Viral Factors Research Articles

COVID-19 liver damage. Features of laboratory and instrumental diagnostics

The aim of the study - to analyze the pathogenesis of liver damage in COVID-19, as well as to study the features of diagnosis. Research materials: literature and own data on the peculiarities of the pathogenesis of liver damage were analyzed, as well as an assessment of laboratory and instrumental diagnostics in patients with COVID-19. The results of the research. In patients, liver damage was manifested by an increase in liver enzymes, as well as a diffuse decrease in its density during CT. The severity of the disease is caused by a cytokine storm caused by a dysfunctional immune response to the virus, viral virulence factors, as well as the presence of concomitant diseases, especially those associated with liver pathology, such as cirrhosis or steatosis. Conclusions. The new COVID-19 coronavirus infection caused by SARS-CoV-2 continues to spread worldwide. The main target is the organs of the respiratory system. However, among the patients with COVID-19, there were lesions of the central nervous system, intestines, myocardium and liver. Liver dysfunction in most cases should be considered as a result of secondary damage due to CVD, ARDS, hypoxia, multiple organ failure, exposure to immune factors, and taking hepatotoxic drugs.

Variation in Viral Tolerance of 21 Grapevine Rootstocks

Grapevine is one of the most economically important fruit crops cultivated worldwide. However, grapevine is highly susceptible to virus infections and exposed to the most diverse forms of viral diseases compared to other fruit crops, and virus-induced incompatibility affects plant growth to different degrees ranging from decline to death. The influence of virus-induced incompatibility could be mitigated to an acceptable level by using appropriate rootstocks. However, the viral tolerance of various grapevine rootstocks with diverse genetic backgrounds remains unclear, along with the identification of the specific viral tolerance factors. In this study, the viral tolerance of 21 grapevine rootstocks was evaluated in a green grafting system. Cabernet Franc varieties infected with a single virus [grapevine leafroll associated virus-1 (GLRaV-1)], a co-infection of two viruses (GLRaV-1 plus grapevine virus A—GVA), and no infection were used as the scions, respectively. The vegetative growth and photosynthetic function of the grafts were analyzed 4 months after grafting. The results indicated that some rootstocks could alleviate the influence of the virus infection, with vegetative growth and photosynthetic function sustained at a normal level, whereas other rootstocks were susceptible to the virus infection, resulting in a decline in the growth and photosynthetic function of the grafts. Our research provides evidence for the existence and diversity of viral tolerance among grapevine rootstocks, offering important information for appropriate rootstock selection in the establishment of new vineyards and in the breeding of grapevine rootstocks with enhanced viral tolerance.

The in vitro replication phenotype of hepatitis B virus (HBV) splice variants Sp3 and Sp9 and their impact on wild-type HBV replication.

The role of hepatitis B virus (HBV) splice variants in HBV replication and pathogenesis currently remains largely unknown. However, HBV splice variants have been associated with the development of hepatocellular carcinoma, suggesting a role in HBV pathogenesis. Several in vitro co-transfection studies have shown that different splice variants have varying impacts on wild-type HBV replication, perhaps contributing to viral persistence. Furthermore, all splice variants are predicted to produce novel fusion proteins. Sp1 hepatitis B splice protein contributes to liver disease progression and apoptosis; however, the function of other HBV splice variant novel fusion proteins remains largely unknown. We show that Sp9 markedly impairs HBV replication in a cell culture co-transfection model, mediated by expression of Sp9 novel fusion proteins. In contrast, Sp3 had no effect on wild-type HBV replication. Together, these studies provide further insights into viral factors contributing to regulation of HBV replication.

