articles

Patient visit behaviour shapes the virus infection dynamics in hosts

Chronic HBV infection is a dynamic process of rapid viral replication and clearance, with large amounts of virus being produced and lost in the body daily. The patient's visit behaviour is closely related to viral load in the body, while the data-driven mathematical model still lacking. Therefore, we first include 28,912 patients to investigate the relationships between the visit behaviour and the HBV-DNA virus load. Then, we propose an HBV virus infection dynamics model that considers the patient's visit behaviour. The system is chaotic once the behaviour of patients during visits depends on the virus load. Our results may help us understand the process of viral transmission, and increasing the visit probability to the clinic can lead to stabilising HBV-DNA viral loads and further help healthcare professionals develop targeted clinical intervention strategies.

Decisive reversal of lethal coronavirus disease 2019 in senescent hamster by synchronic antiviral and immunoregulatory intervention.

The poor prognosis observed in elderly individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a serious clinical burden and the underlying mechanism is unclear, which necessities detailed investigation of disease characteristics and research for efficient countermeasures. To simulate lethal coronavirus disease 2019 (COVID-19) in senescent human patients, 80-week-old male hamsters are intranasally inoculated with different doses of SARS-CoV-2 Omicron BA.5 variant. Exposure to a low dose of the Omicron BA.5 variant results in early activation of the innate immune response, followed by rapid viral clearance and minimal lung damage. However, a high dose of BA.5 results in impaired interferon signaling, cytokine storm, uncontrolled viral replication, and severe lung injury. To decrease viral load and reverse the deterioration of COVID-19, a new bio-mimic decoy called CoVR-MV is used as a preventive or therapeutic agent. Administration of CoVR-MV as a preventive or therapeutic intervention in the early stages of infection can effectively suppress viral load, regulate the immune response, and rescue animals from death and critical illness. These findings underscore the risk associated with SARS-CoV-2 Omicron BA.5 exposure in senescent hamsters and highlight the importance of early intervention to prevent disease progression.

Dynamics and optimal therapy of a stochastic HTLV‐1 model incorporating Ornstein–Uhlenbeck process

As the prevalence of viral infection in body, human T‐cell leukemia virus type 1 (HTLV‐1) is receiving increasing attention. Research on the corresponding virus models is of great significance to tackle the challenges of understanding HTLV‐1 development and treatment. This paper focuses on the dynamic analysis for a stochastic model with nonlinear cytotoxic T lymphocyte (CTL) response, which is driven by Ornstein–Uhlenbeck (OU) process to model the progression of HTLV‐1 in vivo. Rich dynamic behaviors such as the extinction of infected CD4+ T cells (ITCs), stationary distribution (SD), probability density, and finite‐time stability (FTS) of the model are established to reveal the interaction of cell populations. The optimal therapeutic strategy based on the cost‐benefit viewpoint is further obtained. Finally, illustrative numerical simulations are represented to corroborate the effectiveness of treatment and the ambient perturbation's impact that strengthening the noise strength can lead to rapid virus clearance.

Inhalation Delivery of Interferon-λ-Loaded Pulmonary Surfactant Nanoparticles Induces Rapid Antiviral Immune Responses in the Lung.

