Diversity of the HIV-1 Long Terminal Repeat Following Mother-to-Child Transmission

AbstractA study of the human immunodeficiency virus Type 1 (HIV-1) 5′ long terminal repeat (LTR) was performed to determine the extent of variation found within the LTR from 19 mother–infant pairs in Tanzania and to assess whether the LTR is useful in distinguishing maternal sequences that were transmitted to infants. HIV-1 subtypes A, C, and D as well as intersubtype recombinant LTR sequences were detected in mothers and infants. The LTR subtype was 100% concordant between mothers and their infants. Diversity calculations showed a significant reduction in LTR variation in infants compared to their mothers. However, the overall magnitude of LTR variation was less than that found in the env gene from the same individuals. These data suggest a selective constraint active upon the 5′ long terminal repeat that is distinct from immune selective pressure(s) directed against HIV-1 structural genes. Detection of maternal LTR variants that were transmitted to infants may yield important information concerning nonstructural determinants of HIV-1 transmission from mother to infant

Variability of the preC/C region of hepatitis B virus genotype A from a South African cohort predominantly infected with HIV

Hepatitis B virus (HBV) is a serious global health problem, and HBV genotype is an important determinant of disease progression and treatment outcome. The aim of this study was to assess variations of the precore/core (preC/C) region in HBV genotype A. Sequencing of the preC/C and surface (S) genes of HBV was performed on plasma samples from 20 HBV/HIV co-infected and 5 HBV mono-infected individuals. All preC/C study sequences clustered with subgenotype A1, except for two which clustered with subgenotype D4 reference strains. The nucleotide and amino acid variability was far higher in the preC/C region than in the S region. Mutations associated with reduction or failure of HBV e-antigen (HBeAg) production were observed, with a preC start codon mutation being common (24%). Other mutations (e.g., P5H/L and I97L) associated with severe liver disease were also noticed, some of which were located in the major histocompatibility restricted sites. PreC/C intergenotype nucleotide divergence was >7%, while subgenotypes differed by 2.5–7%. Several study sequences were highly divergent from other African subgenotype A1 strains. This study showed that HBeAg-negative chronic hepatitis B is underestimated in subgenotype A1, and also highlighted the variant South African A1 strains. The major advantage of preC/C sequencing is that it informs patient management as HBeAg-negative chronic hepatitis B responds poorly to conventional interferon-α therapy, and some guidelines treat HBeAg-negative chronic hepatitis B differently from HBeAg-positive chronic hepatitis B. These data suggest that subgenotype A1 may be more involved in severe HBV-related diseaseshttp://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1096-9071/hb201

Introducing trainees to research using an online, asynchronous course

Abstract Introduction: Research is an important aspect of many students’ training. However, formal research training is rarely included in curricula. Thus, we developed an online, asynchronous series of modules to introduce trainees to multiple topics that are relevant to the conduct of research. Methods: Research 101 was utilized by first-year medical students and undergraduate students conducting mentored research projects. Students’ knowledge, confidence, and satisfaction were assessed using pre- and post-module surveys with five-point Likert scaled questions, open-ended text responses, and a final quiz. Results: Pre-module survey results showed that learners felt most confident with the Conducting a literature search and Race and racism in medicine modules and least confident with the Submitting an Institutional Review Board protocol at UC module. Post-module survey responses were significantly increased compared to pre-module results for all modules and questions (p < 0.0001). The response to “The content of this module met my needs” was endorsed across all modules (84.9% “yes” responses). A final quiz of 25 multiple-choice questions was completed by 92 participants who received a median score of 21. Content analysis of open-ended post-module survey responses identified several strengths and opportunities for improvement in course content and instructional methods. Conclusions: These data demonstrate that significant learning resulted from completion of Research 101, as post-module survey scores were significantly higher than pre-module survey scores for all modules and questions. Final quiz scores were positive but also highlighted opportunity for additional trainee learning and will guide evolution of future modules

Variability of the preC/C region of hepatitis B virus genotype A from a South African cohort predominantly infected with HIV

