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α-GeTe(111) is a noncentrosymmetric ferroelectric material for which a strong spin-orbit interaction gives rise to giant Rashba split states in the bulk and at the surface. The detailed dispersions of the surface states inside the bulk band gap remains an open question because they are located in the unoccupied part of the electronic structure, making them inaccessible to static angle-resolved photoemission spectroscopy. We show that this difficulty can be overcome via in situ potassium doping of the surface, leading to a rigid shift of 80 meV of the surface states into the occupied states. Thus, we resolve, in great detail, their dispersion and highlight their crossing at the Γ[over ¯] point, which, in comparison with density functional theory calculations, definitively confirms the Rashba mechanism.

The antibody-binding Fc γ receptors (FcγRs) trigger life-saving immune responses and many therapeutic monoclonal antibodies require FcγR engagement for full effect. One proven strategy to improve the efficacy of antibody therapies is to increase receptor binding affinity, in particular binding to FcγRIIIa/CD16a. Currently, affinities are measured using recombinantly-expressed soluble extracellular FcγR domains and CD16a-mediated antibody-dependent immune responses are characterized using cultured cells. It is notable that CD16a is highly processed with multiple N-glycosylation sites, and preventing individual N-glycan modifications affects affinity. Furthermore, multiple groups have demonstrated that CD16a N-glycan composition is variable and composition impacts antibody binding affinity. The level of N-glycosylation at each site is not known though computational prediction indicates low to moderate potential at each site based on primary sequence (40–70%). Here we quantify occupancy of the extracellular domains using complementary mass spectrometry-based methods. All five sites of the tighter-binding CD16a V158 allotype showed 65–100% N-glycan occupancy in proteomics-based experiments. These observations were confirmed using intact protein mass spectrometry that demonstrated the predominant species corresponded to CD16a V158 with five N-glycans, with a smaller contribution from CD16a with four N-glycans. Occupancy was likewise high for the membrane-bound receptor at all detected N-glycosylation sites using CD16a purified from cultured human natural killer cells. Occupancy of the N162 site, critical for antibody binding, appeared independent of N169 occupancy based on analysis of the T171A mutant protein. The weaker-binding CD16a F158 allotype showed higher occupancy of >93% at each site.

Fc mediated effector functions of antibodies play important roles in immunotherapies and vaccine efficacy but assessing those functions in animal models can be challenging due to species differences. Rhesus macaques, Macaca mulatta (Mm) share approximately 93% sequence identity with humans but display important differences in their adaptive immune system that complicates their use in validating therapeutics and vaccines that rely on Fc effector functions. In contrast to humans, macaques only have one low affinity FcγRIII receptor, CD16, which shares a polymorphism at position 158 with human FcγRIIIa with Ile158 and Val158 variants. Here we describe structure-function relationships of the Ile/Val158 polymorphism in Mm FcγRIII. Our data indicate that the affinity of the allelic variants of Mm FcγRIII for the macaque IgG subclasses vary greatly with changes in glycan composition both on the Fc and the receptor. However, unlike the human Phe/Val158 polymorphism in FcγRIIIa, the higher affinity variant corresponds to the larger, more hydrophobic side chain, Ile, even though it is not directly involved in the binding interface. Instead, this side chain appears to modulate glycan-glycan interactions at the Fc/FcγRIII interface. Furthermore, changes in glycan composition on the receptor have a greater effect for the Val158 variant such that with oligomannose type glycans and with glycans only on Asn45 and Asn162, Val158 becomes the variant with higher affinity to Fc. These results have implications not only for the better interpretation of nonhuman primate studies but also for studies performed with human effector cells carrying different FcγRIIIa alleles.

Both endogenous antibodies and a subset of antibody therapeutics engage Fc gamma receptor (FcγR)IIIa/CD16a to stimulate a protective immune response. Increasing the FcγRIIIa/IgG1 interaction improves the immune response and thus represents a strategy to improve therapeutic efficacy. FcγRIIIa is a heavily glycosylated receptor and glycan composition affects antibody-binding affinity. Though our laboratory previously demonstrated that natural killer (NK) cell N-glycan composition affected the potency of one key protective mechanism, antibody-dependent cell-mediated cytotoxicity (ADCC), it was unclear if this effect was due to FcγRIIIa glycosylation. Furthermore, the structural mechanism linking glycan composition to affinity and cellular activation remained undescribed. To define the role of individual amino acid and N-glycan residues, we measured affinity using multiple FcγRIIIa glycoforms. We observed stepwise affinity increases with each glycan truncation step, with the most severely truncated glycoform displaying the highest affinity. Removing the N162 glycan demonstrated its predominant role in regulating antibody-binding affinity, in contrast to four other FcγRIIIa N-glycans. We next evaluated the impact of the N162 glycan on NK cell ADCC. NK cells expressing the FcγRIIIa V158 allotype exhibited increased ADCC following kifunensine treatment to limit N-glycan processing. Notably, an increase was not observed with cells expressing the FcγRIIIa V158 S164A variant that lacks N162 glycosylation, indicating that the N162 glycan is required for increased NK cell ADCC. To gain structural insight into the mechanisms of N162 regulation, we applied a novel protein isotope labeling approach in combination with solution NMR spectroscopy. FG loop residues proximal to the N162 glycosylation site showed large chemical shift perturbations following glycan truncation. These data support a model for the regulation of FcγRIIIa affinity and NK cell ADCC whereby composition of the N162 glycan stabilizes the FG loop and thus the antibody-binding site.

