Standardized framework for assessing soil quality at antimony smelting site by considering microbial-induced resilience and heavy metal contamination.

Antimony smelting activities damage the soil and vegetation surroundings while generating economic value. However, no standardized methods are available to diagnose the extent of soil degradation at antimony smelting sites. This study developed a standardized framework for assessing soil quality by considering microbial-induced resilience and heavy metal contamination at Xikuangshan antimony smelting site. The soil resilience index (SRI) and soil contamination index (SCI) were calculated by Minimum Data Set and geo-accumulation model, respectively. After standardized by a multi-criteria quantitative procedure of modified Nemerow's pollution index (NPI), the integrated assessment of soil quality index (SQI), which is the minimum of SRINPI and SCINPI, was achieved. The results showed that Sb and As were the prominent metal(loid) pollutants, and significant correlations between SQI and SRI indicated that the poor soil quality was mainly caused by the low level of soil resilience. The primary limiting factors of SRI were Fungi in high and middle contaminated areas, and Skermanella in low contaminated area, suggesting that the weak soil resilience was caused by low specific microbial abundances. Microbial regulation and phytoremediation are greatly required to improve the soil quality at antimony smelting sites from the perspectives of pollution control and resilience improvement. This study improves our understanding of ecological effects of antimony smelting sites and provides a theoretical basis for ecological restoration and sustainable development of mining areas.

Reuse potential of municipal solid waste incinerator bottom ash as secondary aggregate: Material characteristics, persistent organic pollutant content and effects of pH and selected environmental lixiviants on leaching behaviour.

Increasing municipal solid waste (MSW) production poses challenges for sustainable urban development. Modern energy-from-waste (EfW) facilities incinerate MSW, reducing mass and recovering energy. In the UK, MSW incineration bottom ash (MSW IBA) is primarily reused in civil engineering applications. This study characterizes UK-produced MSW IBA, examining its pH-dependent leaching behaviour and response to environmental lixiviants. Results show predominant components include a melt phase, primary glass and fine ash aggregations, and a chemical composition dominated by SiO2 (30-50 %), CaO (∼15 %), Fe2O3 (∼10 %), and Al2O3 (∼8%). X-ray absorption near edge structure (XANES) analysis shows that Zn and Cu are most likely oxygen-bound (adsorbed to oxy-hydroxides and as oxides) with some sulphur bound. Polychlorinated biphenyls (PCBs) and polychlorinated dibenzodioxins/furans (PCDD/Fs) are well below regulatory limits, and polycyclic aromatic hydrocarbons (PAHs) were undetectable. Leaching tests indicate trace elements mobilize at pHs ≤ 6. With a natural pH of 11.3 and high buffering capacity, significant acid inputs to the MSW IBA are required to reach this pH, which are improbable in the environment. Wood chip additions increase leachate's dissolved organic carbon (DOC) and reduce pH, but had minimal impact on metal-leaching behaviour. Synthetic plant exudate solutions minimally affect metal leaching at realistic concentrations, only enhancing leaching at ≥ 1500 mg l-1 DOC. This work supports MSW IBA's low-risk in specified civil engineering applications.

Complete Rescue of HTLV-1p12KO Infectivity by Depletion of Monocytes Together with NK and CD8+ T Cells.

The transient depletion of monocytes alone prior to exposure of macaques to HTLV-1 enhances both HTLV-1WT (wild type) and HTLV-1p12KO (Orf-1 knockout) infectivity, but seroconversion to either virus is not sustained over time, suggesting a progressive decrease in virus expression. These results raise the hypotheses that either HTLV-1 persistence depends on a monocyte reservoir or monocyte depletion provides a transient immune evasion benefit. To test these hypotheses, we simultaneously depleted NK cells, CD8+ T cells, and monocytes (triple depletion) prior to exposure to HTLV-1WT or HTLV-1p12KO. Remarkably, triple depletion resulted in exacerbation of infection by both viruses and complete rescue of HTLV-1p12KO infectivity. Following triple depletion, we observed rapid and sustained seroconversion, high titers of antibodies against HTLV-1 p24Gag, and frequent detection of viral DNA in the blood and tissues of all animals when compared with depletion of only CD8+ and NK cells, or monocytes alone. The infection of macaques with HTLV-1WT or HTLV-1p12KO was associated with higher plasma levels of IL-10 after 21 weeks, while IL-6, IFN-γ, IL-18, and IL-1ß were only elevated in animals infected with HTLV-1WT. The repeat depletion of monocytes, NK, and CD8+ cells seven months following the first exposure to HTLV-1 did not further exacerbate viral replication. These results underscore the contribution of monocytes in orchestrating anti-viral immunity. Indeed, the absence of orf-1 expression was fully compensated by the simultaneous depletion of CD8+ T cells, NK cells, and monocytes, underlining the primary role of orf-1 in hijacking host immunity.

