The diagnosis of postacute sequelae of coronavirus disease 2019 (PASC) poses an ongoing medical challenge. To identify biomarkers associated with PASC we analyzed plasma samples collected from PASC ...and coronavirus disease 2019 patients to quantify viral antigens and inflammatory markers. We detect severe acute respiratory syndrome coronavirus 2 spike predominantly in PASC patients up to 12 months after diagnosis.
Many individuals mount nearly identical antibody responses to SARS-CoV-2. To gain insight into how the viral spike (S) protein receptor-binding domain (RBD) might evolve in response to common ...antibody responses, we studied mutations occurring during virus evolution in a persistently infected immunocompromised individual. We use antibody Fab/RBD structures to predict, and pseudotypes to confirm, that mutations found in late-stage evolved S variants confer resistance to a common class of SARS-CoV-2 neutralizing antibodies we isolated from a healthy COVID-19 convalescent donor. Resistance extends to the polyclonal serum immunoglobulins of four out of four healthy convalescent donors we tested and to monoclonal antibodies in clinical use. We further show that affinity maturation is unimportant for wild-type virus neutralization but is critical to neutralization breadth. Because the mutations we studied foreshadowed emerging variants that are now circulating across the globe, our results have implications to the long-term efficacy of S-directed countermeasures.
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•SARS-CoV-2 spike evolves during persistent infection to resist common antibodies•Antibody affinity maturation is critical to neutralization breadth•Intra-host evolution foreshadows mutations in circulating spike variants
Structural and functional analysis of the evolution of SARS-CoV-2 in a persistently infected immunocompromised individual yields insights into mutations that foreshadow emerging viral variants worldwide.
Abstract
Background
Both severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reinfection and persistent infection have been reported, but sequence characteristics in these scenarios have not ...been described. We assessed published cases of SARS-CoV-2 reinfection and persistence, characterizing the hallmarks of reinfecting sequences and the rate of viral evolution in persistent infection.
Methods
A systematic review of PubMed was conducted to identify cases of SARS-CoV-2 reinfection and persistence with available sequences. Nucleotide and amino acid changes in the reinfecting sequence were compared with both the initial and contemporaneous community variants. Time-measured phylogenetic reconstruction was performed to compare intrahost viral evolution in persistent SARS-CoV-2 to community-driven evolution.
Results
Twenty reinfection and 9 persistent infection cases were identified. Reports of reinfection cases spanned a broad distribution of ages, baseline health status, reinfection severity, and occurred as early as 1.5 months or >8 months after the initial infection. The reinfecting viral sequences had a median of 17.5 nucleotide changes with enrichment in the ORF8 and N genes. The number of changes did not differ by the severity of reinfection and reinfecting variants were similar to the contemporaneous sequences circulating in the community. Patients with persistent coronavirus disease 2019 (COVID-19) demonstrated more rapid accumulation of sequence changes than seen with community-driven evolution with continued evolution during convalescent plasma or monoclonal antibody treatment.
Conclusions
Reinfecting SARS-CoV-2 viral genomes largely mirror contemporaneous circulating sequences in that geographic region, while persistent COVID-19 has been largely described in immunosuppressed individuals and is associated with accelerated viral evolution.
Reinfecting SARS-CoV-2 viral genomes largely mirror contemporaneous circulating sequences in that geographic region, while persistent COVID-19 has been largely described in immunosuppressed individuals and is associated with accelerated viral evolution.
Beyond classical metabolic functions in energy storage and energy expenditure, adipose tissue is also a dynamic endocrine organ that secretes bioactive factors into blood plasma. Historically, ...studies of the adipose secretome have predominantly focused on polypeptide adipokines. Recently, adipose-derived blood-borne lipids ("lipokines") have emerged as a distinct class of endocrine factors. Lipokines are intimately connected to intracellular pathways of fatty acid metabolism and therefore uniquely poised to communicate the intracellular energy status of adipocytes to other nonadipose tissues including liver, muscle, and pancreas. Here, we discuss recent progress on our understanding of adipose-secreted lipokines as endocrine regulators of glucose and lipid metabolism. We also provide our perspective on future directions for adipose-secreted lipids, including limitations of the currently available experimental data as well as potential strategies for addressing the remaining open questions.
Antibodies are a potential therapy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but the risk of the virus evolving to escape them remains unclear. Here we map how all mutations ...to the receptor binding domain (RBD) of SARS-CoV-2 affect binding by the antibodies in the REGN-COV2 cocktail and the antibody LY-CoV016. These complete maps uncover a single amino acid mutation that fully escapes the REGN-COV2 cocktail, which consists of two antibodies, REGN10933 and REGN10987, targeting distinct structural epitopes. The maps also identify viral mutations that are selected in a persistently infected patient treated with REGN-COV2 and during in vitro viral escape selections. Finally, the maps reveal that mutations escaping the individual antibodies are already present in circulating SARS-CoV-2 strains. These complete escape maps enable interpretation of the consequences of mutations observed during viral surveillance.
Phase competition underlies many remarkable and technologically important phenomena in transition metal oxides. Vanadium dioxide (VO2) exhibits a first-order metal-insulator transition (MIT) near ...room temperature, where conductivity is suppressed and the lattice changes from tetragonal to monoclinic on cooling. Ongoing attempts to explain this coupled structural and electronic transition begin with two alternative starting points: a Peierls MIT driven by instabilities in electron-lattice dynamics and a Mott MIT where strong electron-electron correlations drive charge localization. A key missing piece of the VO2 puzzle is the role of lattice vibrations. Moreover, a comprehensive thermodynamic treatment must integrate both entropic and energetic aspects of the transition. Here we report that the entropy driving the MIT in VO2 is dominated by strongly anharmonic phonons rather than electronic contributions, and provide a direct determination of phonon dispersions. Our ab initio calculations identify softer bonding in the tetragonal phase, relative to the monoclinic phase, as the origin of the large vibrational entropy stabilizing the metallic rutile phase. They further reveal how a balance between higher entropy in the metal and orbital-driven lower energy in the insulator fully describes the thermodynamic forces controlling the MIT. Our study illustrates the critical role of anharmonic lattice dynamics in metal oxide phase competition, and provides guidance for the predictive design of new materials.
Abstract
Antiretroviral therapy effectively controls human immunodeficiency virus (HIV) replication but it is unable to fully eradicate the HIV reservoir and treatment must be life-long. Progress ...toward a strategy for HIV remission will require overcoming key hurdles to fill gaps in our understanding of HIV persistence, but the identification of individuals who have attained sterilizing or functional HIV cure show that such a goal is achievable. In this review, we first outline challenges in targeting the HIV reservoir, including difficulties identifying HIV-infected cells, ongoing work elucidating the complex intracellular environment that contribute to HIV latency, and barriers to reactivating and clearing the HIV reservoir. We then review reported cases of HIV sterilizing cure and explore natural models of HIV remission and the promise that such HIV spontaneous and posttreatment controllers may hold in our search for a broadly-applicable strategy for the millions of patients living with HIV.
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