Experimental medicine study with stabilised native-like HIV-1 Env immunogens drives long-term antibody responses, but lacks neutralising breadth.

Background: We report findings from an experimental medicine study of rationally designed prefusion stabilised native-like HIV envelope glycoprotein (Env) immunogens, representative of global circulating strains, delivered by sequential intramuscular injection.

Methods: Healthy adult volunteers were enrolled into one of five groups (A to E) each receiving a different schedule of one of two consensus Env immunogens (ConM SOSIP, ConS UFO, either unmodified or stabilised by chemical cross-linking, followed by a boost with two mosaic Env immunogens (Mos3.1 and Mos3.

Multi-Analytical Approach for the Acid-Base, Thermal and Surface Properties Assessment of Waste Biomasses.

A multi-analytical approach was used to comprehensively characterize the acid-base, thermal, and surface properties of agri-food processing wastes (i.e., original and pre-treated bergamot, grape and olive pomaces).

Selective Co(II) and Ni(II) Separation Using the Trihexyl(tetradecyl)phosphonium Decanoate Ionic Liquid.

The room temperature ionic liquid trihexyl(tetradecyl)phosphonium decanoate ([P][Dec]) was employed in the liquid-liquid extraction of Co(II) from hydrochloric acid solutions in the presence of Ni(II). The extraction performance in liquid-liquid separations showed a strong dependence on the acid content of the feed aqueous solution. The best performance in terms of extracted cobalt and selectivity was obtained when the feed contained a HCl concentration above 6 M On the contrary, when the experiment was performed in absence of HCl, a lower extraction and Co/Ni selectivity were obtained.

Profound structural conservation of chemically cross-linked HIV-1 envelope glycoprotein experimental vaccine antigens.

Chemical cross-linking is used to stabilize protein structures with additional benefits of pathogen and toxin inactivation for vaccine use, but its use has been restricted by the potential for local or global structural distortion. This is of particular importance when the protein in question requires a high degree of structural conservation for inducing a biological outcome such as the elicitation of antibodies to conformationally sensitive epitopes. The HIV-1 envelope glycoprotein (Env) trimer is metastable and shifts between different conformational states, complicating its use as a vaccine antigen.

Fine-mapping the immunodominant antibody epitopes on consensus sequence-based HIV-1 envelope trimer vaccine candidates.

The HIV-1 envelope glycoprotein (Env) trimer is the key target for vaccines aimed at inducing neutralizing antibodies (NAbs) against HIV-1. The clinical candidate immunogen ConM SOSIP.v7 is a stabilized native-like HIV-1 Env trimer based on an artificial consensus sequence of all HIV-1 isolates in group M.

Innate cell markers that predict anti-HIV neutralizing antibody titers in vaccinated macaques.

Given the time and resources invested in clinical trials, innovative prediction methods are needed to decrease late-stage failure in vaccine development. We identify combinations of early innate responses that predict neutralizing antibody (nAb) responses induced in HIV-Env SOSIP immunized cynomolgus macaques using various routes of vaccine injection and adjuvants. We analyze blood myeloid cells before and 24 h after each immunization by mass cytometry using a three-step clustering, and we discriminate unique vaccine signatures based on HLA-DR, CD39, CD86, CD11b, CD45, CD64, CD14, CD32, CD11c, CD123, CD4, CD16, and CADM1 surface expression.

Entropy and Enthalpy Effects on Metal Complex Formation in Non-Aqueous Solvents: The Case of Silver(I) and Monoamines.

Access to the enthalpy and entropy of the formation of metal complexes in solution is essential for understanding the factors determining their thermodynamic stability and speciation. As a case study, in this report we systematically examine the complexation of silver(I) in acetonitrile (AN) with the following monoamines: n-propylamine (), n-butylamine (), hexylamine (), diethylamine (), dipropylamine (), dibutylamine (), triethylamine () and tripropylamine (). The study shows that the complex stabilities are quite independent of the length of the substitution chain on the N atom and demonstrates that, in general, the overall enthalpy terms associated with the complex formation are strongly exothermic, whereas the entropy values oppose the complex formations.

The path towards an HIV vaccine.

Since the beginning of the HIV/AIDS epidemy in the eighties, hundreds of phase I human immunization studies were performed, however, only nine tested efficacy in phase IIb/III clinical trials. While immunogens for SARS-CoV-2 did move along the development and clinical trial pipeline at unprecedent speed, two HIV immunization vaccine trials, started in 2016 and 2017, did meet non-efficacy criteria at the interim analysis and were thus, halted by the Data and Safety Monitoring Boards. The challenges in the quest to develop a safe, effective and durable HIV vaccine are unchanged.