Overview of the immunological mechanisms in hepatitis B virus reactivation: Implications for disease progression and management strategies

Hepatitis B virus (HBV) reactivation is a clinically significant challenge in disease management. This review explores the immunological mechanisms underlying HBV reactivation, emphasizing disease progression and management. It delves into host immune responses and reactivation’s delicate balance, spanning innate and adaptive immunity. Viral factors’ disruption of this balance, as are interactions between viral antigens, immune cells, cytokine networks, and immune checkpoint pathways, are examined. Notably, the roles of T cells, natural killer cells, and antigen-presenting cells are discussed, highlighting their influence on disease progression. HBV reactivation’s impact on disease severity, hepatic flares, liver fibrosis progression, and hepatocellular carcinoma is detailed. Management strategies, including anti-viral and immunomodulatory approaches, are critically analyzed. The role of prophylactic anti-viral therapy during immunosuppressive treatments is explored alongside novel immunotherapeutic interventions to restore immune control and prevent reactivation. In conclusion, this comprehensive review furnishes a holistic view of the immunological mechanisms that propel HBV reactivation. With a dedicated focus on understanding its implications for disease progression and the prospects of efficient management strategies, this article contributes significantly to the knowledge base. The more profound insights into the intricate interactions between viral elements and the immune system will inform evidence-based approaches, ultimately enhancing disease management and elevating patient outcomes. The dynamic landscape of management strategies is critically scrutinized, spanning anti-viral and immunomodulatory approaches. The role of prophylactic anti-viral therapy in preventing reactivation during immunosuppressive treatments and the potential of innovative immunotherapeutic interventions to restore immune control and proactively deter reactivation.

Avian Influenza A Viruses Modulate the Cellular Cytoskeleton during Infection of Mammalian Hosts.

Influenza is one of the most prevalent causes of death worldwide. Influenza A viruses (IAVs) naturally infect various avian and mammalian hosts, causing seasonal epidemics and periodic pandemics with high morbidity and mortality. The recent SARS-CoV-2 pandemic showed how an animal virus strain could unpredictably acquire the ability to infect humans with high infection transmissibility. Importantly, highly pathogenic avian influenza A viruses (AIVs) may cause human infections with exceptionally high mortality. Because these latter infections pose a pandemic potential, analyzing the ecology and evolution features of host expansion helps to identify new broad-range therapeutic strategies. Although IAVs are the prototypic example of molecular strategies that capitalize on their coding potential, the outcome of infection depends strictly on the complex interactions between viral and host cell factors. Most of the studies have focused on the influenza virus, while the contribution of host factors remains largely unknown. Therefore, a comprehensive understanding of mammals' host response to AIV infection is crucial. This review sheds light on the involvement of the cellular cytoskeleton during the highly pathogenic AIV infection of mammalian hosts, allowing a better understanding of its modulatory role, which may be relevant to therapeutic interventions for fatal disease prevention and pandemic management.

Transcription termination and readthrough in African swine fever virus.

African swine fever virus (ASFV) is a nucleocytoplasmic large DNA virus (NCLDV) that encodes its own host-like RNA polymerase (RNAP) and factors required to produce mature mRNA. The formation of accurate mRNA 3' ends by ASFV RNAP depends on transcription termination, likely enabled by a combination of sequence motifs and transcription factors, although these are poorly understood. The termination of any RNAP is rarely 100% efficient, and the transcriptional "readthrough" at terminators can generate long mRNAs which may interfere with the expression of downstream genes. ASFV transcriptome analyses reveal a landscape of heterogeneous mRNA 3' termini, likely a combination of bona fide termination sites and the result of mRNA degradation and processing. While short-read sequencing (SRS) like 3' RNA-seq indicates an accumulation of mRNA 3' ends at specific sites, it cannot inform about which promoters and transcription start sites (TSSs) directed their synthesis, i.e., information about the complete and unprocessed mRNAs at nucleotide resolution. Here, we report a rigorous analysis of full-length ASFV transcripts using long-read sequencing (LRS). We systematically compared transcription termination sites predicted from SRS 3' RNA-seq with 3' ends mapped by LRS during early and late infection. Using in-vitro transcription assays, we show that recombinant ASFV RNAP terminates transcription at polyT stretches in the non-template strand, similar to the archaeal RNAP or eukaryotic RNAPIII, unaided by secondary RNA structures or predicted viral termination factors. Our results cement this T-rich motif (U-rich in the RNA) as a universal transcription termination signal in ASFV. Many genes share the usage of the same terminators, while genes can also use a range of terminators to generate transcript isoforms varying enormously in length. A key factor in the latter phenomenon is the highly abundant terminator readthrough we observed, which is more prevalent during late compared with early infection. This indicates that ASFV mRNAs under the control of late gene promoters utilize different termination mechanisms and factors to early promoters and/or that cellular factors influence the viral transcriptome landscape differently during the late stages of infection.

