Virological Factors Research Articles

Re-emergence of Oropouche virus between 2023 and 2024 in Brazil: an observational epidemiological study

Oropouche virus is an arthropod-borne virus that has caused outbreaks of Oropouche fever in central and South America since the 1950s. This study investigates virological factors contributing to the re-emergence of Oropouche fever in Brazil between 2023 and 2024. In this observational epidemiological study, we combined multiple data sources for Oropouche virus infections in Brazil and conducted in-vitro and in-vivo characterisation. We collected serum samples obtained in Manaus City, Amazonas state, Brazil, from patients with acute febrile illnesses aged 18 years or older who tested negative for malaria and samples from people with previous Oropouche virus infection from Coari municipality, Amazonas state, Brazil. Basic clinical and demographic data were collected from the Brazilian Laboratory Environment Management System. We calculated the incidence of Oropouche fever cases with data from the Brazilian Ministry of Health and the 2022 Brazilian population census and conducted age-sex analyses. We used reverse transcription quantitative PCR to test for Oropouche virus RNA in samples and subsequently performed sequencing and phylogenetic analysis of viral isolates. We compared the phenotype of the 2023-24 epidemic isolate (AM0088) with the historical prototype strain BeAn19991 through assessment of titre, plaque number, and plaque size. We used a plaque reduction neutralisation test (PRNT50) to assess the susceptibility of the novel isolate and BeAn19991 isolate to antibody neutralisation, both in serum samples from people previously infected with Oropouche virus and in blood collected from mice that were inoculated with either of the strains. 8639 (81·8%) of 10 557 laboratory-confirmed Oropouche fever cases from Jan 4, 2015, to Aug 10, 2024, occurred in 2024, which is 58·8 times the annual median of 147 cases (IQR 73-325). Oropouche virus infections were reported in all 27 federal units, with 8182 (77·5%) of 10 557 infections occurring in North Brazil. We detected Oropouche virus RNA in ten (11%) of 93 patients with acute febrile illness between Jan 1 and Feb 4, 2024, in Amazonas state. AM0088 had a significantly higher replication at 12 h and 24 h after infection in mammalian cells than the prototype strain. AM0088 had a more virulent phenotype than the prototype in mammalian cells, characterised by earlier plaque formation, between 27% and 65% increase in plaque number, and plaques between 2·4-times and 2·6-times larger. Furthermore, serum collected on May 2 and May 20, 2016, from individuals previously infected with Oropouche virus showed at least a 32-fold reduction in neutralising capacity (ie, median PRNT50 titre of 640 [IQR 320-640] for BeAn19991 vs <20 [ie, below the limit of detection] for AM0088) against the reassortant strain compared with the prototype. These findings provide a comprehensive assessment of Oropouche fever in Brazil and contribute to an improved understanding of the 2023-24 Oropouche virus re-emergence. Our exploratory in-vitro data suggest that the increased incidence might be related to a higher replication efficiency of a new Oropouche virus reassortant for which previous immunity shows lower neutralising capacity. São Paulo Research Foundation, Burroughs Wellcome Fund, Wellcome Trust, US National Institutes of Health, and Brazilian National Council for Scientific and Technological Development. For the Portuguese translation of the abstract see Supplementary Materials section.

Comparison of Dual Monoclonal Antibody Therapies for COVID-19 Evolution: A Multicentric Retrospective Study.