The interferon-λ (IFN-λ)-regulated innate immune responses in the airway expand our understanding toward antiviral strategies against influenza A virus (IAV). The application of IFN-λ as mucosal antiviral therapeutic is still challenging, and advanced research will be necessary to achieve more efficient delivery of recombinant IFN-λs to the damaged respiratory mucosa. In this study, we examine the capability of IFN-λ to stimulate the innate immune response, promoting the swift elimination of IAV in the lungs. Additionally, we develop IFN-λ-loaded nanoparticles incorporated into pulmonary surfactant for inhalation therapy aimed at treating lung infections caused by IAV. We found that inhaled delivery of IFNλ-PSNPs significantly restricted IAV replication in the lungs from 3 days after infection (dpi), and IAV-caused lung histopathologic findings were completely improved in response to IFNλ-PSNPs. More significant and rapid attenuation of viral RNA was observed in the lung of mice with inhaled delivery of IFNλ-PSNPs compared to mice with recombinant IFN-λs. Inhalation treatment of IFNλ-PSNPs to IAV-infected mice can result in the increase of monocyte frequency in concert with restoration of T and B cells composition. Furthermore, the transcriptional profiles of monocytes shifted toward heightened IFN responses following IFNλ-PSNP treatment. These results imply that IFN-λ could serve as a robust inducer of innate immunity in the lungs against IAV infection, and inhalation of IFN-λs encapsulated in PSNPs effectively resolves lung infections caused by IAV through rapid viral clearance. PSNPs facilitated improved delivery of IFN-λs to the lungs, triggering potent antiviral immune responses upon IAV infection onset.

A single-dose MCMV-based vaccine elicits long-lasting immune protection in mice against distinct SARS-CoV-2 variants.

Current vaccines against COVID-19 elicit immune responses that are overall strong but wane rapidly. As a consequence, the necessary booster shots have contributed to vaccine fatigue. Hence, vaccines that would provide lasting protection against COVID-19 are needed, but are still unavailable. Cytomegaloviruses (CMVs) elicit lasting and uniquely strong immune responses. Used as vaccine vectors, they may be attractive tools that obviate the need for boosters. Therefore, we tested the murine CMV (MCMV) as a vaccine vector against COVID-19 in relevant preclinical models of immunization and challenge. We have previously developed a recombinant MCMV vaccine vector expressing the spike protein of the ancestral SARS-CoV-2 (MCMVS). In this study, we show that the MCMVS elicits a robust and lasting protection in young and aged mice. Notably, spike-specific humoral and cellular immunity was not only maintained but also even increased over a period of at least 6 months. During that time, antibody avidity continuously increased and expanded in breadth, resulting in neutralization of genetically distant variants, like Omicron BA.1. A single dose of MCMVS conferred rapid virus clearance upon challenge. Moreover, MCMVS vaccination controlled two variants of concern (VOCs), the Beta (B.1.135) and the Omicron (BA.1) variants. Thus, CMV vectors provide unique advantages over other vaccine technologies, eliciting broadly reactive and long-lasting immune responses against COVID-19.

Early combination therapy of COVID-19 in high-risk patients

PurposeProlonged shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been observed in immunocompromised hosts. Early monotherapy with direct-acting antivirals or monoclonal antibodies, as recommended by the international guidelines, does not prevent this with certainty. Dual therapies may therefore have a synergistic effect.MethodsThis retrospective, multicentre study compared treatment strategies for corona virus disease-19 (COVID-19) with combinations of nirmatrelvir/ritonavir, remdesivir, molnupiravir, and/ or mABs during the Omicron surge. Co-primary endpoints were prolonged viral shedding (≥ 106 copies/ml at day 21 after treatment initiation) and days with SARS-CoV-2 viral load ≥ 106 copies/ml. Therapeutic strategies and risk groups were compared using odds ratios and Fisher’s tests or Kaplan−Meier analysis and long-rank tests. Multivariable regression analysis was performed.Results144 patients were included with a median duration of SARS-CoV-2 viral load ≥ 106 copies/ml of 8.0 days (IQR 6.0–15.3). Underlying haematological malignancies (HM) (p = 0.03) and treatment initiation later than five days after diagnosis (p < 0.01) were significantly associated with longer viral shedding. Prolonged viral shedding was observed in 14.6% (n = 21/144), particularly in patients with underlying HM (OR 3.5; 95% CI 1.2–9.9; p = 0.02). Clinical courses of COVID-19 were mild to moderate with only few adverse effects potentially related to combination treatment.ConclusionEarly combination treatment of COVID-19 effectively prevented prolonged viral shedding in 85.6% of cases. Considering the rapid viral clearance rates and low toxicity, individualized dual therapy approaches may be beneficial in high-risk patients.