ABSTRACT Hepatitis B virus (HBV) is a serious global health problem, and HBV genotype is an important determinant of disease progression and treatment outcome. The aim of this study was to assess variations of the precore/core (preC/C) region in HBV genotype A. Sequencing of the preC/C and surface (S) genes of HBV was performed on plasma samples from 20 HBV/HIV co-infected and 5 HBV mono-infected individuals. All preC/C study sequences clustered with subgenotype A1, except for 2 which clustered with subgenotype D4 reference strains. The nucleotide and amino acid variability was far higher in the preC/C region than in the S region. Mutations associated with reduction or failure of HBV e-antigen (HBeAg) production were observed, with a preC start codon mutation being common (24%). Other mutations (e.g. P5H/L and I97L) associated with severe liver disease were also noticed, some of which were located in the major histocompatibility restricted sites. PreC/C intergenotype nucleotide divergence was &gt;7%, while subgenotypes differed by 2.5 -7%. Several study sequences were highly divergent from other African subgenotype A1 strains. This study showed that HBeAg-negative chronic hepatitis B is underestimated in subgenotype A1, and also highlighted the variant South African A1 strains. The major advantage of preC/C sequencing is that it informs patient management as HBeAgnegative chronic hepatitis B responds poorly to conventional interferon-α therapy, and some guidelines treat HBeAg-negative chronic hepatitis B differently from HBeAg-positive chronic hepatitis B. These data suggest that subgenotype A1 may be more involved in severe HBVrelated diseases

Impact of lamivudine-based antiretroviral treatment on hepatitis B viremia in HIV-coinfected South Africans

This prospective study investigated the impact of lamivudine-containing antiretroviral therapy (ART) on HIV-positive patients in South Africa with baseline hepatitis B virus (HBV) infection. Follow-up samples from 56 HBV/HIV co-infected patients, 25 with occult HBV infection (OBI) and 31 with chronic HBV infection (CHB), were available for analysis. HBV viral loads were quantified at 6, 12, 18, and 24 months post-ART initiation by the COBAS TaqMan HBV Test 48 assay, and the HBV polymerase gene was amplified with an in-house nested polymerase chain reaction assay. During 24 months of lamivudine-based ART, 6 of 8 (75%) OBI and 4 of 6 (67%) CHB patients achieved undetectable levels of HBV DNA, while 2 patients had persistent HBV DNA levels 2 105 despite lamivudine-based ART for 24 months. HIV viremia was undetectable in all patients at 12 months, suggesting high adherence to ART. Several lamivudine-associated HBV resistance mutations, including L180M, A181T, M204I, and M204V, were observed. Sequence analysis also revealed a rare genotype G infection. While resource-limited settings may use lamivudine-based ART because of availability and low cost, antivirals with dual therapy against HBV and HIV (e.g., lamivudine and tenofovir) should always be recommended with the regular monitoring of HBV viremia levels.The South African National Research Foundation, Poliomyelitis Research Foundation, Stella and Paul Lowenstein Trust, and Canon and Collins scholarship.http://www.mdpi.com/journal/virusesam2021Medical Virolog

Hepatitis B virus infection in post-vaccination South Africa : occult HBV infection and circulating surface gene variants

No abstract availableNational Health Laboratory Services (NHLS)Research Trust [grant number: GRANT004_94329] and the Poliomyelitis Research Foundation (PRF) [grant number: 11/74 (MSc)].http://www.elsevier.com/locate/jcvhb201

A Novel Inhibitor of Human La Protein with Anti-HBV Activity Discovered by Structure-Based Virtual Screening and In Vitro Evaluation

Background: Over 350 million people worldwide are infected with hepatitis B virus (HBV), a major cause of liver failure and hepatocellular carcinoma. Current therapeutic agents are highly effective, but are also associated with development of viral resistance. Therefore, strategies for identifying other anti-HBV agents with specific, but distinctive mechanisms of action are needed. The human La (hLa) protein, which forms a stabilizing complex with HBV RNA ribonucleoprotein to promote HBV replication, is a promising target of molecular therapy. Aims: This study aimed to discover novel inhibitors of hLa that could inhibit HBV replication and expression. Methods: A multistage molecular docking approach was used to screen a Specs database and an in-house library against hLa binding sites. Sequential in vitro evaluations were performed to detect potential compounds with high scores in HepG2.2.15 cells. Results: Of the 26 potential compounds with high scores chosen for experimental verification, 12 had HBV DNA inhibition ratios of less than 50 % with P,0.05. Six had significant inhibition of HBV e antigen (HBeAg) levels, and 13 had significant inhibition of HBV surface antigen (HBsAg) levels by in vitro assays. Compounds HBSC-11, HBSC-15 and HBSC-34 (HBSC is system prefix for active compounds screened by the library) were selected for evaluation. HBSC-11 was found to have an obvious inhibitory effect on hLa transcription and expression