Neutralizing antibodies targeting the SARS-CoV-2 Spike protein reduce COVID-19-related risk of hospitalization, particularly in high-risk individuals. The COCOPREV-R study aimed to evaluate and compare clinical outcomes in high-risk SARS-CoV-2 patients treated with dual monoclonal antibody therapies and to identify associated virological factors. The COCOPREV-R study retrospectively collected real-world data from high-risk patients receiving Bamlanivimab/Etesevimab or Casirivimab/Imdevimab dual monoclonal antibody therapies (22 February 2021 to 15 June 2021). The study included 1004 patients with COVID-19, of whom 691 received Bamlanivimab/Etesevimab and 313 received Casirivimab/Imdevimab. The alpha variant represented 90.1% of those for whom data were available. The risk of hospitalization within 30 days was lower with Bamlanivimab/Etesevimab (12.7%, CI 95% [9.9-16.3%]) compared to Casirivimab/Imdevimab (28.4%, CI 95% [22.7-35.1%) (p < 0.001). The 30-day mortality rates were comparable between both groups (p = 0.982). Analysis of SARS-CoV-2 PCR negativity showed no difference between the two treatment groups (95.2% [93.0-96.9%] and 93.5% [89.1-96.6%] until day 30, p = 0.851 for Bamlanivimab/Etesevimab and Casirivimab/Imdevimab, respectively). Among persistently positive samples with available sequencing results (n = 43), Spike protein changes occurred only in Bamlanivimab/Etesevimab (42.9%) vs. Casirivimab/Imdevimab (0.0%) groups. Q493R (25.0%) and E484K (12.5%) were the most common mutations selected by Bamlanivimab/Etesevimab in follow-up samples. Other factors (immunodepression, comorbidities, and age) did not appear to be associated with the occurrence of Spike protein mutations. A higher rate of hospitalization was seen with Casirivimab/Imdevimab (RONAPREVE®) in comparison with Bamlanivimab/Etesevimab treatment, but with the emergence of Spike mutations only in the Bamlanivimab/Etesevimab group.

Reemergence of Oropouche virus between 2023 and 2024 in Brazil.

Oropouche virus (OROV; species Orthobunyavirus oropoucheense) is an arthropod-borne virus that has caused outbreaks of Oropouche fever in Central and South America since the 1950s. This study investigates virological factors contributing to the reemergence of Oropouche fever in Brazil between 2023 and 2024. In this study, we combined OROV genomic, molecular, and serological data from Brazil from 1 January 2015 to 29 June 2024, along with in vitro and in vivo characterization. Molecular screening data included 93 patients with febrile illness between January 2023 and February 2024 from the Amazonas State. Genomic data comprised two genomic OROV sequences from patients. Serological data were obtained from neutralizing antibody tests comparing the prototype OROV strain BeAn 19991 and the 2024 epidemic strain. Epidemiological data included aggregated cases reported to the Brazilian Ministry of Health from 1 January 2014 to 29 June 2024. In 2024, autochthonous OROV infections were detected in previously non-endemic areas across all five Brazilian regions. Cases were reported in 19 of 27 federal units, with 83.2% (6,895 of 8,284) of infections in Northern Brazil and a nearly 200-fold increase in incidence compared to reported cases over the last decade. We detected OROV RNA in 10.8% (10 of 93) of patients with febrile illness between December 2023 and May 2024 in Amazonas. We demonstrate that the 2023-2024 epidemic was caused by a novel OROV reassortant that replicated approximately 100-fold higher titers in mammalian cells compared to the prototype strain. The 2023-2024 OROV reassortant displayed plaques earlier than the prototype, produced 1.7 times more plaques, and plaque sizes were 2.5 larger compared to the prototype. Furthermore, serum collected in 2016 from previously OROV-infected individuals showed at least a 32-fold reduction in neutralizing capacity against the reassortment strain compared to the prototype. These findings provide a comprehensive assessment of Oropouche fever in Brazil and contribute to a better understanding of the 2023-2024 OROV reemergence. The recent increased incidence may be related to a higher replication efficiency of a new reassortant virus that also evades previous immunity.

The Characteristic of HBV Quasispecies Is Related to Occult HBV Infection of Infants Born to Highly Viremic Mothers.

