The G118R plus R263K Combination of Integrase Mutations Associated with Dolutegravir-Based Treatment Failure Reduces HIV-1 Replicative Capacity and Integration.

Human immunodeficiency virus (HIV) treatment with antiretroviral regimens containing integrase strand transfer inhibitors such as dolutegravir (DTG) and bictegravir (BIC) offers high levels of protection against the development of drug resistance mutations. Despite this, resistance to DTG and BIC can occur through the development of the R263K integrase substitution. Failure with DTG has also been associated with the emergence of the G118R substitution. G118R and R263K are usually found separately but have been reported together in highly treatment-experienced persons who experienced treatment failure with DTG. We used cell-free strand transfer and DNA binding assays and cell-based infectivity, replicative capacity, and resistance assays to characterize the G118R plus R263K combination of integrase mutations. R263K reduced DTG and BIC susceptibility ~2-fold, in agreement with our previous work. Single-cycle infectivity assays showed that G118R and G118R plus R263K conferred ~10-fold resistance to DTG. G118R alone conferred low levels of resistance to BIC (3.9-fold). However, the G118R plus R263K combination conferred high levels of resistance to BIC (33.7-fold), likely precluding the use of BIC after DTG failure with the G118R plus R263K combination. DNA binding, viral infectivity, and replicative capacity of the double mutant were further impaired, compared to single mutants. We propose that impaired fitness helps to explain the scarcity of the G118R plus R263K combination of integrase substitutions in clinical settings and that immunodeficiency likely contributes to its development.

HIV-1 resistance against dolutegravir fluctuates rapidly alongside erratic treatment adherence: a case report.

OBJECTIVES: We report a case of incomplete HIV-1 suppression on a dolutegravir, lamivudine, and abacavir single-tablet regimen with the emergence of the H51Y and G118R integrase resistance mutations. METHODS: Integrase sequencing was performed retrospectively by Sanger and next-generation sequencing. Rates of emergence and decline of resistance mutations were calculated using next-generation sequencing data. Dolutegravir plasma concentrations were measured by ultra-performance liquid chromatography-tandem mass spectrometry. The effects of H51Y and G118R on infectivity, fitness, and susceptibility to dolutegravir were quantified using cell-based assays. RESULTS: During periods of non-adherence to treatment, mutations were retrospectively documented only by next-generation sequencing. Misdiagnosis by Sanger sequencing was caused by the rapid decline of mutant strains within the retroviral population. This observation was also true for a M184V lamivudine-resistant reverse transcriptase mutation found in association with integrase mutations on single HIV genomes. Resistance rebound upon treatment re-initiation was swift (>8000 copies per day). Next-generation sequencing indicated cumulative adherence to treatment. Compared to WT HIV-1, relative infectivity was 73%, 38%, and 43%; relative fitness was 100%, 35%, and 10% for H51Y, G118R, and H51Y+G118R viruses, respectively. H51Y did not change the susceptibility to dolutegravir, but G188R and H51Y+G118R conferred 7- and 28-fold resistance, respectively. CONCLUSION: This case illustrates how poorly-fit drug-resistant viruses wax and wane alongside erratic treatment adherence and are easily misdiagnosed by Sanger sequencing. We recommend next-generation sequencing to improve the clinical management of incomplete virological suppression with dolutegravir.

Children mirror adults for the worse: evidence of suicide rates due to air pollution and unemployment.