Analysis of caregiver perspectives on patients with mucopolysaccharidosis II treated with pabinafusp alfa: results of qualitative interviews in Japan.

BACKGROUND: Mucopolysaccharidosis type II (MPS II), or Hunter syndrome, is a rare X-linked metabolic disorder predominantly affecting males. Pabinafusp alfa, an iduronate-2-sulfatase enzyme designed to cross the blood-brain barrier, was approved in Japan in 2021 as the first enzyme replacement therapy targeting both the neuropathic and somatic signs and symptoms of MPS II. This study reports caregivers' experiences of MPS II patients receiving pabinafusp alfa through qualitative interviews. METHODS: Semi-structured, qualitative interviews were conducted with caregivers at seven clinical sites in Japan using a semi-structured moderation guide (Voice of the Caregiver guide). Thematic analysis was applied to the interview transcripts to identify symptoms and health-related quality of life impacts at baseline, changes during treatment, and overall treatment experience. RESULTS: Seven caregivers from 16 trial sites participated, representing seven children aged 8-18 years who had received pabinafusp alfa for 3.3-3.5 years at the time of the interviews. Data suggest a general trend toward improvement in multiple aspects, although not all caregivers observed discernible changes. Reported cognitive improvements included language skills, concentration, self-control, eye contact, mental clarity, concept understanding, following instructions, and expressing personal needs. Further changes were reported that included musculoskeletal improvements and such somatic changes as motor function, mobility, organ involvement, joint mobility, sleep patterns, and fatigue. Four caregivers reported improvements in family quality of life, five expressed treatment satisfaction, and all seven indicated a strong willingness to continue treatment of their children with pabinafusp alfa. CONCLUSION: Caregivers' perspectives in this study demonstrate treatment satisfaction and improvement in various aspects of quality of life following therapy with pabinafusp alfa. These findings enhance understanding of pabinafusp alfa's potential benefits in treating MPS II and contribute to defining MPS II-specific outcome measures for future clinical trials.

STA-21 regulates Th-17/Treg balance and synovial fibroblasts functions in rheumatoid arthritis.

JAK/STAT signaling pathway plays a significant role in cytokines and growth factors signaling involved in the pathogenesis of rheumatoid arthritis (RA). STAT3 is a major downstream signaling mediator of important pro-inflammatory cytokines involved in Th-17 cell differentiation playing a significant role in regulating Th-17/ Treg balance and the development of autoimmune diseases, especially RA. Studies also have reported the role of the STAT3 pathway in inflammatory and destructive functions of synovial fibroblasts (SFs) in RA. STA-21 is a small molecule inhibitor that can inhibit STAT3 activation impairing the expression of STAT3 target genes. In this study, we tested whether a STAT3 inhibitor, STA-21, can alter Th-17/Treg balance and SF functions in RA. Peripheral blood mononuclear cells (PBMC) and SFs were isolated from 34 RA patients undergoing orthopedic surgery and 15 healthy controls to investigate in vitro effects of STA-21. The main assays were MTT assay, PI staining, reverse transcription-PCR (RT-PCR), flow cytometric analysis, and ELISA. Results showed that STA-21 reduced the proportion of Th-17 cells and the expression of STAT3 target genes, RORγt, IL-21, and IL-23R involved in Th-17 cells differentiation while it conversely increased the proportion of Treg cells, which theoretically may result in suppression of inflammation. We found that STAT3 activation and its target gene expression increased in RA-SFs. In addition, results showed that STA-21 can reduce the expression of STAT3 target genes related to cell proliferation, apoptosis, and inflammation leading to a decrease in proliferation and conversely increase in apoptosis of RA-SFs. Overall, our findings provide evidence that STA-21 can reduce inflammatory immune processes conducted by T cells and RA-SFs in RA, suggesting that this compound is a suitable option for clinical studies in RA.