Analysis of viral pneumonia and risk factors associated with severity of influenza virus infection in hospitalized patients from 2012 to 2016

BackgroundInfluenza viruses cause pneumonia in approximately one-third of cases, and pneumonia is an important cause of death. The aim was to identify risk factors associated with severity and those that could predict the development of pneumonia.MethodsThis retrospective, observational study included all adult patients with confirmed influenza virus infection admitted to Son Espases University Hospital during four influenza seasons in Spain (October to May) from to 2012–2016.ResultsOverall, 666 patients with laboratory-confirmed influenza were included, 93 (14%) of which were severe; 73 (10.9%) were admitted to Intensive Care Unit (ICU), 39 (5.8%) died, and 185 (27.7%) developed pneumonia. Compared to less severe cases, patients with severe disease: were less vaccinated (40% vs. 28%, p = 0.021); presented with more confusion (26.9% vs. 6.8%), were more hypoxemic (Horowitz index (PaO2/FiO2) 261 vs. 280), had higher C-reactive protein (CRP) (12.3 vs. 4.0), had more coinfections (26.8% vs. 6.3%) and had more pleural effusion (14% vs. 2.6%) (last six all p < 0.001). Risk factors significantly associated with severity were pneumonia [OR (95% CI) = 4.14 (2.4–7.16)], history of heart disease (1.84, 1.03–3.28), and confusion at admission (4.99, 2.55–9.74). Influenza vaccination was protective (0.53, 0.28–0.98). Compared to those without pneumonia, the pneumonia group had higher CRP (11.3 vs. 4.0, p < 0.001), lower oxygen saturation (92% vs. 94%, p < 0.001), were more hypoxic (PaO2/FiO2 266 vs. 281, p < 0.001), and incurred more mechanical ventilation, septic shock, admission to the ICU, and deaths (all four p < 0.001). Higher CRP and lower oxygen saturation were independent variables for predicting the development of pneumonia.ConclusionsPneumonia, history of heart disease, confusion and no influenza vaccination were independent variables to present complications in patients admitted with influenza infection.

Pathophysiology of chikungunya virus infection associated with fatal outcomes

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes acute, subacute, and chronic human arthritogenic diseases and, in rare instances, can lead to neurological complications and death. Here, we combined epidemiological, virological, histopathological, cytokine, molecular dynamics, metabolomic, proteomic, and genomic analyses to investigate viral and host factors that contribute to chikungunya-associated (CHIK) death. Our results indicate that CHIK deaths are associated with multi-organ infection, central nervous system damage, and elevated serum levels of pro-inflammatory cytokines and chemokines compared with survivors. The histopathologic, metabolite, and proteomic signatures of CHIK deaths reveal hemodynamic disorders anddysregulated immune responses. The CHIKV East-Central-South-African lineage infecting our study population causes both fatal and survival cases. Additionally, CHIKV infection impairs the integrity of the blood-brain barrier, as evidenced by an increase in permeability and altered tight junction protein expression. Overall, our findings improve the understanding of CHIK pathophysiology and the causes of fatal infections.

Viral reprogramming of host transcription initiation.

