Viruses

Background: The impact of respiratory virus infection in patients diagnosed with ataxia-telangiectasia (A-T) has not been well studied. Methods: A prospective case control study was performed at a National Reference Unit for Primary Immunodeficiency in Spain (from November 2018 to July 2019), including patients younger than 20 years. Symptom questionnaires and nasopharyngeal swabs from multiple respiratory viruses’ polymerase chain reaction were collected monthly, and between visits in case of symptoms. Results: Twenty-two individuals were included (11 patients; 11 controls); 164 samples were obtained (81 patients; 84 controls). Patients presented respiratory symptoms more frequently compared with controls (26.5% vs. 3.5%; p < 0.01). Viral detection was observed in 23 (27.3%) episodes in patients and in 15 (17.8%) episodes in controls (p = 0.1). Rhinovirus was the most frequent virus in patients and controls (60% and 53.3%, respectively). Episodes with positive viral detection had associated symptoms in 54% of patients and 18% of controls (p = 0.07). However, patients with A-T presented a similar rate of symptoms during episodes with positive and negative viral detection (26% vs. 27%). The median points given for each questionnaire during symptomatic episodes with negative viral detection were 13/23 points, and during symptomatic positive detection, 7.5/23 points (p = 0.1). In the control group, all but two were asymptomatic during positive viral episodes (score: 2/23 and 3/23 points). Symptomatic episodes, with either positive or negative viral detection, were associated with lower IgA and higher IgM titers and higher CD8+ counts (p < 0.05), particularly when these episodes were moderate/severe. Conclusions: Patients with A-T more frequently present symptomatic viral infections than controls, especially those with lower IgA and higher IgM titers and higher CD8+ counts. Full article

Human cytomegalovirus (CMV) is the leading cause of neurological sequelae in infants. Understanding the risk factors of primary CMV infection is crucial in establishing preventive strategies. Thus, we conducted a retrospective cohort study to identify risk factors of vertical transmission among pregnant women with immunoglobulin (Ig) M positivity. The study included 456 pregnant women with IgM positivity. Information on age, parity, occupation, clinical signs, IgM levels, and IgG avidity index (AI) was collected. The women were divided into infected and non-infected groups. The two groups showed significant differences in IgM level, IgG AI, number of women with low IgG AI, clinical signs, and number of pregnant women with single parity. In the multiple logistic regression analysis, pregnant women with single parity and low IgG AI were independent predictors. Among 40 women who tested negative for IgG antibody in their previous pregnancy, 20 showed low IgG AI in their current pregnancy. Among the 20 women, 4 had vertical transmission. These results provide better understanding of the risk factors of vertical transmission in pregnant women with IgM positivity. Full article

In Belgium, the incorporation of phages into magistral preparations for human application has been permitted since 2018. The stability of such preparations is of high importance to guarantee quality and efficacy throughout treatments. We evaluated the ability to preserve infectivity of four different phages active against three different bacterial species in five different buffer and infusion solutions commonly used in medicine and biotechnological manufacturing processes, at two different concentrations (9 and 7 log pfu/mL), stored at 4 °C. DPBS without Ca²⁺ and Mg²⁺ was found to be the best option, compared to the other solutions. Suspensions with phage concentrations of 7 log pfu/mL were unsuited as their activity dropped below the effective therapeutic dose (6–9 log pfu/mL), even after one week of storage at 4 °C. Strong variability between phages was observed, with Acinetobacter baumannii phage Acibel004 being stable in four out of five different solutions. We also studied the long term storage of lyophilized staphylococcal phage ISP, and found that the titer could be preserved during a period of almost 8 years when sucrose and trehalose were used as stabilizers. After rehydration of the lyophilized ISP phage in saline, the phage solutions remained stable at 4 °C during a period of 126 days. Full article