Immunogenicity and Efficacy of TNX-1800, A Live Virus Recombinant Poxvirus Vaccine Candidate, against SARS-CoV-2 Challenge in Nonhuman Primates.

TNX-1800 is a synthetically derived live recombinant chimeric horsepox virus (rcHPXV) vaccine candidate expressing Wuhan SARS-CoV-2 spike (S) protein. The primary objective of this study was to evaluate the immunogenicity and efficacy of TNX-1800 in two nonhuman primate species challenged with USA-WA1/2020 SARS-CoV-2. TNX-1800 vaccination was well tolerated with no serious adverse events or significant changes in clinical parameters. A single dose of TNX-1800 generated humoral responses in African Green Monkeys and Cynomolgus Macaques, as measured by the total binding of anti-SARS-CoV-2 S IgG and neutralizing antibody titers against the USA-WA1/2020 strain. In addition, a single dose of TNX-1800 induced an interferon-gamma (IFN-γ)-mediated T-cell response in Cynomolgus Macaques. Following challenge with SARS-CoV-2, African Green and Cynomolgus Macaques exhibited rapid clearance of virus in the upper and lower respiratory tract. Future studies will assess the efficacy of TNX-1800 against newly emerging variants and demonstrate its safety in humans.

Neutralizing Antibody Levels as a Correlate of Protection Against SARS-CoV-2 Infection: AModeling Analysis.

Although anti-severe acute respiratory syndrome-coronavirus 2 antibody kinetics have been described in large populations of vaccinated individuals, we still poorly understand how they evolve during a natural infection and how this impacts viral clearance. For that purpose, we analyzed the kinetics of both viral load and neutralizing antibody levels in a prospective cohort of individuals during acute infection with alpha variant. Using a mathematical model, we show that the progressive increase in neutralizing antibodies leads to a shortening of the half-life of both infected cells and infectious viral particles. We estimated that the neutralizing activity reached 90% of its maximal level within 11 days after symptom onset and could reduce the half-life of both infected cells and circulating virus by a 6-fold factor, thus playing a key role to achieve rapid viral clearance. Using this model, we conducted a simulation study to predict in a more general context the protection conferred by pre-existing neutralization titers, due to either vaccination or prior infection. We predicted that a neutralizing activity, as measured by 50% effective dose > 103 , could reduce by 46% the risk of having viral load detectable by standard polymerase chain reaction assays and by 98% the risk of having viral load above the threshold of infectiousness. Our model shows that neutralizing activity could be used to define correlates of protection against infection and transmission.

Gene editing of hematopoietic stem cells restores T-cell response in familial hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory disorder characterized by a life-threatening cytokine storm and immunopathology. Familial HLH type 3 (FHL3) accounts for approximately 30% of all inborn HLH cases worldwide. It is caused by mutations in the UNC13D gene that result in impaired degranulation of cytotoxic vesicles and hence compromised T-cell- and natural killer-cell-mediated killing. Current treatment protocols, including allogeneic hematopoietic stem cell (HSC) transplantation, still show high mortality. We sought to develop and evaluate a curative genome editing strategy in the preclinical FHL3 Jinx mouse model. Jinx mice harbor a cryptic splice donor site in Unc13d intron 26 and develop clinical symptoms of human FHL3 upon infection with lymphocytic choriomeningitis virus (LCMV). We employed clustered regularly interspaced short palindromic repeats (CRISPR)-Cas technology to delete the disease-causing mutation in HSCs and transplanted Unc13d-edited stem cells into busulfan-conditioned Jinx recipient mice. Safety studies included extensive genotyping and chromosomal aberrations analysis by single targeted linker-mediated PCR sequencing (CAST-Seq)-based off-target analyses. Cure from HLH predisposition was assessed by LCMV infection. Hematopoietic cells isolated from transplanted mice revealed efficient gene editing (>95%), polyclonality of the T-cell receptor repertoire, and neither signs of off-target effects nor leukemogenesis. Unc13d transcription levels of edited and wild-type cells were comparable. While LCMV challenge resulted in acute HLH in Jinx mice transplanted with mock-edited HSCs, Jinx mice grafted with Unc13d-edited cells showed rapid virus clearance and protection from HLH. Our study demonstrates that transplantation of CRISPR-Cas edited HSCs supports the development of a functional polyclonal T-cell response in the absence of genotoxicity-associated clonal outgrowth.