Viruses are master remodelers of the host cell environment in support of infection and virus production. For example, viruses typically regulate cell gene expression through modulating canonical cell promoter activity. Here, we show that Epstein Barr virus (EBV) replication causes 'de novo' transcription initiation at 29674 new transcription start sites throughout the cell genome. De novo transcription initiation is facilitated in part by the unique properties of the viral pre-initiation complex (vPIC) that binds a TATT[T/A]AA, TATA box-like sequence and activates transcription with minimal support by additional transcription factors. Other de novo promoters are driven by the viral transcription factors, Zta and Rta and are influenced by directional proximity to existing canonical cell promoters, a configuration that fosters transcription through existing promoters and transcriptional interference. These studies reveal a new way that viruses interact with the host transcriptome to inhibit host gene expression and they shed light on primal features driving eukaryotic promoter function.

Rubisco small subunit (RbCS) is co-opted by potyvirids as the scaffold protein in assembling a complex for viral intercellular movement.

Plant viruses must move through plasmodesmata (PD) to complete their life cycles. For viruses in the Potyviridae family (potyvirids), three viral factors (P3N-PIPO, CI, and CP) and few host proteins are known to participate in this event. Nevertheless, not all the proteins engaging in the cell-to-cell movement of potyvirids have been discovered. Here, we found that HCPro2 encoded by areca palm necrotic ring spot virus (ANRSV) assists viral intercellular movement, which could be functionally complemented by its counterpart HCPro from a potyvirus. Affinity purification and mass spectrometry identified several viral factors (including CI and CP) and host proteins that are physically associated with HCPro2. We demonstrated that HCPro2 interacts with both CI and CP in planta in forming PD-localized complexes during viral infection. Further, we screened HCPro2-associating host proteins, and identified a common host protein in Nicotiana benthamiana-Rubisco small subunit (NbRbCS) that mediates the interactions of HCPro2 with CI or CP, and CI with CP. Knockdown of NbRbCS impairs these interactions, and significantly attenuates the intercellular and systemic movement of ANRSV and three other potyvirids (turnip mosaic virus, pepper veinal mottle virus, and telosma mosaic virus). This study indicates that a nucleus-encoded chloroplast-targeted protein is hijacked by potyvirids as the scaffold protein to assemble a complex to facilitate viral movement across cells.

Maize catalases are recruited by a virus to modulate viral multiplication and infection.

Given the detrimental effects of excessive reactive oxygen species (ROS) accumulation in plant cells, various antioxidant mechanisms have evolved to maintain cellular redox homeostasis, encompassing both enzymatic components (e.g., catalase, superoxide dismutase) and non-enzymatic ones. Despite extensive research on the role of antioxidant systems in plant physiology and responses to abiotic stresses, the potential exploitation of antioxidant enzymes by plant viruses to facilitate viral infection remains insufficiently addressed. Herein, we demonstrate that maize catalases (ZmCATs) exhibited up-regulated enzymatic activities upon sugarcane mosaic virus (SCMV) infection. ZmCATs played crucial roles in SCMV multiplication and infection by catalysing the decomposition of excess cellular H2 O2 and promoting the accumulation of viral replication-related cylindrical inclusion (CI) protein through interaction. Peroxisome-localized ZmCATs were found to be distributed around SCMV replication vesicles in Nicotiana benthamiana leaves. Additionally, the helper component-protease (HC-Pro) of SCMV interacted with ZmCATs and enhanced catalase activities to promote viral accumulation. This study unveils a significant involvement of maize catalases in modulating SCMV multiplication and infection through interaction with two viral factors, thereby enhancing our understanding regarding viral strategies for manipulating host antioxidant mechanisms towards robust viral accumulation.

HIV Viral Load Patterns and Risk Factors Among Women in Prevention of Mother-To-Child Transmission Programs to Inform Differentiated Service Delivery.