Although a combination of immunoprophylaxis and antiviral therapy can effectively prevent mother-to-child transmission (MTCT) of hepatitis B virus (HBV), a considerable number of infants born to highly viremic mothers still develop occult HBV infection (OBI). To uncover the virological factor and risk predictor for OBI in infants, we found that the diversity and complexity of maternal HBV quasispecies in the case group were lower than those in the control group. Mutations with significant differences between the two groups were most enriched in the NTCPbd and PreC regions. Genetic distance at the amino-acid level of the PreC region, especially the combination of three amino-acid mutations in the PreC region, could strongly predict the risk of OBI in infants. HBV quasispecies in OBI infants were highly complex, and the non-synonymous substitutions were mainly found in the RT and HBsAg regions. The sK47E (rtQ55R) and sP49L mutations in OBI infants might contribute to OBI through inhibiting the production of HBV DNA and HBsAg, respectively. This study found the potential virological factors and risk predictors for OBI in infants born to highly viremic mothers, which might be helpful for controlling OBI in infants.

Unraveling factors responsible for pathogenic differences in Lassa virus strains.

Lassa virus (LASV) is the etiological agent of Lassa fever (LF), a severe hemorrhagic disease with potential for lethal outcomes. Apart from acute symptoms, LF survivors often endure long-term complications, notably hearing loss, which significantly impacts their quality of life and socioeconomic status in endemic regions of West Africa. Classified as a Risk Group 4 agent, LASV poses a substantial public health threat in affected areas. Our laboratory previously developed a novel lethal guinea pig model of LF utilizing the clinical isolate LASV strain LF2384. However, the specific pathogenic factors underlying LF2384 infection in guinea pigs remained elusive. In this study, we aimed to elucidate the differences in the immunological response induced by LF2384 and LF2350, another LASV isolate from a non-lethal LF case within the same outbreak. Through comprehensive immunological gene profiling, we compared the expression kinetics of key genes in guinea pigs infected with LASV LF2384 and LF2350. Our analysis revealed differential expression patterns for several immunological genes, including CD94, CD19-2, CD23, IL-7, and CIITA, during LF2384 and LF2350 infection. Moreover, through the generation of recombinant LASVs, we sought to identify the specific viral genes responsible for the observed pathogenic differences between LF2384 and LF2350. Our investigations pinpointed the L protein as a crucial determinant of pathogenicity in guinea pigs infected with LASV LF2384.

Monkeypox Virus Neutralizing Antibodies at Six Months from Mpox Infection: Virologic Factors Associated with Poor Immunologic Response.

A natural monkeypox virus infection may not induce sufficient neutralizing antibody responses in a subset of healthy individuals. The aim of this study was to evaluate monkeypox virus-neutralizing antibodies six months after infection and to assess the virological factors predictive of a poor immunological response. Antibodies were assessed using a plaque reduction neutralization test at six months from mpox infection; mpox cutaneous, oropharyngeal, and anal swabs, semen, and plasma samples were tested during infection. Overall, 95 people were included in the study; all developed detectable antibodies. People who were positive for the monkeypox virus for more days had higher levels of antibodies when considering all tested samples (p = 0.029) and all swabs (p = 0.005). Mpox cycle threshold values were not predictive of antibody titers. This study found that the overall days of monkeypox virus detection in the body, irrespective of the viral loads, were directly correlated with monkeypox virus neutralizing antibodies at six months after infection.

Hepatitis B Virus (HBV) Genotypes in an Ecuadorian Population: A Preliminary Study.

Chronic hepatitis B virus (HBV) infection affects 257-291 million people worldwide. The World Health Organization reported 890,000 HBV-related deaths in 2019, higher than reported previously. There are 10 HBV genotypes (A-J) subdivided into several subgenotypes that differ considerably by geography. Various virologic factors, including genotype and subgenotype, impact the odds of acquiring a chronic HBV infection, the type of treatment prescribed, and the risk of developing hepatocarcinoma. Information on the HBV genotypes and subgenotypes that circulate in Ecuador remains low. To address this gap, the current study took a preliminary look at HBV-infected human samples from this region to identify the most common genotypes and subgenotypes. Samples from 44 patients in the Andean, Coastal, and Amazon regions of Ecuador were amplified and two major genotypes were identified, genotype F (42/44; 95.5%) and genotype E (2 patients; 4.5%). The genotype F subgenotypes were F3 (35/42; 83.33%), F4 (6/42; 14.28%), and F1b (1/42, 2.39%). This is the first epidemiological study to assess the distribution of HBV genotypes in Ecuador. The findings can inform antiviral drug effectivity studies specific to HBV genotypes prevalent in South America.