In Vivo Treatment with Insulin-like Growth Factor 1 Reduces CCR5 Expression on Vaccine-Induced Activated CD4+ T-Cells.

At the heart of the DNA/ALVAC/gp120/alum vaccine's efficacy in the absence of neutralizing antibodies is a delicate balance of pro- and anti-inflammatory immune responses that effectively decreases the risk of SIVmac251 acquisition in macaques. Vaccine efficacy is linked to antibodies recognizing the V2 helical conformation, DC-10 tolerogenic dendritic cells eliciting the clearance of apoptotic cells via efferocytosis, and CCR5 downregulation on vaccine-induced gut homing CD4+ cells. RAS activation is also linked to vaccine efficacy, which prompted the testing of IGF-1, a potent inducer of RAS activation with vaccination. We found that IGF-1 changed the hierarchy of V1/V2 epitope recognition and decreased both ADCC specific for helical V2 and efferocytosis. Remarkably, IGF-1 also reduced the expression of CCR5 on vaccine-induced CD4+ gut-homing T-cells, compensating for its negative effect on ADCC and efferocytosis and resulting in equivalent vaccine efficacy (71% with IGF-1 and 69% without).

A Systematic Review on Childhood Non-Hodgkin Lymphoma: An Overlooked Phenomenon in the Health and Research Sector of Bangladesh.

Globally, childhood cancer, particularly non-Hodgkin lymphomas (NHLs), is a prevalent concern. However, the difficulty becomes even more distressing in lower-middle-income nations such as Bangladesh. The insufficiency of research, resources, inadequate guidelines, expensive treatment costs, and specialized knowledge exacerbate the challenges associated with the treatment of certain types of cancers. Our investigation looked extensively into the circumstances prevailing in Bangladesh, with the objective of providing a comprehensive overview of the current status and approaches to managing NHL in the country. Through this work, our intention was to illuminate the domains that require immediate focus and assistance. To get insight into the present state of NHL in Bangladesh, our analysis focused on a selection of seven research articles and two case reports published between 2018 and 2023. In order to ensure the integrity and consistency of our review, we conducted a detailed selection procedure, employing the systematic PRISMA review methodology. From a pool of 294 papers, we selected the ones that met our predetermined criteria. These papers were sourced from reputable academic databases, such as Google Scholar and PubMed. The findings of our study indicate a higher prevalence of NHL among children in Bangladesh compared to Hodgkin lymphoma (HL). Additionally, this phenomenon exhibits a higher prevalence among male individuals. Our study revealed that in Bangladesh, there is a lack of a dedicated guideline or research center specifically focused on NHL. Additionally, the number of research centers and research dedicated to cancer treatment as a whole is limited. Our research aims to offer a complete analysis of NHL in the context of Bangladesh, with the intention of offering valuable guidance to healthcare professionals and policymakers. The utilization of our research outcomes has the potential to enhance patient care, facilitate the development of more effective clinical protocols, and promote greater accessibility and affordability of therapies. This has the potential to provide improved cancer care not only in Bangladesh but also in other comparable contexts worldwide.

Co-existence of blaIMP, blaNDM-1, and blaSHV, genes of Pseudomonas aeruginosa isolated from Quetta: Antimicrobial resistance and clinical significance.