We previously developed a refined, tumor-selective adenovirus, Ad5_NULL-A20, harboring tropism ablating mutations in each major capsid protein, to ablate all native means of infection. We incorporated a 20-mer peptide (A20) in the fiber knob for selective infection via αvβ6 integrin, a marker of aggressive epithelial cancers. Methods: To ascertain the selectivity of Ad5_NULL-A20 for αvβ6-positive tumor cell lines of pancreatic and breast cancer origin, we performed reporter gene and cell viability assays. Biodistribution of viral vectors in mice harboring xenografts with low, medium, and high αvβ6 levels was quantified by qPCR for viral genomes 48 h post intravenous administration. Results: Ad5_NULL-A20 vector transduced cells in an αvβ6-selective manner, whilst cell killing mediated by oncolytic Ad5_NULL-A20 was αvβ6-selective. Biodistribution analysis following intravenous administration into mice bearing breast cancer xenografts demonstrated that Ad5_NULL-A20 resulted in significantly reduced liver accumulation coupled with increased tumor accumulation compared to Ad5 in all three models, with tumor-to-liver ratios improved as a function of αvβ6 expression. Conclusions: Ad5_NULL-A20-based virotherapies efficiently target αvβ6-integrin-positive tumors following intravenous administration, validating the potential of Ad5_NULL-A20 for systemic applications, enabling tumor-selective overexpression of virally encoded therapeutic transgenes. Full article

There were an estimated 10 million new cases of tuberculosis (TB) disease in 2019. While over 90% of individuals successfully control Mycobacterium tuberculosis (Mtb) infection, which causes TB disease, HIV co-infection often leads to active TB disease. Despite the co-endemic nature of HIV and TB, knowledge of the immune mechanisms contributing to the loss of control of Mtb replication during HIV infection is lacking. Mucosal-associated invariant T (MAIT) cells are innate-like T cells that target and destroy bacterially-infected cells and may contribute to the control of Mtb infection. Studies examining MAIT cells in human Mtb infection are commonly performed using peripheral blood samples. However, because Mtb infection occurs primarily in lung tissue and lung-associated lymph nodes, these studies may not be fully translatable to the tissues. Additionally, studies longitudinally examining MAIT cell dynamics during HIV/Mtb co-infection are rare, and lung and lymph node tissue samples from HIV+ patients are typically unavailable. Nonhuman primates (NHP) provide a model system to characterize MAIT cell activity during Mtb infection, both in Simian Immunodeficiency Virus (SIV)-infected and SIV-naïve animals. Using NHPs allows for a more comprehensive understanding of tissue-based MAIT cell dynamics during infection with both pathogens. NHP SIV and Mtb infection is similar to human HIV and Mtb infection, and MAIT cells are phenotypically similar in humans and NHPs. Here, we discuss current knowledge surrounding MAIT cells in SIV and Mtb infection, how SIV infection impairs MAIT cell function during Mtb co-infection, and knowledge gaps to address. Full article

Hepatocellular carcinoma (HCC) is one of the most frequent and fatal human cancers worldwide and its development and prognosis are intimately associated with chronic infection with hepatitis B virus (HBV). The identification of genetic mutations and molecular mechanisms that mediate HBV-induced tumorigenesis therefore holds promise for the development of potential biomarkers and targets for HCC prevention and therapy. The presence of HBV pre-S gene deletions in the blood and the expression of pre-S deleted proteins in the liver tissues of patients with chronic hepatitis B and HBV-related HCC have emerged as valuable biomarkers for higher incidence rates of HCC development and a higher risk of HCC recurrence after curative surgical resection, respectively. Moreover, pre-S deleted proteins are regarded as important oncoproteins that activate multiple signaling pathways to induce DNA damage and promote growth and proliferation in hepatocytes, leading to HCC development. The signaling molecules dysregulated by pre-S deleted proteins have also been validated as potential targets for the prevention of HCC development. In this review, we summarize the clinical and molecular implications of HBV pre-S gene deletions and pre-S deleted proteins in HCC development and recurrence and highlight their potential applications in HCC prevention and therapy. Full article

Hepatitis A virus (HAV) infection is a common cause of acute viral hepatitis worldwide. Despite decades of research, the pathogenic mechanisms of hepatitis A remain incompletely understood. As the replication of HAV is noncytopathic in vitro, a widely accepted concept has been that virus-specific cytotoxic T cells are responsible for liver injury. However, accumulating evidence suggests that natural killer (NK) cells, NKT cells, and even non-HAV-specific CD8⁺ T cells contribute to liver damage during HAV infection. In addition, intrinsic death of virus-infected hepatocytes has been implicated as a cause of liver injury in a murine model of hepatitis A. Furthermore, genetic variations in host factors such as T cell immunoglobulin-1 (TIM1) and IL-18 binding protein (IL-18BP) have been linked to hepatitis A severity. This review summarizes the current knowledge of the mechanisms of hepatocellular injury in hepatitis A. Different mechanisms may be involved under different conditions and they are not necessarily mutually exclusive. A better understanding of these mechanisms would aid in diagnosis and treatment of diseases associated with HAV infection. Full article