A common allele of HLA is associated with asymptomatic SARS-CoV-2 infection

Studies have demonstrated that at least 20% of individuals infected with SARS-CoV-2 remain asymptomatic1–4. Although most global efforts have focused on severe illness in COVID-19, examining asymptomatic infection provides a unique opportunity to consider early immunological features that promote rapid viral clearance. Here, postulating that variation in the human leukocyte antigen (HLA) loci may underly processes mediating asymptomatic infection, we enrolled 29,947 individuals, for whom high-resolution HLA genotyping data were available, in a smartphone-based study designed to track COVID-19 symptoms and outcomes. Our discovery cohort (n = 1,428) comprised unvaccinated individuals who reported a positive test result for SARS-CoV-2. We tested for association of five HLA loci with disease course and identified a strong association between HLA-B*15:01 and asymptomatic infection, observed in two independent cohorts. Suggesting that this genetic association is due to pre-existing T cell immunity, we show that T cells from pre-pandemic samples from individuals carrying HLA-B*15:01 were reactive to the immunodominant SARS-CoV-2 S-derived peptide NQKLIANQF. The majority of the reactive T cells displayed a memory phenotype, were highly polyfunctional and were cross-reactive to a peptide derived from seasonal coronaviruses. The crystal structure of HLA-B*15:01–peptide complexes demonstrates that the peptides NQKLIANQF and NQKLIANAF (from OC43-CoV and HKU1-CoV) share a similar ability to be stabilized and presented by HLA-B*15:01. Finally, we show that the structural similarity of the peptides underpins T cell cross-reactivity of high-affinity public T cell receptors, providing the molecular basis for HLA-B*15:01-mediated pre-existing immunity.

CD44 targeted delivery of oncolytic Newcastle disease virus encapsulated in thiolated chitosan for sustained release in cervical cancer: a targeted immunotherapy approach.

Cervical cancer accounts for one of most common cancers among women of reproductive age. Oncolytic virotherapy has emerged as a promising immunotherapy modality but it comes with several drawbacks that include rapid clearance of virus from body due to immune-neutralization of virus in host. To overcome this, we encapsulated oncolytic Newcastle disease virus (NDV) in polymeric thiolated chitosan nanoparticles. For active targeting of virus loaded nanoformulation against CD44 (cluster of differentiation 44) receptors which are overly expressed on cancer cells, these nanoparticles were surface functionalized with hyaluronic acid (HA). Using half dose of NDV (TCID50 (50% tissue culture infective dose) single dose 3 × 105), virus loaded nanoparticles were prepared by green synthesis approach through ionotropic gelation method. Zeta analysis was performed to analyse size and charge on nanoparticles. Nanoparticles (NPs) shape and size were analysed by SEM (scanning electron microscope) and TEM (transmission electron microscope) while functional group identification was done by FTIR (fourier transform infrared) and XRD (X-ray diffraction). Viral quantification was done by TCID50 and Multiplicity of infection (MOI) determination while oncolytic potential of NPs encapsulated virus was analysed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay and cell morphology analysis. Zeta analysis showed that average size of NDV loaded thiolated chitosan nanoparticles surface functionalized with HA (HA-ThCs-NDV) was 290.4nm with zeta potential of 22.3 mV and 0.265 PDI (polydispersity index). SEM and TEM analysis showed smooth surface and spherical features of nanoparticles. FTIR and XRD confirmed the presence of characteristic functional groups and successful encapsulation of the virus. In vitro release showed continuous but sustained release of NDV for up to 48 hours. TCID50 for HA-ThCs-NDV nanoparticles was 2.63x 106/mL titter and the nanoformulation exhibited high oncolytic potential in cell morphology analysis and MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay as compared to naked virus, in dose dependent manner. These findings suggest that virus encapsulation in thiolated chitosan nanoparticles and surface functionalization with HA is not only helpful in achieving active targeting while masking virus from immune system but, it also gives sustained release of virus in tumor microenvironment for longer period of time that increases bioavailability of virus.

