The objective of this study was to track the evolution of sequence changes in both the heptad region 1 (HR1) and HR2 domains of gp41 associated with resistance to enfuvirtide (ENF) in a patient cohort receiving long-term ENF treatment. We studied 17 highly antiretroviral agent-experienced patients receiving long-term ENF treatment with virological rebound or a lack of suppression. Sixty-two samples obtained after between 5 and 107 weeks of ENF therapy were analyzed. Baseline samples from 15 of these 17 patients were available for analysis. Viruses from five samples from four patients were also sequenced after the cessation of ENF therapy. Drug susceptibilities were assessed by a pseudotype virus reporter assay. We identified HR1 and HR2 sequence changes over time in relation to the baseline sequences. Mutations in HR1 (amino acids 36 to 45) were noted in all cases, including previously unreported changes N42Q/H and N43Q. In addition to a range of HR2 sequence changes at polymorphic sites, isolates from 6 of 17 (35%) patients developed an S138A substitution in the HR2 domain at least 8 weeks after the start of ENF treatment and also subsequent to the first emergence of HR1 mutations. In most, but not all, cases the S138A mutation accompanied HR1 mutations at position 43. Molecular modeling demonstrates the close proximity of S138A with amino acids 40 and 45 in HR1. Of note, isolates in samples available from four patients demonstrated the loss of both the HR1 and the S138A HR2 mutations following the cessation of therapy. We show that the S138A HR2 mutation increased the level of resistance by approximately threefold over that conferred by the HR1 mutation N43D. Continual evolution of HR1 in the domain from amino acids 36 to 45 was observed during long-term ENF therapy. We have identified, for the first time, an ENF resistance-associated HR2 mutation, S138A, which appeared in isolates from 6 of 17 patients with virological failure and demonstrated its potential to contribute to drug resistance. We propose that this represents a possible secondary and/or compensatory mutation, particularly when it coexists with mutations at position 43 in HR-1.
The Phoenix project is an experiment in the design of autonomous agents for a complex environ- ment. The Phoenix testbed is the environmental simulation component of Phoenix. The Phoenix testbed consists of a task model, a map representation, a user interface and a fire simulation. This paper presents the testbed at the conceptual level and at the functional interface level.
Ultrashort pulse lasers based on fiber optic architecture will play a dominant role in the spread of these lasers into research and industrial applications. The principle challenge is to generate adequate pulse energy from singlemode or quasi-singlemode amplifiers which have small cross-sectional area. We demonstrate a robust, all-fiber erbium amplifier system that produces >100 μJ per pulse with 701 fs pulsewidth and M2 < 1.3. We will discuss the salient amplifier dynamics that influence the pulse generation, shaping, and propagation phenomena in state-of-the-art erbium fiber lasers. Furthermore, we show data relevant to applications and implementation of ultrashort pulse lasers.
Enfuvirtide (ENF), the first human immunodeficiency virus type 1 (HIV-1) fusion inhibitor approved for clinical use, acts by binding to gp41 heptad repeat 1 (HR1) and preventing its interaction with the viral HR2 region. Treatment-emergent resistance to ENF has been mapped to residues within HR1, and these mutations decrease its susceptibility to ENF and may reduce viral fitness and pathogenesis, although the mechanism for these effects is not clear. N43D, a common ENF resistance mutation, was found in in vitro assays to cause a 5-50-fold in antiviral activity. We introduced this mutation into peptide models and determined the impact of this mutation by circular dichroism and X-ray crystallography. We find that the mutation results in a decrease in the thermal stability of the six-helix bundle and causes a significant change in the HR1-HR2 interface, including a loss of HR2 helicity. These data form a mechanistic basis for the decrease in ENF sensitivity and six-helix bundle stability. The E137K polymorphism, generally present at baseline in patients who develop N43D, partially compensates for the loss of stability, and we show that these residues likely form an ion pair. These data form a framework for understanding the impact of resistance mutations on viral fitness and pathogenesis and provide a pathway for the development of novel fusion inhibitor peptides.