Chronic and Occult Hepatitis B Virus Infection in Pregnant Women in Botswana

The hepatitis B virus (HBV) is a global problem; however, the burden of HBV infection in pregnant women in Botswana is unknown. We sought to determine the prevalence of chronic and occult HBV infection in human immunodeficiency virus (HIV)-infected and -uninfected pregnant women in Botswana. Samples from 752 pregnant women were tested for hepatitis B surface antigen (HBsAg), and HBsAg-positive samples were tested for hepatitis B e antigen (HBeAg) and HBV DNA load. Samples that were HBsAg negative were screened for occult HBV infection by determining the HBV DNA load. HBV genotypes were determined based on a 415-base-pair fragment of the surface gene. Among the 752 women tested during pregnancy or early postpartum, 16 (2.1%) (95% confidence interval (CI): 2.0–2.2) were HBsAg-positive. The prevalence of chronic HBV infection was higher (3.1%) among HIV-infected (95% CI: 3.0–3.2) compared with HIV-uninfected women (1.1%) (95% CI: 1.07–1.1, p = 0.057). Among the 622 HBsAg-negative women, the prevalence of occult HBV infection was 6.6% (95% CI: 6.5–6.7). Three of thirteen HBsAg-positive participants were HBeAg-positive, and all were HIV-negative. Of the 11 maternal samples successfully genotyped, five (45.5%) were genotype D3, five (45.5%) were genotype A1, and one was genotype E (9%). Low and similar proportions of HIV-infected and -uninfected pregnant women in Botswana had occult or chronic HBV infection. We identified a subset of HIV-negative pregnant women who had high HBV DNA levels and were HBeAg-positive, and thus likely to transmit HBV to their infants

Changes in timber haul emissions in the context of shifting forest management and infrastructure

<p>Abstract</p> <p>Background</p> <p>Although significant amounts of carbon may be stored in harvested wood products, the extraction of that carbon from the forest generally entails combustion of fossil fuels. The transport of timber from the forest to primary milling facilities may in particular create emissions that reduce the net sequestration value of product carbon storage. However, attempts to quantify the effects of transport on the net effects of forest management typically use relatively sparse survey data to determine transportation emission factors. We developed an approach for systematically determining transport emissions using: 1) -remotely sensed maps to estimate the spatial distribution of harvests, and 2) - industry data to determine landscape-level harvest volumes as well as the location and processing totals of individual mills. These data support spatial network analysis that can produce estimates of fossil carbon released in timber transport.</p> <p>Results</p> <p>Transport-related emissions, evaluated as a fraction of transported wood carbon at 4 points in time on a landscape in western Montana (USA), rose from 0.5% in 1988 to 1.7% in 2004 as local mills closed and spatial patterns of harvest shifted due to decreased logging on federal lands.</p> <p>Conclusion</p> <p>The apparent sensitivity of transport emissions to harvest and infrastructure patterns suggests that timber haul is a dynamic component of forest carbon management that bears further study both across regions and over time. The monitoring approach used here, which draws only from widely available monitoring data, could readily be adapted to provide current and historical estimates of transport emissions in a consistent way across large areas.</p

Role of MicroRNA Profile Modifications in Hepatitis C Virus-Related Mixed Cryoglobulinemia

Hepatitis C virus infection is closely related to lymphoproliferative disorders (LPDs), including mixed cryoglobulinemia (MC) and some lymphomas. Modification of the expression of specific microRNAs (miRNAs) has been associated with different autoimmune diseases and/or LPDs. No data exist about the modifications in miRNA expression in HCV-associated LPDs. The aim of this study was to analyze the expression levels of a panel of miRNAs previously associated with autoimmune/LPDs in a large population of HCV patients with and without MC or non-Hodgkin’s lymphoma (NHL), to identify potential markers of evolution of HCV infection. PBMC expression of miR-Let-7d, miR-16, miR-21, miR-26b, miR-146a and miR-155 was evaluated by real-time PCR in 167 HCV patients (75 with MC [MC-HCV], 11 with HCV-associated NHL [NHL-HCV], 81 without LPD [HCV]) and in 35 healthy subjects (HS). A significant increase in miR-21 (p<0.001), miR-16 (p<0.01) and miR-155 (p<0.01) expression was detected in PBMCs from only NHL patients whereas a significant decrease in miR-26b was detected in both MC and NHL subjects (p<0.01) when compared to HS and HCV groups. A restoration of miR-26b levels was observed in the post-treatment PBMCs of 35 HCV-MC patients experiencing complete virological and clinical response following antiviral therapy. This study, for the first time, shows that specific microRNAs in PBMC from HCV patients who developed MC and/or NHL are modulated differently. The specific, reversible downregulation of miR-26b strongly suggests the key role it plays in the pathogenesis of HCV-related LPDs and its usefulness as a biomarker of the evolution of HCV infection to these disorders