Association of viral kinetics, infection history, NS1 protein with plasma leakage among Indonesian dengue infected patients.

Plasma leakage, a hallmark of disease in Dengue virus (DENV) infection, is an important clinical manifestation and is often associated with numerous factors such as viral factors. The aim of this study is to investigate the association of virus serotype, viral load kinetics, history of infection, and NS1 protein with plasma leakage. Subjects with fever ≤ 48 hours and positive DENV infection were included. Serial laboratory tests, viral load measurements, and ultrasonography examination to assess plasma leakage were performed. DENV-3 was the most common serotype found in the plasma leakage group (35%). Patients with plasma leakage demonstrated a trend of higher viral load and a longer duration of viremia compared to those without. This was significantly observed on the fourth day of fever (p = 0.037). We found higher viral loads on specific days in patients with plasma leakage in both primary and secondary infections compared to those without. In addition, we also observed more rapid viral clearance in patients with secondary infection. NS1 protein, especially after 4 days of fever, was associated with higher peak viral load level, even though it was not statistically significant (p = 0.470). However, pairwise comparison demonstrated that peak viral load level in the group of patients with circulating NS1 detected for 7 days was significantly higher than the 5-day group (p = 0.037). DENV-3 was the most common serotype to cause plasma leakage. Patients with plasma leakage showed a trend of higher viral load and a longer duration of viremia. Higher level of viral load was observed significantly on day 5 in patients with primary infection and more rapid viral clearance was observed in patients with secondary infection. Longer duration of circulating NS1 protein was also seen to be positively correlated with higher peak viral load level although not statistically significant.

Temporal intra-host variability of mpox virus genomes in multiple body tissues.

Whole-genome sequencing (WGS) has been widely used for the genomic characterization and the phylogenesis of mpox virus (MPXV) 2022 multi-country outbreak. To date, no evidence has been reported on intra-host evolution within samples collected over time from a single patient with long-term infection. Fifty-one samples were collected from five patients at different time points post-symptom onset. All samples were confirmed as MPXV DNA positive, amplified by a multiplexed PCR amplicon, and sequenced by WGS. Complete MPXV genomes were assembled by reference mapping and then aligned to perform phylogenetic and hierarchical clustering analysis. Large intra-host variability was observed among the MPXV genomes sequenced from samples of two immunocompromised with advanced HIV-1 infection patients with prolonged MPXV shedding. Overall, 20 nucleotide mutations were identified in the 32 genomes from HIV patients, differently distributed in samples collected from different tissues and at different time points. No sequence compartmentalization nor variation was observed in the three patients with rapid viral clearance. MPXV exhibits adaptation to changing environments within the infected host and consequently demonstrates tissue compartmentalization. Further studies are needed to elucidate the role of this adaptation in forming a pool of genetic variability and contributing to viral persistence and its clinical implications.