Objective: Molecular detection and co-presence of carbapenem-resistant genes in the isolates of Pseudomonas aeruginosa are less commonly reported from Quetta. In the present study, we determined to highlight the antibiotic sensitivity profile and genetic mechanism of carbapenem resistance. Methods: The cross-sectional study was conducted from May to September 2018 at the Hi-tech laboratory, Centre for Advance Studies in Vaccinology and Biotechnology, University of Baluchistan, Quetta. Biochemical and molecular methods were ascertained for the recognition of the isolates and minimum inhibitory concentration was performed using E-test and broth microdilution methods. The molecular basis of carbapenemase activity was determined by identifying carbapenemase genes in the isolates. Results: Of the (n=23) P. aeruginosa isolated from pus aspirates obtained from surgical/burn units, we have detected blaIMP (n=7/8) 87.5%, blaNDM-1 (n=5/8) 62.5%, and blaSHV (n=4/8) 50%. The co-existence of multiple antibiotic-resistant genes, blaIMP, blaNDM-1 and blaSHV was found in (n=2/8) 25% isolates. These isolates displayed resistance against a range of antimicrobials from ß-lactams, tetracyclines, cephalosporins, quinolones, monobactams, aminoglycosides, sulphonamides, phosphoric acid, macrolides, and polypeptide groups, suggesting extensive-drug resistance. Conclusion: The emergence of MBL and ESBL producers is an alarming threat in the region. It is of great importance to determine the resistance mechanism of bacterial bugs. The lack of new antimicrobials particularly against gram-negative bacteria is quite alarming worldwide.

A new hybrid algorithm for intelligent detection of sudden decline syndrome of date palm disease.

Date palm is an important domestic cash crop in most countries. Sudden Decline Syndrome (SDS) causes a huge loss to the crop both in quality and quantity. The literature reports the significance of early detection of disease towards preventive measures to improve the quality of the crop. The number of prevailing detection methods limits to consideration of a certain aspect of disease identification. This study proposes a new hybrid fuzzy fast multi-Otsu K-Means (FFMKO) algorithm integrating the date palm image enhancement, robust thresholding, and optimal clustering for significant disease identification. The algorithm adopts a multi-operator image resizing cost function based on image energy and the dominant color descriptor, the adaptive Fuzzy noise filter, and Otsu image thresholding combined with K-Means clustering enhancements. Besides, we validate the process with histogram equalization and threshold transformation towards enhanced color feature extraction of date palm images. The algorithm authenticates findings on a local dataset of 3293 date palm images and, on a benchmarked data set as well. It achieves an accuracy of 94.175% for successful detection of SDS that outperforms the existing similar algorithms. The impactful findings of this study assure the fast and authentic detection of the disease at an earlier stage to uplift the quality and quantity of the date palm and boost the agriculture-based economy.

VOCs emission from a final landfill cover system induced by ground surface air temperature and barometric pressure fluctuation.

Volatile organic compounds (VOCs) emission flux and their concentration profiles were measured at a final municipal solid waste (MSW) landfill cover in Hangzhou, China. The influencing parameters, especially ground surface air temperature and pressure were monitored concomitantly. Furthermore, a numerical model incorporating coupled thermo-hydro-chemical interaction to assess VOCs emission from this final landfill cover (LFC) system was developed and validated with the field test results. The tested total VOC emission flux from the final cover is 0.0124 µg/m2/s, which indicates that the total amount of VOCs emitted into the atmosphere is 391 mg/m2 annually. Among these, dichloromethane (DCM) dominated VOCs emission flux during May, comprising 51.8% of the total emission flux. The numerical simulation results indicated that the diffusive emission flux of VOCs varied consistently with the fluctuation of atmospheric temperature. Whereas, the advective flux varied inversely with the fluctuation of barometric pressure. The highest difference in diffusive emission flux induced by temperature variation is 183 µg/m2/day and occurred in spring. Moreover, the results demonstrated that the impact of atmospheric temperature and pressure fluctuation on the emission of VOC from final covers is non-negligible when reasonably assessing the risks of landfill and landfill gas emission budget.

Clonal Diversity of Candida auris, Candida blankii, and Kodamaea ohmeri Isolated from Septicemia and Otomycosis in Bangladesh as Determined by Multilocus Sequence Typing.

Candida auris, Candida blankii, and Kodamaea ohmeri have been regarded as emerging fungal pathogens that can cause infections with high mortality. For genotyping of C. auris, a multilocus sequence typing (MLST) scheme based on four locus sequences has been reported, while there is no typing scheme for C. blankii and K. ohmeri. In the present study, the existing MLST scheme of C. auris was modified by adding more locus types deduced from sequence data available in the GenBank database. Furthermore, MLST schemes of C. blankii and K. ohmeri were developed using the four cognate loci (ITS, RPB1, RPB2, D1/D2) and similar sequence regions to those of C. auris. These MLST schemes were applied to identify the ST (sequence type) of clinical isolates of C. auris (n = 7), C. blankii (n = 9), and K. ohmeri (n = 6), derived from septicemia or otomycosis in Bangladesh in 2021. All the C. auris isolates were classified into a single ST (ST5) and clade I, having a Y132F substitution in ERG11p, which is associated with azole resistance. Similarly, all the C. blankii isolates belonged to a single type (ST1). In contrast, six K. ohmeri isolates were assigned to five types (ST1-ST5), suggesting its higher genetic diversity. These findings revealed the availability of MLST schemes for these three fungal species for understanding their clonal diversity among clinical isolates.