Bat flies (Hippoboscoidea: Nycteribiidae and Streblidae) are obligate hematophagous ectoparasites of bats. We collected streblid bat flies from the New World (México) and the Old World (Uganda), and used metagenomics to identify their viruses. In México, we found méjal virus (Rhabdoviridae; Vesiculovirus), Amate virus (Reoviridae: Orbivirus), and two unclassified viruses of invertebrates. Méjal virus is related to emerging zoonotic encephalitis viruses and to the agriculturally important vesicular stomatitis viruses (VSV). Amate virus and its sister taxon from a bat are most closely related to mosquito- and tick-borne orbiviruses, suggesting a previously unrecognized orbivirus transmission cycle involving bats and bat flies. In Uganda, we found mamucuso virus (Peribunyaviridae: Orthobunyavirus) and two unclassified viruses (a rhabdovirus and an invertebrate virus). Mamucuso virus is related to encephalitic viruses of mammals and to viruses from nycteribiid bat flies and louse flies, suggesting a previously unrecognized orthobunyavirus transmission cycle involving hippoboscoid insects. Bat fly virus transmission may be neither strictly vector-borne nor strictly vertical, with opportunistic feeding by bat flies occasionally leading to zoonotic transmission. Many “bat-associated” viruses, which are ecologically and epidemiologically associated with bats but rarely or never found in bats themselves, may actually be viruses of bat flies or other bat ectoparasites. Full article

The human γ-herpesviruses Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) encode oncogenes for B cell transformation but are carried by most infected individuals without symptoms. For this purpose, they manipulate the anti-apoptotic pathway macroautophagy, cellular proliferation and apoptosis, as well as immune recognition. The mechanisms and functional relevance of these manipulations are discussed in this review. They allow both viruses to strike the balance between efficient persistence and dissemination in their human hosts without ever being cleared after infection and avoiding pathologies in most of their carriers. Full article

The bluetongue virus (BTV) is transmitted by Culicoides biting midges and causes bluetongue (BT), an OIE-notifiable disease of ruminants. At least 29 BTV serotypes are described as determined by the outer shell proteins VP2 and VP5. Vaccination is the most effective control measure. Inactivated and live-attenuated vaccines (LAVs) are currently available. These vaccines have their specific pros and cons, and both are not DIVA vaccines. The BT Disabled Infectious Single Animal (DISA) vaccine platform is based on LAV without nonessential NS3/NS3a expression and is applicable for many serotypes by the exchange of outer shell proteins. The DISA vaccine is effective and completely safe. Further, transmission of the DISA vaccine by midges is blocked (DISA principle). Finally, the DISA vaccine enables DIVA because of a lack of antibodies against the immunogenic NS3/NS3a protein (DIVA principle). The deletion of 72 amino acids (72aa) in NS3/NS3a is sufficient to block virus propagation in midges. Here, we show that a prototype DISA vaccine based on LAV with the 72aa deletion enables DIVA, is completely safe and induces a long-lasting serotype-specific protection in cattle. In conclusion, the in-frame deletion of 72-aa codons in the BT DISA/DIVA vaccine platform is sufficient to fulfil all the criteria for modern veterinary vaccines. Full article