Live-attenuated vaccine sCPD9 elicits superior mucosal and systemic immunity to SARS-CoV-2 variants in hamsters

Vaccines play a critical role in combating the COVID-19 pandemic. Future control of the pandemic requires improved vaccines with high efficacy against newly emerging SARS-CoV-2 variants and the ability to reduce virus transmission. Here we compare immune responses and preclinical efficacy of the mRNA vaccine BNT162b2, the adenovirus-vectored spike vaccine Ad2-spike and the live-attenuated virus vaccine candidate sCPD9 in Syrian hamsters, using both homogeneous and heterologous vaccination regimens. Comparative vaccine efficacy was assessed by employing readouts from virus titrations to single-cell RNA sequencing. Our results show that sCPD9 vaccination elicited the most robust immunity, including rapid viral clearance, reduced tissue damage, fast differentiation of pre-plasmablasts, strong systemic and mucosal humoral responses, and rapid recall of memory T cells from lung tissue after challenge with heterologous SARS-CoV-2. Overall, our results demonstrate that live-attenuated vaccines offer advantages over currently available COVID-19 vaccines.

An Oral Galectin Inhibitor in COVID-19-A Phase II Randomized Controlled Trial.

SARS-CoV-2 vaccines play an important role in reducing disease severity, hospitalization, and death, although they failed to prevent the transmission of SARS-CoV-2 variants. Therefore, an effective inhibitor of galectin-3 (Gal-3) could be used to treat and prevent the transmission of COVID-19. ProLectin-M (PL-M), a Gal-3 antagonist, was shown to interact with Gal-3 and thereby prevent cellular entry of SARS-CoV-2 in previous studies. The present study aimed to further evaluate the therapeutic effect of PL-M tablets in 34 subjects with COVID-19. The efficacy of PL-M was evaluated in a randomized, double-blind, placebo-controlled clinical study in patients with mild to moderately severe COVID-19. Primary endpoints included changes in the absolute RT-PCR Ct values of the nucleocapsid and open reading frame (ORF) genes from baseline to days 3 and 7. The incidence of adverse events, changes in blood biochemistry, inflammatory biomarkers, and levels of antibodies against COVID-19 were also evaluated as part of the safety evaluation. PL-M treatment significantly (p = 0.001) increased RT-PCR cycle counts for N and ORF genes on days 3 (Ct values 32.09 ± 2.39 and 30.69 ± 3.38, respectively) and 7 (Ct values 34.91 ± 0.39 and 34.85 ± 0.61, respectively) compared to a placebo treatment. On day 3, 14 subjects in the PL-M group had cycle counts for the N gene above the cut-off value of 29 (target cycle count 29), whereas on day 7, all subjects had cycle counts above the cut-off value. Ct values in placebo subjects were consistently less than 29, and no placebo subjects were RT-PCR-negative until day 7. Most of the symptoms disappeared completely after receiving PL-M treatment for 7 days in more patients compared to the placebo group. PL-M is safe and effective for clinical use in reducing viral loads and promoting rapid viral clearance in COVID-19 patients by inhibiting SARS-CoV-2 entry into cells through the inhibition of Gal-3.

Susceptibility and Permissivity of Zebrafish (Danio rerio) Larvae to Cypriniviruses

The zebrafish (Danio rerio) represents an increasingly important model organism in virology. We evaluated its utility in the study of economically important viruses from the genus Cyprinivirus (anguillid herpesvirus 1, cyprinid herpesvirus 2 and cyprinid herpesvirus 3 (CyHV-3)). This revealed that zebrafish larvae were not susceptible to these viruses after immersion in contaminated water, but that infections could be established using artificial infection models in vitro (zebrafish cell lines) and in vivo (microinjection of larvae). However, infections were transient, with rapid viral clearance associated with apoptosis-like death of infected cells. Transcriptomic analysis of CyHV-3-infected larvae revealed upregulation of interferon-stimulated genes, in particular those encoding nucleic acid sensors, mediators of programmed cell death and related genes. It was notable that uncharacterized non-coding RNA genes and retrotransposons were also among those most upregulated. CRISPR/Cas9 knockout of the zebrafish gene encoding protein kinase R (PKR) and a related gene encoding a protein kinase containing Z-DNA binding domains (PKZ) had no impact on CyHV-3 clearance in larvae. Our study strongly supports the importance of innate immunity-virus interactions in the adaptation of cypriniviruses to their natural hosts. It also highlights the potential of the CyHV-3-zebrafish model, versus the CyHV-3-carp model, for study of these interactions.