Differentiated service delivery (DSD) approaches decrease frequency of clinic visits for individuals who are stable on antiretroviral therapy. It is unclear how to optimize DSD models for postpartum women living with HIV (PWLH). We evaluated longitudinal HIV viral load (VL) and cofactors, and modelled DSD eligibility with virologic failure (VF) among PWLH in prevention of mother-to-child transmission programs. This analysis used programmatic data from participants in the Mobile WAChX trial (NCT02400671). Women were assessed for DSD eligibility using the World Health Organization criteria among general people living with HIV (receiving antiretroviral therapy for ≥6 months and having at least 1 suppressed VL [<1000 copies/mL] within the past 6 months). Longitudinal VL patterns were summarized using group-based trajectory modelling. VF was defined as having a subsequent VL ≥1000 copies/mL after being assessed as DSD-eligible. Predictors of VF were determined using log-binomial models among DSD-eligible PWLH. Among 761 women with 3359 VL results (median 5 VL per woman), a 3-trajectory model optimally summarized longitudinal VL, with most (80.8%) women having sustained low probability of unsuppressed VL. Among women who met DSD criteria at 6 months postpartum, most (83.8%) maintained viral suppression until 24 months. Residence in Western Kenya, depression, reported interpersonal abuse, unintended pregnancy, nevirapine-based antiretroviral therapy, low-level viremia (VL 200-1000 copies/mL), and drug resistance were associated with VF among DSD-eligible PWLH. Most postpartum women maintained viral suppression from early postpartum to 24 months and may be suitable for DSD referral. Women with depression, drug resistance, and detectable VL need enhanced services.

Inflammatory Response Associated with West Nile Neuroinvasive Disease: A Systematic Review.

West Nile virus (WNV) infection is a seasonal arbovirosis with the potential to cause severe neurological disease. Outcomes of the infection from WNV depend on viral factors (e.g., lineage) and host-intrinsic factors (e.g., age, sex, immunocompromising conditions). Immunity is essential to control the infection but may also prove detrimental to the host. Indeed, the persistence of high levels of pro-inflammatory cytokines and chemokines is associated with the development of blood-brain barrier (BBB) damage. Due to the importance of the inflammatory processes in the development of West Nile neuroinvasive disease (WNND), we reviewed the available literature on the subject. According to the 2020 updated PRISMA guidelines, all peer-reviewed articles regarding the inflammatory response associated with WNND were included. One hundred and thirty-six articles were included in the data analysis and sorted into three groups (in vitro on-cell cultures, in vivo in animals, and in humans). The main cytokines found to be increased during WNND were IL-6 and TNF-α. We highlighted the generally small quantity and heterogeneity of information about the inflammatory patterns associated with WNND. Further studies are needed to understand the pathogenesis of WNND and to investigate the extent and the way the host inflammatory response either helps in controlling the infection or in worsening the outcomes. This might prove useful both for the development of target therapies and for the development of molecular markers allowing early identification of patients displaying an inflammatory response that puts them at a higher risk of developing neuroinvasive disease and who might thus benefit from early antiviral therapies.

Characterization of SLA RNA promoter from dengue virus and its interaction with the viral non-structural NS5 protein

The Dengue virus (DENV) is the most significant arthropod-borne viral pathogen in humans with 400 million infections annually. DENV comprises four distinct serotypes (DENV-1 to -4) which complicates vaccine development. Any of the four serotypes can cause clinical illness but with distinctive infection dynamics. Variations in sequences identified within the four genomes induce structural differences in crucial RNA motifs that were suggested to be correlated to the degree of pathogenicity among DENV-1 to -4. In particular, the RNA Stem-loop A (SLA) at the 5′-end of the genome, acts as a key regulator of the viral replication cycle by interacting with the viral NS5 polymerase to initiate the minus-strand viral RNA synthesis and later to methylate and cap the synthesized RNA. The molecular details of this interaction remain not fully described. Here, we report the solution secondary structures of SLA from DENV-1 to -4. Our results highlight that the four SLA exhibit structural and dynamic differences. Secondly, to determine whether SLA RNA contains serotype-specific determinants for the recognition by the viral NS5 protein, we investigated interactions between SLA from DENV -1 to -4 and DENV2 NS5 using combined biophysical approaches. Our results show that NS5 from DENV2 is able to bind SLA from other serotypes, but that other viral or host factors may be necessary to stabilize the complex and promote the catalytically active state of the NS5. By contrast, we show that a serotype-specific binding is driven by specific interactions involving conformational changes within the SLA RNA.