Virological non-suppression and associated factors among adult patients receiving antiretroviral therapy at selected health facilities in uMgungundlovu district of KwaZulu Natal, South Africa: a cross-sectional study.

virological non-suppression is not only associated with increased risk of transmission of the Human Immunodeficiency virus (HIV) to others; perinatally and sexually, but it also decreases the life expectancy among the individuals who are on antiretroviral therapy (ART). This study sought to determine the level of virological non-suppression among ART patients from selected health facilities of a sub-district in uMgungundlovu district. This sub-district has high HIV transmission rates in KwaZulu Natal (KZN) and had one of the highest HIV prevalence in the district in 2018; population weighted HIV prevalence of 36.3% among men and women aged 15-49 years old, which was twice the average national prevalence of 18.8%. this descriptive, cross-sectional, and quantitative study was conducted among participants who were HIV-positive, 18 years old and above, and initiated on ART between January 2017 and January 2019 at selected PHC facilities of Vulindlela sub district. Health facility treatment registers, patient medical files and face-to-face interviews were used to collect the data and these were captured onto an Excel spreadsheet, cleaned, coded before importation into Epiinfo 17 for statistical analyses. Logistic regression analyses were conducted to investigate the factors associated with virological non-suppression. the study found a majority of participants were females (240/401 (60%)). The mean age of the participants was 38.1 (SD=11.2), with most participants who were between the ages of 29 and 39 years old (167 (41.7%)). Virological non-suppression was observed among 10% (40/401) of participants. The odds of virological non-suppression were higher among participants who were married (aOR 4.76, 95% CI 1.49-15.19; p=0.008). a virological non-suppression of 10% translates to viral suppression of 90%, which is below the target of UNAIDS 95-95-95 strategy. Hiding and skipping medication indicate how non-disclosure continues to hinder HIV treatment adherence. High odds of virological non-suppression among married participants indicate non-disclosure of the positive HIV status, or lack in spousal support.

Employment of a high throughput functional assay to define the critical factors that influence vaccine induced cross-variant neutralizing antibodies for SARS-CoV-2

The scale and duration of neutralizing antibody responses targeting SARS-CoV-2 viral variants represents a critically important serological parameter that predicts protective immunity for COVID-19. In this study, we describe the development and employment of a new functional assay that measures neutralizing antibodies for SARS-CoV-2 and present longitudinal data illustrating the impact of age, sex and comorbidities on the kinetics and strength of vaccine-induced antibody responses for key variants in an Asian volunteer cohort. We also present an accurate quantitation of serological responses for SARS-CoV-2 that exploits a unique set of in-house, recombinant human monoclonal antibodies targeting the viral Spike and nucleocapsid proteins and demonstrate a reduction in neutralizing antibody titres across all groups 6 months post-vaccination. We also observe a marked reduction in the serological binding activity and neutralizing responses targeting recently newly emerged Omicron variants including XBB 1.5 and highlight a significant increase in cross-protective neutralizing antibody responses following a third dose (boost) of vaccine. These data illustrate how key virological factors such as immune escape mutations combined with host demographic factors such as age and sex of the vaccinated individual influence the strength and duration of cross-protective serological immunity for COVID-19.