Preemptive antiviral therapy in lung transplantation from hepatitis C donors results in a rapid and sustained virologic response

ObjectiveThe study objective was to assess the safety and efficacy of a preemptive direct-acting antiviral therapy in lung transplants from hepatitis C virus donors to uninfected recipients. MethodsThis study is a prospective, open-label, nonrandomized, pilot trial. Recipients of hepatitis C virus nucleic acid test positive donor lungs underwent preemptive direct-acting antiviral therapy with glecaprevir 300 mg/pibrentasvir 120 mg for 8 weeks from January 1, 2019, to December 31, 2020. Recipients of nucleic acid test positive lungs were compared with recipients of lungs from nucleic acid test negative donors. Primary end points were Kaplan–Meier survival and sustained virologic response. Secondary outcomes included primary graft dysfunction, rejection, and infection. ResultsFifty-nine lung transplantations were included: 16 nucleic acid test positive and 43 nucleic acid test negative. Twelve nucleic acid test positive recipients (75%) developed hepatitis C virus viremia. Median time to clearance was 7 days. All nucleic acid test positive patients had undetectable hepatitis C virus RNA by week 3, and all alive patients (n = 15) remained negative during follow-up with 100% sustained virologic response at 12 months. One nucleic acid test positive patient died of primary graft dysfunction and multiorgan failure. Three of 43 nucleic acid test negative patients (7%) had hepatitis C virus antibody positive donors. None of them developed hepatitis C virus viremia. One-year survival was 94% for nucleic acid test positive recipients and 91% for nucleic acid test negative recipients. There was no difference in primary graft dysfunction, rejection, or infection. One-year survival for nucleic acid test positive recipients was similar to a historical cohort of the Scientific Registry of Transplant Recipients (89%). ConclusionsRecipients of hepatitis C virus nucleic acid test positive lungs have similar survival as recipients of nucleic acid test negative lungs. Preemptive direct-acting antiviral therapy results in rapid viral clearance and sustained virologic response at 12 months. Preemptive direct-acting antiviral may partially prevent hepatitis C virus transmission.

Can T Cells Abort SARS-CoV-2 and Other Viral Infections?

Despite the highly infectious nature of the SARS-CoV-2 virus, it is clear that some individuals with potential exposure, or even experimental challenge with the virus, resist developing a detectable infection. While a proportion of seronegative individuals will have completely avoided exposure to the virus, a growing body of evidence suggests a subset of individuals are exposed, but mediate rapid viral clearance before the infection is detected by PCR or seroconversion. This type of "abortive" infection likely represents a dead-end in transmission and precludes the possibility for development of disease. It is, therefore, a desirable outcome on exposure and a setting in which highly effective immunity can be studied. Here, we describe how early sampling of a new pandemic virus using sensitive immunoassays and a novel transcriptomic signature can identify abortive infections. Despite the challenges in identifying abortive infections, we highlight diverse lines of evidence supporting their occurrence. In particular, expansion of virus-specific T cells in seronegative individuals suggests abortive infections occur not only after exposure to SARS-CoV-2, but for other coronaviridae, and diverse viral infections of global health importance (e.g., HIV, HCV, HBV). We discuss unanswered questions related to abortive infection, such as: 'Are we just missing antibodies? Are T cells an epiphenomenon? What is the influence of the dose of viral inoculum?' Finally, we argue for a refinement of the current paradigm that T cells are only involved in clearing established infection; instead, we emphasise the importance of considering their role in terminating early viral replication by studying abortive infections.

