Non-suppressible HIV-1 viremia (NSV) can occur in persons with HIV despite adherence to combinati... more Non-suppressible HIV-1 viremia (NSV) can occur in persons with HIV despite adherence to combination antiretroviral therapy (ART) and in the absence of significant drug resistance. Here, we show that plasma NSV sequences are comprised primarily of large clones without evidence of viral evolution over time. We defined proviruses that contribute to plasma viremia as producer, and those that did not as non-producer. Compared to ART-suppressed individuals, NSV participants had a significantly larger producer reservoir. Producer proviruses were enriched in chromosome 19 and in proximity to the activating H3K36me3 epigenetic mark. CD4+ cells from NSV participants demonstrated upregulation of anti-apoptotic genes and downregulation of pro-apoptotic and type I/II interferon-related pathways. Furthermore, NSV participants showed no elevation in HIV-specific CD8+ cell responses and producer proviruses were enriched for HLA escape mutations. We identified critical host and viral mediators of NS...
Bacterial vaginosis (BV), the overgrowth of diverse anaerobic bacteria in the vagina, is the most... more Bacterial vaginosis (BV), the overgrowth of diverse anaerobic bacteria in the vagina, is the most common cause of vaginal symptoms worldwide. BV frequently recurs after antibiotic therapy, and the best probiotic treatments only result in transient changes from BV-associated states to “optimal” communities dominated by a single species of Lactobacillus. Therefore, additional treatment strategies are needed to durably alter vaginal microbiota composition for patients with BV. Vaginal microbiota transplantation (VMT), the transfer of vaginal fluid from a healthy person with an optimal vaginal microbiota to a recipient with BV, has been proposed as one such alternative. However, VMT carries potential risks, necessitating strict safety precautions. Here, we present an FDA-approved donor screening protocol and detailed methodology for donation collection, storage, screening, and analysis of VMT material. We find that Lactobacillus viability is maintained for over six months in donated mat...
Profiling coronaviruses Among the coronaviruses that infect humans, four cause mild common colds,... more Profiling coronaviruses Among the coronaviruses that infect humans, four cause mild common colds, whereas three others, including the currently circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), result in severe infections. Shrock et al. used a technology known as VirScan to probe the antibody repertoires of hundreds of coronavirus disease 2019 (COVID-19) patients and pre–COVID-19 era controls. They identified hundreds of antibody targets, including several antibody epitopes shared by the mild and severe coronaviruses and many specific to SARS-CoV-2. A machine-learning model accurately classified patients infected with SARS-CoV-2 and guided the design of an assay for rapid SARS-CoV-2 antibody detection. The study also looked at how the antibody response and viral exposure history differ in patients with diverging outcomes, which could inform the production of improved vaccine and antibody therapies. Science , this issue p. eabd4250
SummaryThe hallmark of severe COVID-19 disease has been an uncontrolled inflammatory response, re... more SummaryThe hallmark of severe COVID-19 disease has been an uncontrolled inflammatory response, resulting from poorly understood immunological dysfunction. We explored the hypothesis that perturbations in FoxP3+ T regulatory cells (Treg), key enforcers of immune homeostasis, contribute to COVID-19 pathology. Cytometric and transcriptomic profiling revealed a distinct Treg phenotype in severe COVID-19 patients, with an increase in both Treg proportions and intracellular levels of the lineage-defining transcription factor FoxP3, which correlated with poor outcomes. Accordingly, these Tregs over-expressed a range of suppressive effectors, but also pro-inflammatory molecules like IL32. Most strikingly, they acquired similarity to tumor-infiltrating Tregs, known to suppress local anti-tumor responses. These traits were most marked in acute patients with severe disease, but persisted somewhat in convalescent patients. These results suggest that Tregs may play nefarious roles in COVID-19, v...
Structure-based immunogen design Vaccine design for highly mutable pathogens is hindered by a pau... more Structure-based immunogen design Vaccine design for highly mutable pathogens is hindered by a paucity of conserved immunogenic epitopes. Gaiha et al. employed a structure-based technique using network theory to assign scores to protein structure in order to infer mutational constraints (see the Perspective by McMichael and Carrington). The authors validated the method on proteins with published functional outcomes and then assessed mutational constraints within the HIV proteome. Highly networked residues strongly associated with immune control of HIV infection and may lead to protective immunogens for pathogens for which there is currently no efficient vaccine. Science , this issue p. 480 ; see also p. 438
Recent work (Cohen & Welling, 2016) has shown that generalizations of convolutions, based on grou... more Recent work (Cohen & Welling, 2016) has shown that generalizations of convolutions, based on group theory, provide powerful inductive biases for learning. In these generalizations, filters are not only translated but can also be rotated, flipped, etc. However, coming up with exact models of how to rotate a 3 x 3 filter on a square pixel-grid is difficult. In this paper, we learn how to transform filters for use in the group convolution, focussing on roto-translation. For this, we learn a filter basis and all rotated versions of that filter basis. Filters are then encoded by a set of rotation invariant coefficients. To rotate a filter, we switch the basis. We demonstrate we can produce feature maps with low sensitivity to input rotations, while achieving high performance on MNIST and CIFAR-10.