53 Healthcare Quality, Race, and Neuropsychological Functioning in Black/African-American Individuals with HIV

Objective:Rates of HIV are disproportionately high among Black individuals in the United States (CDC, 2020). Black individuals are at increased risk for neurocognitive impairment due to HIV (Marquine et al., 2016) and experience health disparities including increased morbidity and mortality (Asari, 2018; Manly et al., 1998). We sought to examine the relationship between perceived quality of healthcare and neuropsychological functioning among people living with HIV (PLWH) who identify as Black compared to those who are non-Black.Participants and Methods:151 PLWH in the Los Angeles area (52% Black, age = 49.85 ± 10.54, education = 13.23 ± 2.11; 87% cisgender men, 8% cisgender women, 1% transgender men, 3% transgender women) completed comprehensive neuropsychological (NP) assessments (from which demographically-corrected domain and global T-scores were derived), psychiatric and sociodemographic interviews, and self-report questionnaires, including a measure of perceived healthcare quality (i.e., QUOTE-HIV). Statistical analyses included chi-square, t-test, ANOVA, and stepwise linear regression.Results:Only 14% of Black PLWH had private healthcare insurance (versus Medicare/Medicaid) compared to 33% of nonBlack PLWH (x2=11.33, p&lt;.01). Black participants were significantly older than nonBlack participants (p&lt;.01), but did not differ on gender, education, income, CD4 count, or HIV viral load. Younger Black participants (based on a median split for age; n = 23) reported the lowest perceived quality of healthcare (i.e., QUOTE-HIV total performance score), while older Black participants (n = 56) reported the highest perceived care (F = 3.80, p = .01), but the same relationship was not observed in nonBlack participants. In a stepwise multivariate regression model, including demographic and virological factors as well as healthcare quality, only household income and overall perceived healthcare quality (i.e., QUOTE-HIV total performance score) were significantly associated with Global NP T-scores among Black PLWH (R2=.12, F(1, 66)=4.46, p=.02).Conclusions:When assessing healthcare quality and healthcare experiences among people living with HIV, race and age are important to consider. Private healthcare coverage may be less accessible to people of color, and in a multivariate model, only income and healthcare quality significantly predicted neuropsychological functioning in Black PLWH. When examining HIV and health outcomes, the complex relationships among quality of healthcare and health disparities, neuropsychological functioning, and structural racism warrant further investigation.

Genetic, virological, infectious, and pharmacological risk factors for CD4&lt;sup&gt;+&lt;/sup&gt; T-cell regeneration failure in HIV-infected subjects receiving ART

In 10 to 40% of HIV-infected patients being adherent to highly active antiretroviral therapy (HAART), viral load suppression is not accompanied by a significant increase in the number of CD4+ T-lymphocytes. This phenomenon, known as immunological non-response to treatment, is associated with a high risk of developing AIDS-associated and non-AIDS-associated diseases, as well as premature death. The bases of immunological non-response to HAART are poorly understood, while information on the risk factors for its development is scattered.The aim of the present review is to organize data on non-immune-system risk factors for the development of immunological nonresponse to HAART.Materials and methods. Electronic searching using PubMed, Science Direct, and Scopus were conducted.Results and discussion. The database search delivered information on genetic, virological, infectious, and pharmacological risk factors for the development of immunological non-response to HAART. Each factor contribution might be substantially different. Still, none of them can be considered a trigger mechanism for this phenomenon.Conclusion. Immunological non-response to HAART is a polyetiological condition. Apparently, this phenomenon is based on normally imperceptible immune system features or defects, which manifest during the CD4+ T-cell regeneration.

Depression, psychosocial factors, and laboratory routine testing in people living with HIV in Northeastern Mexico: prevalence, correlations, and its associations

Introduction: Depression is up to five times more prevalent in people living with HIV (PLWHIV). There are neurohormonal, virological and psychosocial factors involved and it is associated with antiretroviral treatment non-adherence, decreased life expectancy, faster progression to AIDS and premature death. Studies support that with lower CD4 levels, and the higher viral load (VL), depression increases. Objective: To establish whether there is a correlation and association between the VL and CD4 count with depression and its symptoms in PLWHIV. Method: Under follow-up in the Infectious Disease outpatient clinic a survey of sociodemographic variables, and a Beck's Depression Inventory (BDI) was applied to the study subjects, whose results were analyzed using Rho Spearman (rs) and Chi Squared test (X2) with VL and CD4 levels. Results: 137 individuals were included, from 18-73 years, which 97 (70.8%) were male assigned at birth. The prevalence of depression reported, was 25.5%. A positive correlation was found between VL and BDI score, and a negative correlation between BDI score and CD4. In addition, correlation was found between VL, and depressive symptoms such as guilt, discouragement and self-image perception. These symptoms were strongly associated with death wishes, previous suicide attempts, and treatment non-dherence. Conclusion: VL may have implication in depression and its symptoms in this population, so their control is extremely important to prevent depressive episodes and suicidal behavior and prolong treatment adherence.

