Despite the high inhibition of viral replication achieved by current anti-HIV drugs, many patients fail treatment, often with emergence of drug-resistant virus. Clinical observations show that the relationship between adherence and likelihood of resistance differs dramatically across drug class. We developed a mathematical model that explains these observations and makes novel predictions. Our model incorporates drug properties, fitness differences between susceptible and resistant strains, mutation, and adherence. We show that antiviral activity falls quickly for drugs with sharp dose-response curves and short half-lives, such as boosted protease inhibitors, limiting the time when resistance can be selected. We find that poor adherence to such drugs causes failure via growth of susceptible virus, explaining puzzling clinical observations. Furthermore, our model predicts that certain single-pill combination therapies can prevent resistance regardless of patient adherence. Our approach represents a first step for simulating clinical trials and may help select novel drug regimens for investigation.

Precision medicine in cancer proposes that genomic characterization of tumors can inform personalized targeted therapies1–5. This proposition, however, is complicated by spatial and temporal heterogeneity6–14. Here we study genomic and expression profiles across 127 multi-sector or longitudinal specimens from 52 glioblastoma (GBM) patients. Using bulk and single-cell data, we find that samples from the same tumor mass share genomic and expression signatures, while geographically separated multifocal tumors and/or long-term recurrent tumors are seeded from different clones. Chemical screening of patient-derived glioma cells (PDCs) shows that therapeutic response is associated to genetic similarity, and multifocal tumors enriched with PIK3CA mutations have a heterogeneous drug response pattern. Importantly, we show that targeting truncal events is more efficacious in reducing tumor burden. In summary, this work demonstrates that evolutionary inference from integrated genomic analysis in multi-sector biopsies can inform targeted therapeutic interventions for GBM patients.

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In response to the coronavirus disease 2019 (COV-ID-19) pandemic, countries are launching economic recovery programs to mitigate unemployment and stabilize core industries. Although it is understandably difficult to contemplate other hazards in the midst of this outbreak, it is important to remember that we face another major crisis that threatens human prosperity-climate change. Leveraging COVID-19 recovery programs to simultaneously advance the climate agenda presents a strategic opportunity to transition toward a more sustainable post-COVID-19 world.The climate and COVID-19 crises are global and unprecedented in their level of disruption, and require coordinated responses by policy-makers, businesses, and broader society. But they are also different. The pandemic directly threatens individuals and health systems, whereas climate change undermines broader natural and human systems. COVID-19 requires responses within days and weeks, whereas reactions to the climate crisis appear less acute. Nevertheless, science suggests that climate impacts will worsen the longer we wait. So, we are faced with overlapping crises that require immediate societal mobilization.Yet, as nations marshall massive resources to mitigate the economic and social impacts of COVID-19, they may be missing the chance to address climate change. Indeed, earlier experiences show that policy responses to major calamities, such as the 2008 global financial crisis and the Millennium drought in Australia, tend to focus on stabilizing incumbent industries, technologies, and practices rather than seizing the opportunity for sustainable transformation.At this early stage of the pandemic, we are witnessing how worldwide lockdowns have decreased air pollution and greenhouse gas emissions because of reduced transportation, electricity generation, and industrial production. This shows how intertwined modern economic life and fossil fuels have become, and suggests consideration of climate implications in economic recovery plans.However, there is variation in political responses to COVID-19. The United States has rolled back certain environmental regulations and appears poised to direct stimulus funds toward reinvigorating the fossil fuel industry. The German Council of Economic Experts submit-