Intrauterine Transmission of Hepatitis B Cannot Be Ruled Out by A Single Negative Hepatitis B e Antigen (HBeAg) Result among Hepatitis B Surface Antigen (HBsAg) - Positive Pregnant Women

BACKGROUND: The risk factors for intrauterine transmission of hepatitis B virus (HBV) in hepatitis B surface antigen (HBsAg)-positive pregnant women are poorly understood. Numerous factors are considered to be involved, including placental barrier, obstetric environment, high viral load, and positivity of hepatitis B e antigen (HBeAg). This study was conducted to investigate the role of placenta barrier, clinical, and viral factors in intrauterine transmission of HBV.METHODS: A cross-sectional study was conducted involving 1,353 pregnant women who underwent HBsAg screening. Eighty-four (6.2%) women were detected as HBsAg positive and were examined for HBsAg level, anti-HBs, anti-HBc, HBeAg/hepatitis B e antibody (anti-HBe) status, and HBV DNA presence in cord blood. Quantitative HBV DNA was analyzed using real-time polymerase chain reaction (PCR).RESULTS: Eighty-four of 1,353 subjects were HBsAg-positive. HBV DNA was positive in 28/84 (33.7%) maternal sera, 19/79 (24.05%) placental specimens, and 9/83 (10.84%) in cord blood. There were significant associations between HBV DNA in maternal serum (p=0.000) and placental tissue (p=0.000) with HBV DNA in the cord blood. No clinical factors were associated with HBV DNA transmission in cord blood. Sixty percent of viral load &gt;5.3 log10 copies/mL were found in the cord blood, of which 43.8% HBeAg positive and 3.1% HBeAg negative.CONCLUSION: Reduced transmission via compartments established the placenta’s barrier function in mother-to-child transmission. A high maternal viral load and positive HBeAg were risk factors for intrauterine transmission, while negative HBeAg still has the possibility of transmission.KEYWORDS: mother-to-child transmission, hepatitis B virus, intrauterine

The risk factors associated with post-transplantation BKPyV nephropathy and BKPyV DNAemia: a prospective study in kidney transplant recipients

BackgroundBK polyomavirus (BKPyV) infection after kidney transplantation can lead to serious complications such as BKPyV-associated nephropathy (BKPyVAN) and graft loss. The aim of this study was to investigate the incidence of BKPyVAN after implementing a BKPyV screening program, to map the distribution of BKPyV genotypes and subtypes in the Uppsala-Örebro region and to identify host and viral risk factors for clinically significant events.MethodsThis single-center prospective cohort study included kidney transplant patients aged ≥ 18 years at the Uppsala University Hospital in Sweden between 2016 and 2018. BKPyV DNA was analyzed in plasma and urine every 3 months until 18 months after transplantation. Also genotype and subtype were determined. A logistic regression model was used to analyze selected risk factors including recipient sex and age, AB0 incompatibility and rejection treatment prior to BKPyVAN or high-level BKPyV DNAemia.ResultsIn total, 205 patients were included. Of these, 151 (73.7%) followed the screening protocol with 6 plasma samples, while184 (89.8%) were sampled at least 5 times. Ten (4.9%) patients developed biopsy confirmed BKPyVAN and 33 (16.1%) patients met criteria for high-level BKPyV DNAemia. Male sex (OR 2.85, p = 0.025) and age (OR 1.03 per year, p = 0.020) were identified as significant risk factors for developing BKPyVAN or high-level BKPyV DNAemia. BKPyVAN was associated with increased viral load at 3 months post transplantation (82,000 vs. < 400 copies/mL; p = 0.0029) and with transient, high-level DNAemia (n = 7 (27%); p < 0.0001). The most common genotypes were subtype Ib2 (n = 50 (65.8%)) and IVc2 (n = 20 (26.3%)).ConclusionsMale sex and increasing age are related to an increased risk of BKPyVAN or high-level BKPyV DNAemia. BKPyVAN is associated with transient, high-level DNAemia but no differences related to viral genotype were detected.

