The impact of neutralizing antibody and ADCC responses on HIV-1 envelope evolution in early infection

The development of an effective HIV-1 vaccine remains a global priority. Neutralizing antibodies (nAbs), which block infection by cell-free virus, are likely to be an important response for vaccines to elicit. However, evidence from the RV144 vaccine trial and non-human primate vaccine studies suggest antibody-dependent cellular cytotoxicity (ADCC) responses, which target virus-infected cells, may also be protective. This thesis uses deep sequencing, together with immune assays, to characterise HIV-1 Envelope evolution associated with both nAb and ADCC responses in early infection, and investigates broadly neutralizing and non-neutralizing monoclonal antibody ADCC activity against subtype C viruses. Recent advances in deep sequencing approaches, coupled with the primer ID method which barcodes each viral genome, enabled us to generate thousands of viral sequences to accurately track viral population dynamics in early infection. In all participants investigated, there was a significant drop in the relative frequency of wildtype (WT) virus following nAb responses. However, in three of the seven participants, when controlling for changes in viral load (VL) over time, we observed that the WT load (frequency of the WT residue x total VL) remained relatively stable despite an effective nAb response. Instead, there was an outgrowth of the escaped virus with a concomitant increase in viral loads. We found that nAbs were inefficient at blocking cell-cell transmission of early WT and escape viruses, identifying this as one mechanism by which viruses may persist despite the presence of nAbs. These results suggest that other antibody effector functions such as ADCC, which target infected cells, may be important to elicit in a protective HIV-1 vaccines. If ADCC responses are important in controlling viral populations, one would expect to find evidence of viral escape from these responses. In all nine participants investigated, we found ADCC responses emerged prior to nAb responses, and in three individuals we observed sequence changes prior to detectable nAbs. To evaluate if these changes were due to ADCC pressure on the virus, we introduced select mutations into infectious molecular clones encoding the cognate early/acute envelope (Env-IMCs). In one participant, the mutation introduced conferred resistance to both nAb and ADCC responses, while in two participants, mutations were identified which resulted in resistance to ADCC but had no effect on neutralization, suggesting escape from ADCC. Longitudinal analysis in one of these participants, which targeted the CD4- binding site, revealed three distinct escape pathways, of which two conferred resistance to ADCC, and confirmed that ADCC responses can directly drive viral evolution in vivo. Finally, we investigated the ADCC activity of eleven anti-HIV-1 monoclonal antibodies (mAbs), including seven broadly neutralizing antibodies (bnAbs) and four non-neutralizing antibodies (nnAbs), against a panel of nine acute subtype C Env-IMCs. We found bnAbs had low to moderate ADCC breadth (11-66%). In contrast, while the two V2 nnAbs we tested were narrow and weak, the two nnAbs targeting CD4-induced epitopes (A32 and C11) mediated the broadest (78-100%) and most potent (0.06-0.81 μg/mL) ADCC against this panel. In addition, a nonlinear relationship was found between ADCC activity and strength of mAb binding to the infected cell surface (rs = -0.5309, p=0.0001). In conclusion, in contrast to studies which evaluated limited number of sequences, utilizing deep sequencing approaches, we found that the WT load remained relatively stable following early nAb pressure, albeit at lower relative frequency to the escape variant. Evasion of antibody responses through cell-cell transmission may contribute to the persistence of WT virus, providing further motivation for the importance of antibody effector functions that target infected cells in a protective HIV-1 vaccine. For the first time, we provide evidence of ADCC-mediated immune pressure in early infection, showing that these responses can exert selective pressure on HIV-1. However, the limited number of sequence changes relative to those observed following nAb pressure suggests that this response does not put as much selective pressure on the virus as nAbs. Lastly, the moderate breadth of bnAb ADCC activity provides evidence that there are common epitopes on free virions and on the surface of infected cells. This indicates bnAbs with potent and broad ADCC should be identified to include in antibody-based treatment and cure strategies, which aim to eliminate infected cells. Altogether, these data suggest that while eliciting nAbs should be the primary goal of HIV-1 vaccine design, ADCC-mediating antibodies may also play an important role

Ferromagnetism in Correlated Electron Systems: Generalization of Nagaoka's Theorem