High seroprevalence of Leishmania infantum is linked to immune activation in people with HIV: a two-stage cross-sectional study in Bahia, Brazil.

Visceral leishmaniasis is an opportunistic disease in HIV-1 infected individuals, unrecognized as a determining factor for AIDS diagnosis. The growing geographical overlap of HIV-1 and Leishmania infections is an emerging challenge worldwide, as co-infection increases morbidity and mortality for both infections. Here, we determined the prevalence of people living with HIV (PWH) with a previous or ongoing infection by Leishmania infantum and investigated the virological and immunological factors associated with co-infection. We adopted a two-stage cross-sectional cohort (CSC) design (CSC-I, n = 5,346 and CSC-II, n = 317) of treatment-naïve HIV-1-infected individuals in Bahia, Brazil. In CSC-I, samples collected between 1998 and 2013 were used for serological screening for leishmaniasis by an in-house Enzyme-Linked Immunosorbent Assay (ELISA) with SLA (Soluble Leishmania infantum Antigen), resulting in a prevalence of previous or ongoing infection of 16.27%. Next, 317 PWH were prospectively recruited from July 2014 to December 2015 with the collection of sociodemographic and clinical data. Serological validation by two different immunoassays confirmed a prevalence of 15.46 and 8.20% by anti-SLA, and anti-HSP70 serology, respectively, whereas 4.73% were double-positive (DP). Stratification of these 317 individuals in DP and double-negative (DN) revealed a significant reduction of CD4+ counts and CD4+/CD8+ ratios and a tendency of increased viral load in the DP group, as compared to DN. No statistical differences in HIV-1 subtype distribution were observed between the two groups. However, we found a significant increase of CXCL10 (p = 0.0076) and a tendency of increased CXCL9 (p = 0.061) in individuals with DP serology, demonstrating intensified immune activation in this group. These findings were corroborated at the transcriptome level in independent Leishmania- and HIV-1-infected cohorts (Swiss HIV Cohort and Piaui Northeast Brazil Cohort), indicating that CXCL10 transcripts are shared by the IFN-dominated immune activation gene signatures of both pathogens and positively correlated to viral load in untreated PWH. This study demonstrated a high prevalence of PWH with L. infantum seropositivity in Bahia, Brazil, linked to IFN-mediated immune activation and a significant decrease in CD4+ levels. Our results highlight the urgent need to increase awareness and define public health strategies for the management and prevention of HIV-1 and L. infantum co-infection.

Recurrent Episodes of Encephalopathy/Encephalitis Secondary to Influenza Virus in a Pediatric Patient.

Influenza virus commonly causes acute upper respiratory tract infections in pediatrics. Rarely, influenza-associated encephalopathy/encephalitis may occur in 4 of 100,000 children annually in the United States. North American literature, however, is sparse regarding the incidence of recurrent episodes. This report characterizes the clinical manifestations and identifies genetic, virologic and/or epidemiologic factors making children susceptible for recurring episodes of influenza-associated encephalopathy/encephalitis.