Trivial injury with devastating complication-A case of pediatric pancreatic pseudocyst.

Key Clinical Message: Pancreatic pseudocysts are rare in the pediatric population, commonly a result of trauma. Timely diagnosis and adequate management with a multidisciplinary approach are the key to avoid morbidity and mortality. Larger cysts often require surgical intervention. Abstract: We report a case of a 4-year-old female child who presented with a massive pancreatic pseudocyst. Pseudocysts >10 cm are at an increased risk of rupture, hence require surgical intervention. Percutaneous external drainage via pigtail catheter was followed by cysto-gastrostomy due to continuous high output. The postoperative period was uneventful.

Cholera toxin B scaffolded, focused SIV V2 epitope elicits antibodies that influence the risk of SIVmac251 acquisition in macaques.

Introduction: An efficacious HIV vaccine will need to elicit a complex package of innate, humoral, and cellular immune responses. This complex package of responses to vaccine candidates has been studied and yielded important results, yet it has been a recurring challenge to determine the magnitude and protective effect of specific in vivo immune responses in isolation. We therefore designed a single, viral-spike-apical, epitope-focused V2 loop immunogen to reveal individual vaccine-elicited immune factors that contribute to protection against HIV/SIV. Method: We generated a novel vaccine by incorporating the V2 loop B-cell epitope in the cholera toxin B (CTB) scaffold and compared two new immunization regimens to a historically protective 'standard' vaccine regimen (SVR) consisting of 2xDNA prime boosted with 2xALVAC-SIV and 1xΔV1gp120. We immunized a cohort of macaques with 5xCTB-V2c vaccine+alum intramuscularly simultaneously with topical intrarectal vaccination of CTB-V2c vaccine without alum (5xCTB-V2/alum). In a second group, we tested a modified version of the SVR consisting of 2xDNA prime and boosted with 1xALVAC-SIV and 2xALVAC-SIV+CTB-V2/alum, (DA/CTB-V2c/alum). Results: In the absence of any other anti-viral antibodies, V2c epitope was highly immunogenic when incorporated in the CTB scaffold and generated highly functional anti-V2c antibodies in the vaccinated animals. 5xCTB-V2c/alum vaccination mediated non-neutralizing ADCC activity and efferocytosis, but produced low avidity, trogocytosis, and no neutralization of tier 1 virus. Furthermore, DA/CTB-V2c/alum vaccination also generated lower total ADCC activity, avidity, and neutralization compared to the SVR. These data suggest that the ΔV1gp120 boost in the SVR yielded more favorable immune responses than its CTB-V2c counterpart. Vaccination with the SVR generates CCR5- α4ß7+CD4+ Th1, Th2, and Th17 cells, which are less likely to be infected by SIV/HIV and likely contributed to the protection afforded in this regimen. The 5xCTB-V2c/alum regimen likewise elicited higher circulating CCR5- α4ß7+ CD4+ T cells and mucosal α4ß7+ CD4+ T cells compared to the DA/CTB-V2c/alum regimen, whereas the first cell type was associated with reduced risk of viral acquisition. Conclusion: Taken together, these data suggest that individual viral spike B-cell epitopes can be highly immunogenic and functional as isolated immunogens, although they might not be sufficient on their own to provide full protection against HIV/SIV infection.

Vaccine plus microbicide effective in preventing vaginal SIV transmission in macaques.

