Enhanced control of pathogenic Simian immunodeficiency virus SIVmac239 replication in macaques immunized with an interleukin-12 plasmid and a DNA prime-viral vector boost vaccine regimen

DNA priming has previously been shown to elicit augmented immune responses when administered by electroporation (EP) or codelivered with a plasmid encoding interleukin-12 (pIL-12). We hypothesized that the efficacy of a DNA prime and recombinant adenovirus 5 boost vaccination regimen (DNA/rAd5) would be improved when incorporating these vaccination strategies into the DNA priming phase, as determined by pathogenic simian immunodeficiency virus SIVmac239 challenge outcome. The whole SIVmac239 proteome was delivered in 5 separate DNA plasmids (pDNA-SIV) by EP with or without pIL-12, followed by boosting 4 months later with corresponding rAd5-SIV vaccine vectors. Remarkably, after repeated low-dose SIVmac239 mucosal challenge, we demonstrate 2.6 and 4.4 log reductions of the median SIV peak and set point viral loads in rhesus macaques (RMs) that received pDNA-SIV by EP with pIL-12 compared to the median peak and set point viral loads in mock-immunized controls (P < 0.01). In 5 out of 6 infected RMs, strong suppression of viremia was observed, with intermittent "blips" in virus replication. In 2 RMs, we could not detect the presence of SIV RNA in tissue and lymph nodes, even after 13 viral challenges. RMs immunized without pIL-12 demonstrated a typical maximum of 1.5 log reduction in virus load. There was no significant difference in the overall magnitude of SIV-specific antibodies or CD8 T-cell responses between groups; however, pDNA delivery by EP with pIL-12 induced a greater magnitude of SIV-specific CD4 T cells that produced multiple cytokines. This vaccine strategy is relevant for existing vaccine candidates entering clinical evaluation, and this model may provide insights into control of retrovirus replication.     

Addressing antimicrobial resistance by improving access and quality of care—A review of the literature from East Africa

Universal access to healthcare, including quality medicines, is a fundamental human right but is still out of reach for many in low- and middle-income countries (LMICs). An existing framework capturing variability of access to healthcare in low-resource settings includes the 5 dimensions: availability, accessibility, affordability, adequacy, and acceptability. This framework encompasses key components, including health infrastructure and means to access it as well as service organisation, costs, and factors that influence users’ satisfaction. However, in reality, the effectiveness of accessed healthcare is measured by the likelihood of a positive outcome. We therefore propose an expansion of this framework to include an additional dimension, “aspects of quality,” incorporating quality, which critically influences the ability of the accessed services to generate optimal health outcomes. Within this framework, we explore literature from East Africa likely relevant to a range of LMIC contexts, mainly focusing on the provision of widely used antimicrobials such as antimalarials and antibiotics. We argue that major inadequacies exist across all 6 dimensions of access and quality of drugs and their provision. While the global focus is on curbing excessive antimicrobial use to tackle the antimicrobial resistance (AMR) crisis, major constraints around access shape patients’ health-seeking decisions leading to potentially problematic practices that might exacerbate the AMR problem. We advocate for a holistic approach to tackling these inadequacies, encompassing all dimensions of access and quality of healthcare in order to improve health outcomes while simultaneously counteracting the AMR crisis.     

A highly potent and safe pyrrolopyridine-based allosteric HIV-1 integrase inhibitor targeting host LEDGF/p75-integrase interaction site

Allosteric integrase inhibitors (ALLINIs) are a class of experimental anti-HIV agents that target the noncatalytic sites of the viral integrase (IN) and interfere with the IN-viral RNA interaction during viral maturation. Here, we report a highly potent and safe pyrrolopyridine-based ALLINI, STP0404, displaying picomolar IC₅₀ in human PBMCs with a >24,000 therapeutic index against HIV-1. X-ray structural and biochemical analyses revealed that STP0404 binds to the host LEDGF/p75 protein binding pocket of the IN dimer, which induces aberrant IN oligomerization and blocks the IN-RNA interaction. Consequently, STP0404 inhibits proper localization of HIV-1 RNA genomes in viral particles during viral maturation. Y99H and A128T mutations at the LEDGF/p75 binding pocket render resistance to STP0404. Extensive in vivo pharmacological and toxicity investigations demonstrate that STP0404 harbors outstanding therapeutic and safety properties. Overall, STP0404 is a potent and first-in-class ALLINI that targets LEDGF/p75 binding site and has advanced to a human trial.     

Computational design strategies for combinatorial libraries

Medicinal chemistry principles are being increasingly applied to the design of smaller, high purity, information-rich libraries. Recent computational advances in statistical methodology, the design of libraries to reduce ADMET problems, targeting protein families and revisiting natural products as sources of inspiration for scaffolds and reagents are all areas of progressive research.     