Predicting Hepatocellular Carcinoma Risk in Chronic Hepatitis B Patients Receiving Finite Periods of Antiviral Therapy

PURPOSE: Hepatocellular carcinoma (HCC) is one of the most severe complications in chronic hepatitis B virus (HBV) infection. HCC can still develop in patients with chronic HBV (CHB) infection undergoing antiviral therapy. Several effective scoring systems for the prediction of HCC risk in CHB patients have been established. However, very few of them are designed for CHB patients receiving nucleos(t)ide analogues (NAs) therapy. Furthermore, none are available for HCC risk prediction in CHB patients receiving finite periods of antiviral therapy. METHODS: This study enrolled 790 consecutive treatment-naïve patients with CHB infection who had visited our liver clinics from 2008 to 2012 for pretreatment assessment before receiving antiviral therapies. The treatments were provided at finite periods according to the National Health Insurance Policy in Taiwan. The last follow-up date was 31 December 2021. We analyzed the virological and clinical factors in these 790 CHB patients receiving finite periods of NA treatments and identified the most significant risk factors for HCC to establish a novel predictive scoring system. By using stepwise selection in a multivariate Cox proportional hazards model, we divided the patients into three risk groups. RESULTS: Our predictive scoring system included five independent variables: genotype C (adjusted HR [aHR] = 2.23), NA-withdraw-related hepatitis relapse (aHR = 6.96), male (aHR = 4.19), liver cirrhosis (aHR = 11.14), and T1768A core promoter mutation (aHR = 3.21). This model revealed significant differences in HCC incidence among the three risk groups. The 5-year cumulative HCC risk significantly differed among the three risk groups (low risk: 1.33%, moderate risk: 4.99%, and high risk: 17.46%), with log-rank test p &lt; 0.001. CONCLUSION: Our predictive scoring system is a promising tool for the prediction of HCC in CHB patients receiving finite NA treatments. Genotype C, NA-withdraw-related hepatitis relapse, male gender, liver cirrhosis, and the T1768A HBV core promoter mutation were significant independent risk factors.

Behavioral, Virologic and Immunologic Factors Associated with the Acquisition and Severity of Herpes Simplex Virus Type 2 Infection among Women

Behavioral, Virologic and Immunologic Factors Associated with the Acquisition and Severity of Herpes Simplex Virus Type 2 Infection among Women

C2729T mutation associated with HBV mother-to-child transmission reduces HBV production via suppressing LHBs expression

ABSTRACT Mother-to-child transmission (MTCT) is still the main route of hepatitis B virus (HBV) infection. However, the virological factors affecting HBV MTCT have not been fully elucidated. In this study, based on a prospective cohort of mother-infant pairs with positive maternal hepatitis B surface antigen (HBsAg), we found that the average nucleotide mutation rate of HBV preS1 promoter (SPI) region in the immunoprophylaxis success group was significantly higher than that in the immunoprophylaxis failure group. Among the nucleotide mutations of the HBV SPI region, the C2729T mutation had the highest frequency. Next, we found that the C2729T mutation promoted HBsAg release but reduced HBV production by suppressing the expression of large hepatitis B surface antigen (LHBs), and overexpressing LHBs could rescue this phenomenon. Based on the fact that the C2729T mutation could alter the binding site of hepatocyte nuclear factor 1 (HNF1) in the HBV SPI region, we uncovered that such an alteration could downregulate the transcriptional activity of SPI by attenuating the binding ability of HNF1 and HBV SPI region. This study suggests that HBV C2729T mutation may contribute to the immunoprophylaxis success of HBV MTCT by reducing HBV production, which supplements the virological factors affecting HBV MTCT.

Pre-Vaccination Human Papillomavirus Genotypes and HPV16 Variants among Women Aged 25 Years or Less with Cervical Cancer.