The human immunodeficiency virus epidemic continues in sub-Saharan Africa, and particularly affects adolescent girls and women who have limited access to antiretroviral therapy. Here we report that the risk of vaginal simian immunodeficiency virus (SIV)mac251 acquisition is reduced by more than 90% using a combination of a vaccine comprising V1-deleted (V2 enhanced) SIV envelope immunogens with topical treatment of the zinc-finger inhibitor SAMT-247. Following 14 weekly intravaginal exposures to the highly pathogenic SIVmac251, 80% of a cohort of 20 macaques vaccinated and treated with SAMT-247 remained uninfected. In an arm of 18 vaccinated-only animals without microbicide, 40% of macaques remained uninfected. The combined SAMT-247/vaccine regimen was significantly more effective than vaccination alone. By analysing immune correlates of protection, we show that, by increasing zinc availability, SAMT-247 increases natural killer cytotoxicity and monocyte efferocytosis, and decreases T-cell activation to augment vaccine-induced protection.

Metal contamination in soil and vegetables around Savar tannery area, Dhaka, Bangladesh: A preliminary study for risk assessment.

Monitoring of heavy metal concentrations in soil and their accumulation in vegetables grown in the newly shifted tannery area of Savar, Bangladesh, is crucial for human health. Heavy metals (i.e., Cr, Pb, Cu, Zn, Ni, and Cd) concentrations in soil and vegetable samples were determined by atomic absorption spectrophotometer (AAS). In soil, 3220 mg/kg Cr was observed, which was 32-fold greater than the WHO/FAO recommended limit. Ecological risk indices such as the contamination factor, enrichment factor, pollution load index, and geoaccumulation index showed metal levels as moderately to very highly contaminated. The non-carcinogenic risk (NCR) was found to be higher, and the carcinogenic risk (CR) exceeded the acceptable value 1 × 10-6 and posed greater risks to children than adults, especially for Cr in soil. The main exposure pathway for soil metals was 97.8-99.9% due to oral ingestion. The concentration of heavy metals especially Cr, Pb, Zn, and Cd, in vegetables was alarming as they crossed the safety limit. The calculated mean hazard index (8.71) for vegetable samples showed elevated levels of potential NCR, while CR for Cr and Cd, exceeded the acceptable limit of 1 × 10-6, indicating the probability of cancer risk to humans through the consumption of vegetables. This study revealed a to-and-fro analysis of the present scenario of the tannery area, giving importance to human health and the environment.

Effects of Antidepressants on COVID-19 Outcomes: Retrospective Study on Large-Scale Electronic Health Record Data.

BACKGROUND: Antidepressants exert an anticholinergic effect in varying degrees, and various classes of antidepressants can produce a different effect on immune function. While the early use of antidepressants has a notional effect on COVID-19 outcomes, the relationship between the risk of COVID-19 severity and the use of antidepressants has not been properly investigated previously owing to the high costs involved with clinical trials. Large-scale observational data and recent advancements in statistical analysis provide ample opportunity to virtualize a clinical trial to discover the detrimental effects of the early use of antidepressants. OBJECTIVE: We primarily aimed to investigate electronic health records for causal effect estimation and use the data for discovering the causal effects of early antidepressant use on COVID-19 outcomes. As a secondary aim, we developed methods for validating our causal effect estimation pipeline. METHODS: We used the National COVID Cohort Collaborative (N3C), a database aggregating health history for over 12 million people in the United States, including over 5 million with a positive COVID-19 test. We selected 241,952 COVID-19-positive patients (age >13 years) with at least 1 year of medical history. The study included a 18,584-dimensional covariate vector for each person and 16 different antidepressants. We used propensity score weighting based on the logistic regression method to estimate causal effects on the entire data. Then, we used the Node2Vec embedding method to encode SNOMED-CT (Systematized Nomenclature of Medicine-Clinical Terms) medical codes and applied random forest regression to estimate causal effects. We used both methods to estimate causal effects of antidepressants on COVID-19 outcomes. We also selected few negatively effective conditions for COVID-19 outcomes and estimated their effects using our proposed methods to validate their efficacy. RESULTS: The average treatment effect (ATE) of using any one of the antidepressants was -0.076 (95% CI -0.082 to -0.069; P<.001) with the propensity score weighting method. For the method using SNOMED-CT medical embedding, the ATE of using any one of the antidepressants was -0.423 (95% CI -0.382 to -0.463; P<.001). CONCLUSIONS: We applied multiple causal inference methods with novel application of health embeddings to investigate the effects of antidepressants on COVID-19 outcomes. Additionally, we proposed a novel drug effect analysis-based evaluation technique to justify the efficacy of the proposed method. This study offers causal inference methods on large-scale electronic health record data to discover the effects of common antidepressants on COVID-19 hospitalization or a worse outcome. We found that common antidepressants may increase the risk of COVID-19 complications and uncovered a pattern where certain antidepressants were associated with a lower risk of hospitalization. While discovering the detrimental effects of these drugs on outcomes could guide preventive care, identification of beneficial effects would allow us to propose drug repurposing for COVID-19 treatment.