Low-pathogenicity avian influenza viruses (LPAIV) introduced by migratory birds circulate in wild birds and can be transmitted to poultry. These viruses can mutate to become highly pathogenic avian influenza viruses causing severe disease and death in poultry. In March 2019, an H7N3 avian influenza virus—A/Spot-billed duck/South Korea/WKU2019-1/2019 (H7N3)—was isolated from spot-billed ducks in South Korea. This study aimed to evaluate the phylogenetic and mutational analysis of this isolate. Molecular analysis revealed that the genes for HA (hemagglutinin) and NA (neuraminidase) of this strain belonged to the Central Asian lineage, whereas genes for other internal proteins such as polymerase basic protein 1 (PB1), PB2, nucleoprotein, polymerase acidic protein, matrix protein, and non-structural protein belonged to that of the Korean lineage. In addition, a monobasic amino acid (PQIEPR/GLF) at the HA cleavage site, and the non-deletion of the stalk region in the NA gene indicated that this isolate was a typical LPAIV. Nucleotide sequence similarity analysis of HA revealed that the highest homology (99.51%) of this isolate is to that of A/common teal/Shanghai/CM1216/2017 (H7N7), and amino acid sequence of NA (99.48%) was closely related to that of A/teal/Egypt/MB-D-487OP/2016 (H7N3). An in vitro propagation of the A/Spot-billed duck/South Korea/WKU2019-1/2019 (H7N3) virus showed highest (7.38 Log₁₀ TCID₅₀/mL) virus titer at 60 h post-infection, and in experimental mouse lungs, the virus was detected at six days’ post-infection. Our study characterizes genetic mutations, as well as pathogenesis in both in vitro and in vivo model of a new Korea H7N3 viruses in 2019, carrying multiple potential mutations to become highly pathogenic and develop an ability to infect humans; thus, emphasizing the need for routine surveillance of avian influenza viruses in wild birds. Full article

Sexually transmitted infections (STIs) represent a worldwide public health problem and, although many of them are curable, they continue to be neglected, especially in areas with a low human development index, such as in the northern region of Brazil. This review describes the results of 30 years of studies at the Virus Laboratory at the Federal University of Pará, including the prevalence and molecular epidemiology of HIV-1, HTLV-1/2, HPV, HBV, Treponema pallidum and Chlamydia trachomatis among urban and non-urban populations, and also in vulnerable groups in the Brazilian Amazon. Control strategies and challenges in preventing STIs are discussed considering this immense geographic region, where essential health services are unable to reach the entire population, especially the most vulnerable, such as female sex workers, people who use illicit drugs, remnants of quilombolos and indigenous communities. Full article

The future prevalence and virulence of SARS-CoV-2 is uncertain. Some emerging pathogens become avirulent as populations approach herd immunity. Although not all viruses follow this path, the fact that the seasonal coronaviruses are benign gives some hope. We develop a general mathematical model to predict when the interplay among three factors, correlation of severity in consecutive infections, population heterogeneity in susceptibility due to age, and reduced severity due to partial immunity, will promote avirulence as SARS-CoV-2 becomes endemic. Each of these components has the potential to limit severe, high-shedding cases over time under the right circumstances, but in combination they can rapidly reduce the frequency of more severe and infectious manifestation of disease over a wide range of conditions. As more reinfections are captured in data over the next several years, these models will help to test if COVID-19 severity is beginning to attenuate in the ways our model predicts, and to predict the disease. Full article

Pregnant women who are infected with SARS-CoV-2 are at an increased risk of adverse perinatal outcomes. With this study, we aimed to better understand the relationship between maternal infection and perinatal outcomes, especially preterm births, and the underlying medical and interventionist factors. This was a prospective observational study carried out in 78 centers (Spanish Obstetric Emergency Group) with a cohort of 1347 SARS-CoV-2 PCR-positive pregnant women registered consecutively between 26 February and 5 November 2020, and a concurrent sample of PCR-negative mothers. The patients’ information was collected from their medical records, and the association of SARS-CoV-2 and perinatal outcomes was evaluated by univariable and multivariate analyses. The data from 1347 SARS-CoV-2-positive pregnancies were compared with those from 1607 SARS-CoV-2-negative pregnancies. Differences were observed between both groups in premature rupture of membranes (15.5% vs. 11.1%, p < 0.001); venous thrombotic events (1.5% vs. 0.2%, p < 0.001); and severe pre-eclampsia incidence (40.6 vs. 15.6%, p = 0.001), which could have been overestimated in the infected cohort due to the shared analytical signs between this hypertensive disorder and COVID-19. In addition, more preterm deliveries were observed in infected patients (11.1% vs. 5.8%, p < 0.001) mainly due to an increase in iatrogenic preterm births. The prematurity in SARS-CoV-2-affected pregnancies results from a predisposition to end the pregnancy because of maternal disease (pneumonia and pre-eclampsia, with or without COVID-19 symptoms). Full article