BACKGROUND: Every year, more than 700,000 people die due to suicide, one of the most common reasons for youth death. While many studies have revealed two main factors for suicidal behavior: impulsive suicidal behavior due to mental illness and financial stress, it is not clear what happens if individuals face deterioration of mental health and economic recession. This paper attempts to answer this question and how suicide rates are correlated with these factors. METHODS: We empirically investigate whether economic recessions and air pollution trigger suicides by examining Japan, a country with one of the highest suicide rates, from 2014 to 2021. We take advantage of the characteristics of the COVID-19 pandemic and the periods before the pandemic, when both economic recessions and reductions in air pollution occurred simultaneously. Using monthly and municipal- level data, we construct a triple difference model that takes air pollution and unemployment as treatments. RESULTS: Our findings show that high (upper half of each period) levels of air pollution and unemployment have substantial impacts on the suicide rates of adults (22.9% in the short term) and children (42.7% in the short term, 36.0% in the long term), indicating that the increase in suicide rates among children is almost twice as high as that among adults. Our study finds that unemployment and air pollution alone are not associated with increased suicide rates but their simultaneous occurrence triggers suicides during the pandemic. CONCLUSIONS: Our study urges suicide prevention, particularly among children, as an essential consideration for public health. Furthermore, our results indicate the need for the government to allocate resources to recover air quality and the economy simultaneously during a recession to reduce suicide mortality of both child and adults.

Does sustainability activities performance matter during financial crises? Investigating the case of COVID-19.

As a market for sustainability investing is growing rapidly, understanding the impact of environmental, social, and governance (ESG) activities on firms' financial performance is becoming increasingly important. In this study, we examine the effect of ESG performance on stock returns and volatility during the financial crisis resulting from the coronavirus (COVID-19) pandemic. To quantify the impact, we use company-level daily ESG score data and United Nations Global Compact (GC) score data. In our dataset, ESG scores indicate ESG performance that is deemed important to financial materiality, and the GC score indicates the firm reputation for following UN rules. Our results indicate that during the pandemic, an increase in the ESG score, especially the E score component, is related to higher returns and lower volatility. Conversely, increasing GC scores is correlated with lower stock returns and higher volatility. In addition, we find that firms in lower return groups benefit more than other firms. Focusing on energy sector impacts, we show that although the non-energy sector benefits more than the energy sector from increasing E scores, energy sector firms can still reduce their stock price volatility by increasing these scores. Our study offers significant implications for ESG investment strategies during financial crises.

Progressive emergence of an S153F plus R263K combination of integrase mutations in the proviral DNA of one individual successfully treated with dolutegravir.

OBJECTIVES: The development of HIV drug resistance against the integrase strand transfer inhibitor dolutegravir is rare. We report here the transient detection, by near full-genome ultradeep sequencing, of minority HIV-1 subtype B variants bearing the S153F and R263K integrase substitutions in the proviral DNA from blood cells of one patient who successfully initiated dolutegravir-based ART, over 24 weeks. Our objective was to study the effects of these substitutions. METHODS: Strand transfer and DNA-binding activities of recombinant integrase proteins were measured in cell-free assays. Cell-based resistance, infectivity and replicative capacities were measured using molecular clones. Structural modelling was performed to understand experimental results. RESULTS: R263K emerged first, followed by the addition of S153F at Week 12. By Week 24, both mutations remained present, but at lower prevalence. We confirmed the coexistence of S153F and R263K on single viral genomes. Combining S153F or S153Y with R263K decreased integration and viral replicative capacity and conferred high levels of drug resistance against all integrase inhibitors. Alone, S153Y and S153F did little to infectivity or dolutegravir resistance. We identified altered DNA binding as a mechanism of resistance. The patient remained with undetectable viral loads at all timepoints. CONCLUSIONS: Drug-resistant minority variants have often been reported under suppressive ART. Our study adds to these observations by unravelling a progression towards higher levels of resistance through a novel pathway despite continuous undetectable viral loads. Poorly replicative HIV drug-resistant minority proviral variants did not compromise viral suppression in one individual treated with dolutegravir.

Global mortality benefits of COVID-19 action.

The rapid spread of COVID-19 motivated countries worldwide to mitigate mortality through actions including social distancing, home quarantine, school closures, and case isolation. We estimate the global mortality benefits of these actions. We use county-level data on COVID-19 from January 2020, project the number of mortalities until September 2020, and calculate the global mortality benefits using the age- and country-specific value of a statistical life (VSL). Implementing all four types of actions above would save approximately 40.76 trillion USD globally, with social distancing accounting for 55% of the benefits. The monetary benefit would be the largest in the US, Japan and China. Our findings indicate that global actions during COVID-19 have substantial economic benefits and must be implemented in response to COVID-19.