Effect of Passive Administration of Monoclonal Antibodies Recognizing Simian Immunodeficiency Virus (SIV) V2 in CH59-Like Coil/Helical or ß-Sheet Conformations on Time of SIVmac251 Acquisition.

The monoclonal antibodies (MAbs) NCI05 and NCI09, isolated from a vaccinated macaque that was protected from multiple simian immunodeficiency virus (SIV) challenges, both target an overlapping, conformationally dynamic epitope in SIV envelope variable region 2 (V2). Here, we show that NCI05 recognizes a CH59-like coil/helical epitope, whereas NCI09 recognizes a ß-hairpin linear epitope. In vitro, NCI05 and, to a lesser extent, NCI09 mediate the killing of SIV-infected cells in a CD4-dependent manner. Compared to NCI05, NCI09 mediates higher titers of antibody-dependent cellular cytotoxicity (ADCC) to gp120-coated cells, as well as higher levels of trogocytosis, a monocyte function that contributes to immune evasion. We also found that passive administration of NCI05 or NCI09 to macaques did not affect the risk of SIVmac251 acquisition compared to controls, demonstrating that these anti-V2 antibodies alone are not protective. However, NCI05 but not NCI09 mucosal levels strongly correlated with delayed SIVmac251 acquisition, and functional and structural data suggest that NCI05 targets a transient state of the viral spike apex that is partially opened, compared to its prefusion-closed conformation. IMPORTANCE Studies suggest that the protection against SIV/simian-human immunodeficiency virus (SHIV) acquisition afforded by the SIV/HIV V1 deletion-containing envelope immunogens, delivered by the DNA/ALVAC vaccine platform, requires multiple innate and adaptive host responses. Anti-inflammatory macrophages and tolerogenic dendritic cells (DC-10), together with CD14+ efferocytes, are consistently found to correlate with a vaccine-induced decrease in the risk of SIV/SHIV acquisition. Similarly, V2-specific antibody responses mediating ADCC, Th1 and Th2 cells expressing no or low levels of CCR5, and envelope-specific NKp44+ cells producing interleukin 17 (IL-17) also are reproducible correlates of decreased risk of virus acquisition. We focused on the function and the antiviral potential of two monoclonal antibodies (NCI05 and NCI09) isolated from vaccinated animals that differ in antiviral function in vitro and recognize V2 in a linear (NCI09) or coil/helical (NCI05) conformation. We demonstrate that NCI05, but not NCI09, delays SIVmac251 acquisition, highlighting the complexity of antibody responses to V2.

HIV vaccine candidate efficacy in female macaques mediated by cAMP-dependent efferocytosis and V2-specific ADCC.

The development of an effective vaccine to protect against HIV acquisition will be greatly bolstered by in-depth understanding of the innate and adaptive responses to vaccination. We report here that the efficacy of DNA/ALVAC/gp120/alum vaccines, based on V2-specific antibodies mediating apoptosis of infected cells (V2-ADCC), is complemented by efferocytosis, a cyclic AMP (cAMP)-dependent antiphlogistic engulfment of apoptotic cells by CD14+ monocytes. Central to vaccine efficacy is the engagement of the CCL2/CCR2 axis and tolerogenic dendritic cells producing IL-10 (DC-10). Epigenetic reprogramming in CD14+ cells of the cyclic AMP/CREB pathway and increased systemic levels of miRNA-139-5p, a negative regulator of expression of the cAMP-specific phosphodiesterase PDE4D, correlated with vaccine efficacy. These data posit that efferocytosis, through the prompt and effective removal of apoptotic infected cells, contributes to vaccine efficacy by decreasing inflammation and maintaining tissue homeostasis.