Nagaoka's theorem on ferromagnetism in the Hubbard model with one electron less than half filling is generalized to the case where all possible nearest-neighbor Coulomb interactions (the density-density interaction $V$, bond-charge interaction $X$, exchange interaction $F$, and hopping of double occupancies $F'$) are included. It is shown that for ferromagnetic exchange coupling ($F>0$) ground states with maximum spin are stable already at finite Hubbard interaction $U>U_c$. For non-bipartite lattices this requires a hopping amplitude $t\leq0$. For vanishing $F$ one obtains $U_c\to\infty$ as in Nagaoka's theorem. This shows that the exchange interaction $F$ is important for stabilizing ferromagnetism at finite $U$. Only in the special case $X=t$ the ferromagnetic state is stable even for $F=0$, provided the lattice allows the hole to move around loops.Comment: 13 pages, uuencoded postscript, includes 1 table and 2 figure

Computer-aided recording of automatic endoscope washing and disinfection processes as an integral part of medical documentation for quality assurance purposes

<p>Abstract</p> <p>Background</p> <p>The reprocessing of medical endoscopes is carried out using automatic cleaning and disinfection machines. The documentation and archiving of records of properly conducted reprocessing procedures is the last and increasingly important part of the reprocessing cycle for flexible endoscopes.</p> <p>Methods</p> <p>This report describes a new computer program designed to monitor and document the automatic reprocessing of flexible endoscopes and accessories in fully automatic washer-disinfectors; it does not contain nor compensate the manual cleaning step. The program implements national standards for the monitoring of hygiene in flexible endoscopes and the guidelines for the reprocessing of medical products. No FDA approval has been obtained up to now. The advantages of this newly developed computer program are firstly that it simplifies the documentation procedures of medical endoscopes and that it could be used universally with any washer-disinfector and that it is independent of the various interfaces and software products provided by the individual suppliers of washer-disinfectors.</p> <p>Results</p> <p>The computer program presented here has been tested on a total of four washer-disinfectors in more than 6000 medical examinations within 9 months.</p> <p>Conclusions</p> <p>We present for the first time an electronic documentation system for automated washer-disinfectors for medical devices e.g. flexible endoscopes which can be used on any washer-disinfectors that documents the procedures involved in the automatic cleaning process and can be easily connected to most hospital documentation systems.</p

Multi-dimensional modeling and simulation of semiconductor nanophotonic devices

Self-consistent modeling and multi-dimensional simulation of semiconductor nanophotonic devices is an important tool in the development of future integrated light sources and quantum devices. Simulations can guide important technological decisions by revealing performance bottlenecks in new device concepts, contribute to their understanding and help to theoretically explore their optimization potential. The efficient implementation of multi-dimensional numerical simulations for computer-aided design tasks requires sophisticated numerical methods and modeling techniques. We review recent advances in device-scale modeling of quantum dot based single-photon sources and laser diodes by self-consistently coupling the optical Maxwell equations with semiclassical carrier transport models using semi-classical and fully quantum mechanical descriptions of the optically active region, respectively. For the simulation of realistic devices with complex, multi-dimensional geometries, we have developed a novel hp-adaptive finite element approach for the optical Maxwell equations, using mixed meshes adapted to the multi-scale properties of the photonic structures. For electrically driven devices, we introduced novel discretization and parameter-embedding techniques to solve the drift-diffusion system for strongly degenerate semiconductors at cryogenic temperature. Our methodical advances are demonstrated on various applications, including vertical-cavity surface-emitting lasers, grating couplers and single-photon sources

Social Safety Nets for Food and Nutritional Security in India

This paper brings together existing literature on the Mahatma Gandhi National Rural Employment Guarantee Act (MGNRGEA) and the Public Distribution System (PDS) in India, offering a narrative review of the evidence on impacts on food security, health and nutrition of beneficiaries. Both programs operate on a large scale and have the capacity to impact the factors leading to undernutrition. It is evident that despite the deficiencies in implementation, both the MGNREGA and the PDS are inclusive and reach the poor and the marginalized who are likely to also experience greater undernutrition and poor health. Data challenges have however prevented researchers from conducting studies that assess the ultimate impact of these two large-scale programs on health and nutrition. The evidence that exists suggests largely positive impacts indicating a clear potential to make these programs more nutrition sensitive not just by incorporating elements that would explicitly address nutritional concerns but also by directing specific attention to innovations that strengthen critical complementarities and synergies that exist between the two programs