The P2 nucleic acid binding protein of Sugarcane bacilliform virus is a viral pathogenic factor.

Saccharum spp. is the primary source of sugar and plays a significant role in global renewable bioenergy. Sugarcane bacilliform virus (SCBV) is one of the most important viruses infecting sugarcane, causing severe yield losses and quality degradation. It is of great significance to reveal the pathogenesis of SCBV and resistance breeding. However, little is known about the viral virulence factors or RNA silencing suppressors and the molecular mechanism of pathogenesis. To systematically investigate the functions of the unknown protein P2 encoded by SCBV ORF2. Phylogenetic analysis was implemented to infer the evolutionary relationship between the P2 of SCBV and other badnaviruses. The precise subcellular localization of P2 was verified in the transient infiltrated Nicotiana benthamiana epidermal mesophyll cells and protoplasts using the Laser scanning confocal microscope (LSCM). The post-transcriptional gene silencing (PTGS) and transcriptional gene silencing (TGS) RNA silencing suppressor activity of P2 was analyzed, respectively. Furthermore, restriction digestion and RT-qPCR assays were conducted to verify the probable mechanism of P2 on repressing DNA methylation. To explore the pathogenicity of P2, a potato virus X-based viral vector was used to heterologously express SCBV P2 and the consequent H2O2 accumulation was detected by the 3,3'-diaminobenzidine (DAB) staining method. Phylogenetic analysis shows that SCBV has no obvious sequence similarity and low genetic relatedness to Badnavirus and Tungrovirus representatives. LSCM studies show that P2 is localized in both the cytoplasm and nucleus. Moreover, P2 is shown to be a suppressor of PTGS and TGS, which can not only repress ssRNA-induced gene silencing but also disrupt the host RNA-directed DNA methylation (RdDM) pathway. In addition, P2 can trigger an oxidative burst and cause typical hypersensitive-like response (HLR) necrosis in systemic leaves of N. benthamiana when expressed by PVX. Overall, our results laid a foundation for deciphering the molecular mechanism of SCBV pathogenesis and made progress for resistance breeding.

Viral and Host Factors Are Associated With Mortality in Hospitalized Patients With COVID-19.

Persistent mortality in adults hospitalized due to acute COVID-19 justifies pursuit of disease mechanisms and potential therapies. The aim was to evaluate which virus and host response factors were associated with mortality risk among participants in Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3) trials. A secondary analysis of 2625 adults hospitalized for acute SARS-CoV-2 infection randomized to 1 of 5 antiviral products or matched placebo in 114 centers on 4 continents. Uniform, site-level collection of participant baseline clinical variables was performed. Research laboratories assayed baseline upper respiratory swabs for SARS-CoV-2 viral RNA and plasma for anti-SARS-CoV-2 antibodies, SARS-CoV-2 nucleocapsid antigen (viral Ag), and interleukin-6 (IL-6). Associations between factors and time to mortality by 90 days were assessed using univariate and multivariable Cox proportional hazards models. Viral Ag ≥4500 ng/L (vs <200 ng/L; adjusted hazard ratio [aHR], 2.07; 1.29-3.34), viral RNA (<35 000 copies/mL [aHR, 2.42; 1.09-5.34], ≥35 000 copies/mL [aHR, 2.84; 1.29-6.28], vs below detection), respiratory support (<4 L O2 [aHR, 1.84; 1.06-3.22]; ≥4 L O2 [aHR, 4.41; 2.63-7.39], or noninvasive ventilation/high-flow nasal cannula [aHR, 11.30; 6.46-19.75] vs no oxygen), renal impairment (aHR, 1.77; 1.29-2.42), and IL-6 >5.8 ng/L (aHR, 2.54 [1.74-3.70] vs ≤5.8 ng/L) were significantly associated with mortality risk in final adjusted analyses. Viral Ag, viral RNA, and IL-6 were not measured in real-time. Baseline virus-specific, clinical, and biological variables are strongly associated with mortality risk within 90 days, revealing potential pathogen and host-response therapeutic targets for acute COVID-19 disease.