Rashba materials have appeared as an ideal playground for spin-to-charge conversion in prototype spintronics devices. Among them, α-GeTe(111) is a non-centrosymmetric ferroelectric semiconductor for which a strong spin-orbit interaction gives rise to giant Rashba coupling. Its room temperature ferroelectricity was recently demonstrated as a route towards a new type of highly energy-efficient non-volatile memory device based on switchable polarization. Currently based on the application of an electric field, the writing and reading processes could be outperformed by the use of femtosecond light pulses requiring exploration of the possible control of ferroelectricity on this timescale. Here, we probe the room temperature transient dynamics of the electronic band structure of α-GeTe(111) using time and angle-resolved photoemission spectroscopy. Our experiments reveal an ultrafast modulation of the Rashba coupling mediated on the fs timescale by a surface photovoltage, namely an increase corresponding to a 13% enhancement of the lattice distortion. This opens the route for the control of the ferroelectric polarization in α-GeTe(111) and ferroelectric semiconducting materials in quantum heterostructures., (© 2022. The Author(s).)

Electron-phonon coupling, i.e., the scattering of lattice vibrations by electrons and vice versa, is ubiquitous in solids and can lead to emergent ground states such as superconductivity and charge-density wave order. A broad spectral phonon line shape is often interpreted as a marker of strong electron-phonon coupling associated with Fermi surface nesting, i.e., parallel sections of the Fermi surface connected by the phonon momentum. Alternatively broad phonons are known to arise from strong atomic lattice anharmonicity. Here, we show that strong phonon broadening can occur in the absence of both Fermi surface nesting and lattice anharmonicity, if electron-phonon coupling is strongly enhanced for specific values of electron-momentum, k. We use inelastic neutron scattering, soft x-ray angle-resolved photoemission spectroscopy measurements and ab-initio lattice dynamical and electronic band structure calculations to demonstrate this scenario in the highly anisotropic tetragonal electron-phonon superconductor YNi 2 B 2 C. This new scenario likely applies to a wide range of compounds., (© 2022. The Author(s).)

Individuals infected with HIV-1 require lifelong antiretroviral therapy, because interruption of treatment leads to rapid rebound viraemia. Here we report on a phase 1b clinical trial in which a combination of 3BNC117 and 10-1074, two potent monoclonal anti-HIV-1 broadly neutralizing antibodies that target independent sites on the HIV-1 envelope spike, was administered during analytical treatment interruption. Participants received three infusions of 30 mg kg -1 of each antibody at 0, 3 and 6 weeks. Infusions of the two antibodies were generally well-tolerated. The nine enrolled individuals with antibody-sensitive latent viral reservoirs maintained suppression for between 15 and more than 30 weeks (median of 21 weeks), and none developed viruses that were resistant to both antibodies. We conclude that the combination of the anti-HIV-1 monoclonal antibodies 3BNC117 and 10-1074 can maintain long-term suppression in the absence of antiretroviral therapy in individuals with antibody-sensitive viral reservoirs.

HIV-1 immunotherapy with a combination of first generation monoclonal antibodies was largely ineffective in pre-clinical and clinical settings and was therefore abandoned. However, recently developed single-cell-based antibody cloning methods have uncovered a new generation of far more potent broadly neutralizing antibodies to HIV-1 (refs 4, 5). These antibodies can prevent infection and suppress viraemia in humanized mice and nonhuman primates, but their potential for human HIV-1 immunotherapy has not been evaluated. Here we report the results of a first-in-man dose escalation phase 1 clinical trial of 3BNC117, a potent human CD4 binding site antibody, in uninfected and HIV-1-infected individuals. 3BNC117 infusion was well tolerated and demonstrated favourable pharmacokinetics. A single 30 mg kg(-1) infusion of 3BNC117 reduced the viral load in HIV-1-infected individuals by 0.8-2.5 log10 and viraemia remained significantly reduced for 28 days. Emergence of resistant viral strains was variable, with some individuals remaining sensitive to 3BNC117 for a period of 28 days. We conclude that, as a single agent, 3BNC117 is safe and effective in reducing HIV-1 viraemia, and that immunotherapy should be explored as a new modality for HIV-1 prevention, therapy and cure.