Our January 2010 issue profiled Richard Wilson, who lived with and worked on risk-related issues from his early days in England, when he had only a few seconds to take cover from a V-1 rocket, to his trips to the damaged Chernobyl reactor in 1987.(1) In this issue, Wilson writes a personal perspective that represents the integration of more than a half-century of thinking and writing about risk analysis. We hope that you enjoy his reflections and insights. The research articles in this issue are almost all about risk management. With federal and other environmental and risk management budgets under increasing pressure, regulators are looking for risk-based approaches to prioritize inspections and other enforcement efforts. For example, supported by the U.S. Department of Energy, Travis Walter and colleagues studied the siting of indoor sampling devices that can provide results in minutes and hence be able to warn populations at risk. The approach is demonstrated with a convention center. Sponsored by the Japanese Food Safety Commission, M. Kadohira and colleagues analyzed spongiform encephalopathy in Japanese cattle. Even though cases are rare, the authors assert that the results reinforce the need for animal health managers to carefully monitor control measures to effectively manage risks. Worldwide, there are over a million leaking underground storage tanks, and an approach that identifies those most likely to be leaking is desirable to risk managers. Richard Enander et al. tested approaches for prioritizing the inspection of potentially leaking underground storage tanks. Timothy McDaniels et al. considered decisions about managing forestlands that have been severely affected by mountain pine beetles in British Columbia. They worked with 14 regional forest management specialists, finding that these experts preferred alternatives that are more flexible than the current policies. Henry Roman et al. created an expert elicitation process to assess the uncertainty in economic values assigned to the value of life. The authors focused on the consequences of air pollution. Supported by the National Institute for Occupational Safety and Health, Michael Yu et al. examined decision making during an emergency, that is, when risks and their likelihoods are not known to decisionmakers. The authors designed and tested a scenario-based approach for subsurface coal mine emergencies. Analysis of national-scale data can sometimes lead us to the ecological fallacy and other times can be quite revealing. Levan Elbakidze and Yanhong Jin studied the association between terrorist attacks and country-level characteristics. They observed that the risk of being attacked is associated with a country's annual financial contribution to the U.N. general operating budget, per capita GDP, political freedom, and openness to trade. The authors provide explanations for these associations. One wonders how closely these mirror terrorists’ objectives. Detlof vonWinterfeldt et al. examined the creation and use of information when the developer of information is not the same as the users. Funded by the Electric Power Research Institute, the authors highlight how some of the outcomes of research are influenced by values, motivations, and biases. Members of the public serve as their own personal risk managers for some hazards. Ellen Peters et al. focused on purchase of protective devices, such as those that would reduce the chances of a successful burglary, and substantial flood-related losses. The authors found that respondents had a difficult time factoring time into their assessments, and they suggest options that might encourage people to appreciate the long-term value of having protective devices, despite up-front costs. Severine Deguen et al. examined the value of assessing the public's psychological response to polluted air. They tested 22 scaled items on over 2,500 residents of eight French cities. The authors report that the scale is robust, reproducible, and discriminates between subpopulations that are more susceptible to poor air quality. David Durham et al. tested the efficacy of the widely used health belief model of individual health behaviors Using the 2009–2010 influenza A(H1N1) pandemic, their survey data showed that respondents’ beliefs changed during the course of the event. The authors’ efforts to understand how and why these beliefs changed are quite interesting, despite the small sample sizes. We suspect that almost every member of SRA has both been in front of a public audience and been part of a public audience listening to an expert. Robin Gregory et al. reexamined the fascinating question of how experts and the public factor uncertainty into their preferences. Using a web-based survey, the authors were able to compare expert and public preferences to hypothetical risk management options, finding interesting differences that are not explained by variations in numeracy or concern about environmental impacts. Finally, the issue has one paper that is about risk communication. John Edwards et al. used an experimental design to assess errors in public risk-related behaviors in order to test risk communication tools. The authors used 10 different graphical methods to display data. Funded by the Defense Threat Reduction Agency, they found that error bar and boxplot displays were the most effective way of eliciting accurate results. Not surprisingly, inaccurate choices increased with time pressure. Next, in another in our series of short Editor's Choice essays, EIC Micheal Greenberg discusses the risk issues associated with maintenance and repair of our nation's deteriorating infrastructure.