The HIV-1 envelope glycoprotein (Env) mediates host cell fusion and is the primary target for HIV-1 vaccine design. The Env undergoes a series of functionally important conformational rearrangements upon engagement of its host cell receptor, CD4. As the sole target for broadly neutralizing antibodies, our understanding of these transitions plays a critical role in vaccine immunogen design. Here, we review available experimental data interrogating the HIV-1 Env conformation and detail computational efforts aimed at delineating the series of conformational changes connecting these rearrangements. These studies have provided a structural mapping of prefusion closed, open, and transition intermediate structures, the allosteric elements controlling rearrangements, and state-to-state transition dynamics. The combination of these investigations and innovations in molecular modeling set the stage for advanced studies examining rearrangements at greater spatial and temporal resolution. Full article

Natural hosts of most arenaviruses are rodents. The human-pathogenic Lassa virus and several non-pathogenic arenaviruses such as Morogoro virus (MORV) share the same host species, namely Mastomys natalensis (M. natalensis). In this study, we investigated the history of infection and virus transmission within the natural host population. To this end, we infected M. natalensis at different ages with MORV and measured the health status of the animals, virus load in blood and organs, the development of virus-specific antibodies, and the ability of the infected individuals to transmit the virus. To explore the impact of the lack of evolutionary virus–host adaptation, experiments were also conducted with Mobala virus (MOBV), which does not share M. natalensis as a natural host. Animals infected with MORV up to two weeks after birth developed persistent infection, seroconverted and were able to transmit the virus horizontally. Animals older than two weeks at the time of infection rapidly cleared the virus. In contrast, MOBV-infected neonates neither developed persistent infection nor were able to transmit the virus. In conclusion, we demonstrate that MORV is able to develop persistent infection in its natural host, but only after inoculation shortly after birth. A related arenavirus that is not evolutionarily adapted to M. natalensis is not able to establish persistent infection. Persistently infected animals appear to be important to maintain virus transmission within the host population. Full article

MUC1 belongs to the family of cell surface (cs-) mucins. Experimental evidence indicates that its presence reduces in vivo influenza viral infection severity. However, the mechanisms by which MUC1 influences viral dynamics and the host immune response are not yet well understood, limiting our ability to predict the efficacy of potential treatments that target MUC1. To address this limitation, we use available in vivo kinetic data for both virus and macrophage populations in wildtype and MUC1 knockout mice. We apply two mathematical models of within-host influenza dynamics to this data. The models differ in how they categorise the mechanisms of viral control. Both models provide evidence that MUC1 reduces the susceptibility of epithelial cells to influenza virus and regulates macrophage recruitment. Furthermore, we predict and compare some key infection-related quantities between the two mice groups. We find that MUC1 significantly reduces the basic reproduction number of viral replication as well as the number of cumulative macrophages but has little impact on the cumulative viral load. Our analyses suggest that the viral replication rate in the early stages of infection influences the kinetics of the host immune response, with consequences for infection outcomes, such as severity. We also show that MUC1 plays a strong anti-inflammatory role in the regulation of the host immune response. This study improves our understanding of the dynamic role of MUC1 against influenza infection and may support the development of novel antiviral treatments and immunomodulators that target MUC1. Full article

More than one year into the novel coronavirus disease 2019 (COVID-19) pandemic, healthcare systems across the world continue to be overwhelmed with soaring daily cases. The treatment spectrum primarily includes ventilation support augmented with repurposed drugs and/or convalescent plasma transfusion (CPT) from recovered COVID-19 patients. Despite vaccine variants being recently developed and administered in several countries, challenges in global supply chain logistics limit their timely availability to the wider world population, particularly in developing countries. Given the measured success of conventional CPT in treating several infections over the past decade, recent studies have reported its effectiveness in decreasing the duration and severity of COVID-19 symptoms. In this review, we conduct a literature search of published studies investigating the use of CPT to treat COVID-19 patients from January 2020 to January 2021. The literature search identified 181 records of which 39 were included in this review. A random-effects model was used to aggregate data across studies, and mortality rates of 17 vs. 32% were estimated for the CPT and control patient groups, respectively, with an odds ratio (OR) of 0.49. The findings indicate that CPT shows potential in reducing the severity and duration of COVID-19 symptoms. However, early intervention (preferably within 3 days), recruitment of donors, and plasma potency introduce major challenges for its scaled-up implementation. Given the low number of existing randomized clinical trials (RCTs, four with a total of 319 patients), unanticipated risks to CPT recipients are highlighted and discussed. Nevertheless, CPT remains a promising COVID-19 therapeutic option that merits internationally coordinated RCTs to achieve a scientific risk–benefit consensus. Full article