Objective: Risk factors for the HIV-associated lipodystrophy syndrome (HALS) were studied in a single-centre, cross-sectional study. -, Patients and Methods: 278 consecutive HIV-infected outpatients at a German tertiary care centre were enrolled. Changes in body shape were quantified using linear analogue scales. Cumulative treatment duration for each antiretroviral drug, CD4 cells, viral load and age were investigated as potential risk factors for a clinical diagnosis of lipodystrophy syndrome by logistic regression., Results: HALS was diagnosed in 88 patients. The risk of HALS increased significantly with longer protease inhibitor treatment (relative risk 1.61 (95% confidence interval, 1. 24 to 2.09, per year); older age and a history of low CD4 cell counts were cofactors in this multivariate model, but nucleoside analogues did not contribute significantly. Neither pattern nor severity of disease were predicted by these risk factors. Treatment durations and other risk factors were highly correlated with each other., Conclusions: These findings support a pathogenetic role for protease inhibitor toxicity, advanced HIV disease, and ageing. No evidence for an additional effect of nucleoside analogues was found. The high correlation of potential risk factors indicates that this and other available studies may be too small to detect multiple risk factors without major confounding.

Background: Highly active antiretroviral treatment (HAART) reduces the risk of wasting in HIV infection and may alter the prognostic weight of wasting. The phase angle from bioelectrical impedance analysis (BIA) can be interpreted as a surrogate marker for the catabolic reaction to chronic HIV infection and opportunistic disease., Objective: Our objective was to assess the prognostic ability of the phase angle in HIV-infected patients in the era of HAART., Design: Two cross-sectional observation studies were conducted in 1996 and 1997 at a German university outpatient HIV clinic. In the 1996 and 1997 cohorts, HAART was prescribed to 17 of 212 and 168 of 257 patients at baseline and to 179 of 212 and 234 of 257 patients during observation, respectively. Whole-body BIA was assessed at 50 KHz. Time to clinical progression and survival were calculated by using Cox proportional hazard models with time-dependent covariates. Median observation times were 1000 and 515 d for the 1996 and 1997 cohorts, respectively., Results: Higher phase angle was associated with a lower relative mortality risk, adjusted for viral load and CD4(+) cell count, of 0.49 (95% CI: 0.30, 0.81) per degree in 1996 and of 0.33 (95% CI: 0.18, 0.61) in 1997. The influence of phase angle on time to clinical progression, adjusted for viral load and CD4(+) cell count, was not significant in 1996 but the relative risk was 0.58 (0.36, 0.83) in 1997., Conclusion: Despite the favorable effects of HAART on the nutritional status of HIV-infected persons, low phase angle remains an independent adverse prognostic marker of clinical progression and survival.

Background: Triple antiretroviral treatment including protease inhibitors (PIs) delays the clinical progression of HIV infection and may thus reduce the risk of malnutrition. However, fat redistribution (lipodystrophy) was recognized recently as a metabolic side effect of PIs., Objective: The study aimed to assess the effect of triple antiretroviral treatment on body composition and on the prevalence of malnutrition., Design: Two cross-sectional studies, 1 in 1996 (t96; n = 247) and 1 in 1997 (t97; n = 266), were conducted in HIV-infected outpatients. Among patients who participated in both studies, 111 patients started a new antiretroviral treatment including a PI between t96 and t97 and were studied longitudinally. Total body water (TBW), intracellular water (ICW), extracellular water (ECW), and fat mass were estimated by monofrequency bioelectrical impedance analysis (BIA)., Results: Prevalence of malnutrition was reduced by 30-50% from t96 to t97, depending on the definition used. In the longitudinal study, TBW and the ratio between ICW and ECW increased and fat mass decreased (P < 0.001). BIA indicated a greater increase in ICW in 23 (21%) patients with clinically apparent fat redistribution than in patients without this syndrome, but estimates of fat mass changes were not significantly different., Conclusions: Triple antiretroviral treatment may protect HIV-infected patients against the development of malnutrition. Whole-body BIA data suggest an increase in appendicular body cell mass associated with improved antiretroviral treatment. However, the method is unreliable in detecting fat redistribution, and current prediction equations will need to be recalibrated for HIV-infected patients receiving highly active antiretroviral treatment.