COVID-19 immune signatures in Uganda persist in HIV co-infection and diverge by pandemic phase

Little is known about the pathobiology of SARS-CoV-2 infection in sub-Saharan Africa, where severe COVID-19 fatality rates are among the highest in the world and the immunological landscape is unique. In a prospective cohort study of 306 adults encompassing the entire clinical spectrum of SARS-CoV-2 infection in Uganda, we profile the peripheral blood proteome and transcriptome to characterize the immunopathology of COVID-19 across multiple phases of the pandemic. Beyond the prognostic importance of myeloid cell-driven immune activation and lymphopenia, we show that multifaceted impairment of host protein synthesis and redox imbalance define core biological signatures of severe COVID-19, with central roles for IL-7, IL-15, and lymphotoxin-α in COVID-19 respiratory failure. While prognostic signatures are generally consistent in SARS-CoV-2/HIV-coinfection, type I interferon responses uniquely scale with COVID-19 severity in persons living with HIV. Throughout the pandemic, COVID-19 severity peaked during phases dominated by A.23/A.23.1 and Delta B.1.617.2/AY variants. Independent of clinical severity, Delta phase COVID-19 is distinguished by exaggerated pro-inflammatory myeloid cell and inflammasome activation, NK and CD8+ T cell depletion, and impaired host protein synthesis. Combining these analyses with a contemporary Ugandan cohort of adults hospitalized with influenza and other severe acute respiratory infections, we show that activation of epidermal and platelet-derived growth factor pathways are distinct features of COVID-19, deepening translational understanding of mechanisms potentially underlying SARS-CoV-2-associated pulmonary fibrosis. Collectively, our findings provide biological rationale for use of broad and targeted immunotherapies for severe COVID-19 in sub-Saharan Africa, illustrate the relevance of local viral and host factors to SARS-CoV-2 immunopathology, and highlight underemphasized yet therapeutically exploitable immune pathways driving COVID-19 severity.

Predictors of HIV rebound differ by timing of antiretroviral therapy initiation.

BACKGROUNDIdentifying factors that predict the timing of HIV rebound after treatment interruption will be crucial for designing and evaluating interventions for HIV remission.METHODSWe performed a broad evaluation of viral and immune factors that predict viral rebound (AIDS Clinical Trials Group A5345). Participants initiated antiretroviral therapy (ART) during chronic (N = 33) or early (N = 12) HIV infection with ≥ 2 years of suppressive ART and restarted ART if they had 2 viral loads ≥ 1,000 copies/mL after treatment interruption.RESULTSCompared with chronic-treated participants, early-treated individuals had smaller and fewer transcriptionally active HIV reservoirs. A higher percentage of HIV Gag-specific CD8+ T cell cytotoxic response was associated with lower intact proviral DNA. Predictors of HIV rebound timing differed between early- versus chronic-treated participants, as the strongest reservoir predictor of time to HIV rebound was level of residual viremia in early-treated participants and intact DNA level in chronic-treated individuals. We also identified distinct sets of pre-treatment interruption viral, immune, and inflammatory markers that differentiated participants who had rapid versus slow rebound.CONCLUSIONThe results provide an in-depth overview of the complex interplay of viral, immunologic, and inflammatory predictors of viral rebound and demonstrate that the timing of ART initiation modifies the features of rapid and slow viral rebound.TRIAL REGISTRATIONClinicalTrials.gov NCT03001128FUNDINGNIH National Institute of Allergy and Infectious Diseases, Merck.