A Case Study to Dissect Immunity to SARS-CoV-2 in a Neonate Nonhuman Primate Model.

Most children are less severely affected by coronavirus-induced disease 2019 (COVID-19) than adults, and thus more difficult to study progressively. Here, we provide a neonatal nonhuman primate (NHP) deep analysis of early immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in blood and mucosal tissues. In addition, we provide a comparison with SARS-CoV-2-infected adult NHP.

Dichotomy in Neutralizing Antibody Induction to Peptide-Conjugated Vaccine in Squalene Emulsion Contrast With Aluminum Hydroxide Formulation.

W614A-3S peptide is a modified 3S motif of the HIV-gp41 (mutation W614A). We previously detected the presence of natural neutralizing antibodies directed against W614A-3S peptide (NAbs) in long-term non-progressor HIV patients. Here, we compared the efficacy of W614A-3S peptide formulated in either squalene emulsion (SQE) or in aluminum hydroxide (Alum) in inducing broadly-NAbs (bNAbs).

Seasonal Betacoronavirus Antibodies' Expansion Post-BNT161b2 Vaccination Associates with Reduced SARS-CoV-2 VoC Neutralization.

SARS-CoV-2 vaccination is known to induce antibodies that recognize also variants of concerns (VoCs) of the virus. However, epidemiological and laboratory evidences indicate that these antibodies have a reduced neutralization ability against VoCs. We studied binding and neutralizing antibodies against the Spike protein domains and subunits of the Wuhan-Hu-1 virus and its alpha, beta, delta VoCs and of seasonal betacoronaviruses (HKU1 and OC43) in a cohort of 31 health care workers prospectively followed post-vaccination with BNT162b2-Comirnaty.

Interplay of diverse adjuvants and nanoparticle presentation of native-like HIV-1 envelope trimers.

The immunogenicity of HIV-1 envelope (Env) trimers is generally poor. We used the clinically relevant ConM SOSIP trimer to compare the ability of different adjuvants (squalene emulsion, ISCOMATRIX, GLA-LSQ, and MPLA liposomes) to support neutralizing antibody (NAb) responses in rabbits. The trimers were administered as free proteins or on nanoparticles.

Intercalation Ability of Novel Monofunctional Platinum Anticancer Drugs: A Key Step in Their Biological Action.

Phenanthriplatin (PtPPH) is a monovalent platinum(II)-based complex with a large cytotoxicity against cancer cells. Although the aqua-activated drug has been assumed to be the precursor for DNA damage, it is still under debate whether the way in which that metallodrug attacks to DNA is dominated by a direct binding to a guanine base or rather by an intercalated intermediate product. Aiming to capture the mechanism of action of PtPPH, the present contribution used theoretical tools to systematically assess the sequence of all possible mechanisms on drug activation and reactivity, for example, hydrolysis, intercalation, and covalent damage to DNA.

Neutralizing antibody responses to SARS-CoV-2 in symptomatic COVID-19 is persistent and critical for survival.

Understanding how antibody responses to SARS-CoV-2 evolve during infection may provide important insight into therapeutic approaches and vaccination for COVID-19. Here we profile the antibody responses of 162 COVID-19 symptomatic patients in the COVID-BioB cohort followed longitudinally for up to eight months from symptom onset to find SARS-CoV-2 neutralization, as well as antibodies either recognizing SARS-CoV-2 spike antigens and nucleoprotein, or specific for S2 antigen of seasonal beta-coronaviruses and hemagglutinin of the H1N1 flu virus. The presence of neutralizing antibodies within the first weeks from symptoms onset correlates with time to a negative swab result (p = 0.

Continuous HIV-1 Escape from Autologous Neutralization and Development of Cross-Reactive Antibody Responses Characterizes Slow Disease Progression of Children.

The antibodies with different effector functions evoked by Human Immunodeficiency Virus type 1 (HIV-1) transmitted from mother to child, and their role in the pathogenesis of infected children remain unresolved. So, too, the kinetics and breadth of these responses remain to be clearly defined, compared to those developing in adults. Here, we studied the kinetics of the autologous and heterologous neutralizing antibody (Nab) responses, in addition to antibody-dependent cellular cytotoxicity (ADCC), in HIV-1 infected children with different disease progression rates followed from close after birth and five years on.

Isoquinoline-based Eu(iii) luminescent probes for citrate sensing in complex matrix.