In 2007, Australia introduced a national human papillomavirus (HPV) vaccination program. In 2017, the onset of cervical screening changed from 18 to 25 years of age, utilising human papillomavirus (HPV) nucleic acid testing. The objective of the study is to describe the HPV genotypes and HPV16 variants in biopsies from women ≤ 25 years of age with cervical carcinoma (CC) (cases), compared with those aged >25 years (controls), in a pre-vaccination cohort. HPV genotyping of archival paraffin blocks (n = 96) was performed using the INNO-LiPA HPV Genotyping assay. HPV16-positive samples were analysed for variants by type-specific PCR spanning L1, E2 and E6 regions. HPV16 was the commonest genotype in cases (54.5%, 12/22) and controls (66.7%, 46/69) (p = 0.30), followed by HPV18 (36.3%, 8/22 vs. 17.3% 12/69, respectively) (p = 0.08). Furthermore, 90% (20/22) of cases and 84.1% (58/69) of controls were positive for HPV16 or 18 (p = 0.42); 100% (22/22) of cases and 95.7% (66/69) of controls had at least one genotype targeted by the nonavalent vaccine (p = 0.3). The majority of HPV16 variants (87.3%, 48/55) were of European lineage. The proportion of unique nucleotide substitutions was significantly higher in cases (83.3%, 10/12) compared with controls (34.1%, 15/44), (p < 0.003, χ2, OR 9.7, 95%CI 1.7-97.7). Virological factors may account for the differences in CCs observed in younger compared with older women. All CCs in young women in this study had preventable 9vHPV types, which is important messaging for health provider adherence to new cervical screening guidelines.

Immunomodulatory Activity of the Tyrosine Kinase Inhibitor Dasatinib to Elicit NK Cytotoxicity against Cancer, HIV Infection and Aging.

Tyrosine kinase inhibitors (TKIs) have been extensively used as a treatment for chronic myeloid leukemia (CML). Dasatinib is a broad-spectrum TKI with off-target effects that give it an immunomodulatory capacity resulting in increased innate immune responses against cancerous cells and viral infected cells. Several studies reported that dasatinib expanded memory-like natural killer (NK) cells and γδ T cells that have been related with increased control of CML after treatment withdrawal. In the HIV infection setting, these innate cells are associated with virus control and protection, suggesting that dasatinib could have a potential role in improving both the CML and HIV outcomes. Moreover, dasatinib could also directly induce apoptosis of senescence cells, being a new potential senolytic drug. Here, we review in depth the current knowledge of virological and immunogenetic factors associated with the development of powerful cytotoxic responses associated with this drug. Besides, we will discuss the potential therapeutic role against CML, HIV infection and aging.

Antiretroviral treatment failure and associated factors among people living with HIV on therapy in Homa Bay, Kenya: A retrospective study.

Despite large numbers of patients accessing antiretroviral treatment (ART) in Kenya, few studies have explored factors associated with virologic failure in Western Kenya, specifically. We undertook a study in Homa Bay County, Kenya to assess the extent of virologic treatment failure and factors associated with it. This was an observational retrospective study conducted from September 2020 to January 2021. Data were abstracted from the records of patients who had been on ART for at least six months at the time of data collection after systematic sampling stratified by age group at ART initiation (0-14 and 15+ years), using probability proportion to the numbers of patients attending the facility. Confirmed viral treatment failure was defined as viral load ≥1000 copies/ml based on two consecutive viral load measurements after at least three months of enhanced adherence counseling. Data were analyzed using descriptive statistics and Cox regression modeling. Of the 2,007 patients sampled, 160 (8.0%) had confirmed virologic treatment failure. Significantly higher virologic treatment failure rates were identified among male patients 78/830 (9.4%) and children 115/782 (14.7%). Factors associated with virologic treatment failure (VTF), were age 0-14 years, adjusted hazard ratio (AHR) 4.42, (95% Confidence Interval [CI], 3.12, 6.32), experience of treatment side effects AHD: 2.43, (95% CI, 1.76, 3.37), attending level 2/3 health facility, AHR: 1.87, (95% CI: 1.29, 2,72), and history of opportunistic infections (OIs), AHR: 1.81, (95% CI, 1.76, 3.37). Children, attendees of level 2/3 health facilities, patients with a history of OIs, and those experiencing treatment side-effects are at risk of VTF. Increased focus on children and adolescents on screening for drug resistance, administration of and adherence to medication, and on effective information and education on side-effects is critical. Additionally, there is need for increased training and support for health care workers at primary level care facilities.