Migration patterns and navigation cues of Atlantic salmon post-smolts migrating from 12 rivers through the coastal zones around the Irish Sea

The freshwater phase of the first seaward migration of juvenile Atlantic salmon (Salmo salar) is relatively well understood when compared with our understanding of the marine phase of their migration. In 2021, 1008 wild and 60 ranched Atlantic salmon smolts were tagged with acoustic transmitters in 12 rivers in England, Scotland, Northern Ireland and Ireland. Large marine receiver arrays were deployed in the Irish Sea at two locations: at the transition of the Irish Sea into the North Atlantic between Ireland and Scotland, and between southern Scotland and Northern Ireland, to examine the early phase of the marine migration of Atlantic salmon smolts. After leaving their natal rivers' post-smolt migration through the Irish Sea was rapid with minimum speeds ranging from 14.03 to 38.56 km.day⁻¹ for Atlantic salmon smolts that entered the Irish Sea directly from their natal river, to 9.69–39.94 km.day⁻¹ for Atlantic salmon smolts that entered the Irish Sea directly from their natal estuary. Population minimum migration success through the study area was strongly correlated with the distance of travel, populations further away from the point of entry to the open North Atlantic exhibited lower migration success. Post-smolts from different populations experienced different water temperatures on entering the North Atlantic. This was largely driven by the timing of their migration and may have significant consequences for feeding and ultimately survivorship. The influence of water currents on post-smolt movement was investigated using data from previously constructed numerical hydrodynamic models. Modeled water current data in the northern Irish Sea showed that post-smolts had a strong preference for migrating when the current direction was at around 283° (west-north-west) but did not migrate when exposed to strong currents in other directions. This is the most favorable direction for onward passage from the Irish Sea to the continental shelf edge current, a known accumulation point for migrating post-smolts. These results strongly indicate that post-smolts migrating through the coastal marine environment are: (1) not simply migrating by current following (2) engage in active directional swimming (3) have an intrinsic sense of their migration direction and (4) can use cues other than water current direction to orientate during this part of their migration.     

Comparison of microbial communities in sequencing batch reactors (SBRs) exposed to trace erythromycin and erythromycin-H2O

Wastewater treatment plants (WWTPs) are major collection pools of antibiotics of which low concentrations may induce antibiotic resistance in their microbial communities and pose threat to human health. However, information is still limited on the microbial community alteration in WWTPs upon exposure to low-dose antibiotics due to absence of negative control systems without input of resistant bacteria and resistance genes. Here we report the impact of trace erythromycin (ERY) and dehydrated erythromycin (ERY-H₂O) on microbial community dynamics in three long-term (1 year) running sequencing batch reactors (SBRs), R1 (ERY-H₂O), R2 (ERY), and negative control R3. The PhyloChip microarray analysis showed that ERY-H₂O and ERY significantly altered their microbial communities based on bacterial richness (e.g., 825 operational taxonomic units (OTUs) in R1, 699 OTUs in R2, and 920 OTUs in R3) and population abundance (15 and 48 subfamilies with >80 % abundance decrease in R1 and R2, respectively). ERY-H₂O and ERY have broad but distinct antimicrobial spectrums. For example, bacteria of all the major phyla (i.e., Proteobacteria, Actinobacteria, Bacteroidetes, and Chloroflexi) present in SBRs were severely inhibited by ERY-H₂O and ERY, but bacteria of Acidobacteria, Chlorobi, Firmicutes, Nitrospira and OP10 phyla were only inhibited by ERY. Very limited bacterial groups showed antibiotic resistance to ERY-H₂O or ERY through forming biofilms (e.g., Zoogloea) or synthesizing resistant proteins (e.g., Thauera, Candidatus Accumulibacter, Candidatus Competibacter, and Dechloromonas) in the SBRs. Inhibition was observed to be the main effect of ERY-H₂O and ERY on microbial communities in the reactors. The results would broaden our knowledge of effects of low-dose antibiotics on microbial communities in WWTPs.     

Contrasting diversity dynamics of phoretic mites and beetles associated with vertebrate carrion

Carrion is an ephemeral and nutrient-rich resource that attracts a diverse array of arthropods as it decomposes. Carrion-associated mites often disperse between animal carcasses using phoresy, the transport of one species by another. Yet few studies have contrasted the dynamics of mite assemblages with other insect taxa present at carrion. We examined and compared the changes in abundance, species richness and composition of mite and beetle assemblages sampled at kangaroo carcasses in a grassy eucalypt woodland at four different times over a 6-month period. We found that the majority of mites were phoretic, with the mesostigmatid genera Uroseius (Uropodidae), Macrocheles (Macrochelidae) and Parasitus (Parasitidae) the most abundant taxa (excluding astigmatid mites). Abundance and richness patterns of mites and beetles were very different, with mites reaching peak abundance and richness at weeks 6 and 12, and beetles at weeks 1 and 6. Both mites and beetles showed clear successional patterns via changes in species presence and relative abundance. Our study shows that mesostigmatid mite assemblages have a delay in peak abundance and richness relative to beetle assemblages. This suggests that differences in dispersal and reproductive traits of arthropods may contribute to the contrasting diversity dynamics of carrion arthropod communities, and further highlights the role of carrion as a driver of diversity and heterogeneity in ecosystems.