A neutral Eu(iii) complex containing the S,S enantiomer of isoQC3A ligand (isoQC3A = N-isoquinolyl-N,N',N'-trans-l,2-cyclohexylenediaminetriacetate) was synthesized and characterized. The complex was spectroscopically investigated and the results compared with those obtained for the similar bis-anionic ligand bisoQcd (bisoQcd = N,N'-bis(2-isoquinolinmethyl)-trans-1,2-diaminocyclohexane N,N'-diacetate). Both Eu(iii)-complexes show similar binding constants upon titration with the main analytes contained in interstitial extracellular fluid (i.

Effect of the Heteroaromatic Antenna on the Binding of Chiral Eu(III) Complexes to Bovine Serum Albumin.

The cationic enantiopure () and luminescent Eu(III) complex [Eu(bQcd)(HO)] OTf (with bQcd = -bis(2-quinolinmethyl)--1,2-diaminocyclohexane -diacetate and OTf = triflate) was synthesized and characterized. At physiological pH, the 1:1 [Eu(bQcd)(HO)] species, possessing two water molecules in the inner coordination sphere, is largely dominant. The interaction with bovine serum albumin (BSA) was studied by means of several experimental techniques, such as luminescence spectroscopy, isothermal titration calorimetry (ITC), molecular docking (MD), and molecular dynamics simulations (MDS).

Broadly neutralizing antibodies potently inhibit cell-to-cell transmission of semen leukocyte-derived SHIV162P3.

Background: HIV-1 sexual transmission occurs mostly through infected semen, which contains both free virions and infected leukocytes. Transmission initiated by infected cells has been shown by several in vitro and in vivo studies and a reduced capacity of broadly neutralizing antibodies (bNAbs) to inhibit cell-to-cell transmission has also been reported. However, due to limitations of available experimental models, there is yet no clarity to which extend bNAbs can prevent transmission mediated by semen leukocytes.

A new tripodal kojic acid derivative for iron sequestration: Synthesis, protonation, complex formation studies with Fe, Al, Cu and Zn, and in vivo bioassays.

This work presents the simple and low cost synthesis of a new tripodal ligand, in which three units of kojic acid are coupled to a tris(2-aminoethyl)amine (tren) backbone molecule. The protonation equilibria, together with the complex formation equilibria of this ligand with Fe, Al, Cu and Zn ions were studied. The complementary use of potentiometric, spectrophotometric and NMR techniques, and of Density Functional Theory (DFT) calculations, has allowed a thorough characterization of the different species involved in equilibrium.

Eu(iii) and Tb(iii) complexes of 6-fold coordinating ligands showing high affinity for the hydrogen carbonate ion: a spectroscopic and thermodynamic study.

In the present contribution, four classes of Ln(iii) complexes (Ln = Eu and Tb) have been synthesized and characterized in aqueous solution. They differ by charge, Ln(bpcd)+ [bpcd2- = N,N'-bis(2-pyridylmethyl)-trans-1,2-diaminocyclohexane N,N'-diacetate] and Ln(bQcd)+ (bQcd2- = N,N'-bis(2-quinolinmethyl)-trans-1,2-diaminocyclohexane N,N'-diacetate) being positively charged and Ln(PyC3A) (PyC3A3- = N-picolyl-N,N',N'-trans-l,2-cyclohexylenediaminetriacetate) and Ln(QC3A) (QC3A3- = N-quinolyl-N,N',N'-trans-l,2-cyclohexylenediaminetriacetate) being neutral. Combined DFT, spectrophotometric and potentiometric studies reveal the presence, under physiological conditions (pH 7.

Rational Design of DNA-Expressed Stabilized Native-Like HIV-1 Envelope Trimers.

The HIV-1-envelope glycoprotein (Env) is the main target of antigen design for antibody-based prophylactic vaccines. The generation of broadly neutralizing antibodies (bNAb) likely requires the appropriate presentation of stabilized trimers preventing exposure of non-neutralizing antibody (nNAb) epitopes. We designed a series of membrane-bound Envs with increased trimer stability through the introduction of key stabilization mutations.

Using Theory To Reinterpret the Kinetics of Monofunctional Platinum Anticancer Drugs: Stacking Matters.

The monofunctional platinum drug phenanthriplatin (phenPt) blocks the replication of cancer cells even if it reacts with only one guanine base. However, there is still insufficient experimental data to improve its cytotoxicity and all previously proposed chemical modifications of the parent structure have resulted in a loss of activity. We use theoretical tools to illustrate the key steps in the biological mechanisms of phenPt; that is, its activation in water and the subsequent attack on DNA.

Combined Skin and Muscle DNA Priming Provides Enhanced Humoral Responses to a Human Immunodeficency Virus Type 1 Clade C Envelope Vaccine.

Intradermal (i.d.) and intramuscular (i.