Relationship between Disease Severity, Immune Response, and Viral Clearance in Unvaccinated Patients with COVID-19: A Cross-sectional Study

Introduction: The clinical manifestations of Coronavirus Disease-2019 (COVID-19) range from asymptomatic cases to severe respiratory failure. It is unclear whether disease severity is determined by an excess viral load or a dysregulated immune response. It is also unclear whether the severe immune response is successful in rapid viral clearance. Aim: To understand the relationship between immune response, viral clearance, and the severity of illness in unvaccinated patients suffering from COVID-19. Materials and Methods: This was a cross-sectional observational study of 65 unvaccinated patients suffering from Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) confirmed COVID-19, conducted at a dedicated COVID-19 centre, Dr. D.Y. Patil Hospital, Pimpri, Pune, Maharashtra, India. from September 2020 to April 2021. The subjects were enrolled between day 10 and day 14 of the onset of symptoms and from two distinct clinical groups. Group A consisted of 34 mild cases, and Group B consisted of 31 severe cases, classified according to the national guidelines issued by the Indian Council of Medical Research (ICMR). The clinical progress of the illness and laboratory test records were carefully reviewed. A repeat throat swab for Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) RTPCR, blood levels of COVID-19 specific antibodies Immunoglobin G (IgG) and IgM, C-reactive protein (CRP), and D-dimer levels were measured on day 14 of the illness. The data were analysed using MedCalc and Epi Info software. Chi-square and Fisher’sExact tests were used to assess variables such as viral detection, antibody response, and inflammatory markers. Results: In Group A, 2/34 (5.88%) patients tested RT-PCR negative {Cycle threshold (Ct) value cut-off above 35} compared to 5/31 (16.13%) in Group B (p=0.0829). In Groups A and B, respectively, the mean antibody titers were 35390.47 and 36426.11 (p=0.7469), the mean CRP values were 4.91 (p&lt;0.001) and 31.01 mg/dL, and the mean D-dimer levels were 895 and 2896 ng/mL (p&lt;0.001). Conclusion: Both mild and severe COVID-19 cases had a significant antibody response which, however, did not help in viral clearance. Most patients remained RT-PCR positive on day 14 regardless of the disease severity.

Modelling the spatial dynamics of oncolytic virotherapy in the presence of virus-resistant tumour cells.

Oncolytic virotherapy is a promising form of cancer treatment that uses native or genetically engineered viruses to target, infect and kill cancer cells. Unfortunately, this form of therapy is not effective in a substantial proportion of cancer patients, partly due to the occurrence of infection-resistant tumour cells. To shed new light on the mechanisms underlying therapeutic failure and to discover strategies that improve therapeutic efficacy we designed a cell-based model of viral infection. The model allows us to investigate the dynamics of infection-sensitive and infection-resistant cells in tumour tissue in presence of the virus. To reflect the importance of the spatial configuration of the tumour on the efficacy of virotherapy, we compare three variants of the model: two 2D models of a monolayer of tumour cells and a 3D model. In all model variants, we systematically investigate how the therapeutic outcome is affected by the properties of the virus (e.g. the rate of viral spread), the tumour (e.g. production rate of resistant cells, cost of resistance), the healthy stromal cells (e.g. degree of resistance to the virus) and the timing of treatment. We find that various therapeutic outcomes are possible when resistant cancer cells arise at low frequency in the tumour. These outcomes depend in an intricate but predictable way on the death rate of infected cells, where faster death leads to rapid virus clearance and cancer persistence. Our simulations reveal three different causes of therapy failure: rapid clearance of the virus, rapid selection of resistant cancer cells, and a low rate of viral spread due to the presence of infection-resistant healthy cells. Our models suggest that improved therapeutic efficacy can be achieved by sensitizing healthy stromal cells to infection, although this remedy has to be weighed against the toxicity induced in the healthy tissue.