The relationship between SARS-CoV-2 viral load and risk of disease progression remains largely un... more The relationship between SARS-CoV-2 viral load and risk of disease progression remains largely undefined in coronavirus disease 2019 (COVID-19). We quantified SARS-CoV-2 viral load from participants with a diverse range of COVID-19 severity, including those requiring hospitalization, outpatients with mild disease, and individuals with resolved infection. SARS-CoV-2 plasma RNA was detected in 27% of hospitalized participants and 13% of outpatients diagnosed with COVID-19. Amongst the participants hospitalized with COVID-19, higher prevalence of detectable SARS-CoV-2 plasma viral load was associated with worse respiratory disease severity, lower absolute lymphocyte counts, and increased markers of inflammation, including C-reactive protein and IL-6. SARS-CoV-2 viral loads, especially plasma viremia, were associated with increased risk of mortality. SARS-CoV-2 viral load may aid in the risk stratification of patients with COVID-19 and its role in disease pathogenesis should be further ...
Non-suppressible HIV-1 viremia (NSV) can occur in persons with HIV despite adherence to combinati... more Non-suppressible HIV-1 viremia (NSV) can occur in persons with HIV despite adherence to combination antiretroviral therapy (ART) and in the absence of significant drug resistance. Here, we show that plasma NSV sequences are comprised primarily of large clones without evidence of viral evolution over time. We defined proviruses that contribute to plasma viremia as producer, and those that did not as non-producer. Compared to ART-suppressed individuals, NSV participants had a significantly larger producer reservoir. Producer proviruses were enriched in chromosome 19 and in proximity to the activating H3K36me3 epigenetic mark. CD4+ cells from NSV participants demonstrated upregulation of anti-apoptotic genes and downregulation of pro-apoptotic and type I/II interferon-related pathways. Furthermore, NSV participants showed no elevation in HIV-specific CD8+ cell responses and producer proviruses were enriched for HLA escape mutations. We identified critical host and viral mediators of NS...
Bacterial vaginosis (BV), the overgrowth of diverse anaerobic bacteria in the vagina, is the most... more Bacterial vaginosis (BV), the overgrowth of diverse anaerobic bacteria in the vagina, is the most common cause of vaginal symptoms worldwide. BV frequently recurs after antibiotic therapy, and the best probiotic treatments only result in transient changes from BV-associated states to “optimal” communities dominated by a single species of Lactobacillus. Therefore, additional treatment strategies are needed to durably alter vaginal microbiota composition for patients with BV. Vaginal microbiota transplantation (VMT), the transfer of vaginal fluid from a healthy person with an optimal vaginal microbiota to a recipient with BV, has been proposed as one such alternative. However, VMT carries potential risks, necessitating strict safety precautions. Here, we present an FDA-approved donor screening protocol and detailed methodology for donation collection, storage, screening, and analysis of VMT material. We find that Lactobacillus viability is maintained for over six months in donated mat...
Profiling coronaviruses Among the coronaviruses that infect humans, four cause mild common colds,... more Profiling coronaviruses Among the coronaviruses that infect humans, four cause mild common colds, whereas three others, including the currently circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), result in severe infections. Shrock et al. used a technology known as VirScan to probe the antibody repertoires of hundreds of coronavirus disease 2019 (COVID-19) patients and pre–COVID-19 era controls. They identified hundreds of antibody targets, including several antibody epitopes shared by the mild and severe coronaviruses and many specific to SARS-CoV-2. A machine-learning model accurately classified patients infected with SARS-CoV-2 and guided the design of an assay for rapid SARS-CoV-2 antibody detection. The study also looked at how the antibody response and viral exposure history differ in patients with diverging outcomes, which could inform the production of improved vaccine and antibody therapies. Science , this issue p. eabd4250
SummaryThe hallmark of severe COVID-19 disease has been an uncontrolled inflammatory response, re... more SummaryThe hallmark of severe COVID-19 disease has been an uncontrolled inflammatory response, resulting from poorly understood immunological dysfunction. We explored the hypothesis that perturbations in FoxP3+ T regulatory cells (Treg), key enforcers of immune homeostasis, contribute to COVID-19 pathology. Cytometric and transcriptomic profiling revealed a distinct Treg phenotype in severe COVID-19 patients, with an increase in both Treg proportions and intracellular levels of the lineage-defining transcription factor FoxP3, which correlated with poor outcomes. Accordingly, these Tregs over-expressed a range of suppressive effectors, but also pro-inflammatory molecules like IL32. Most strikingly, they acquired similarity to tumor-infiltrating Tregs, known to suppress local anti-tumor responses. These traits were most marked in acute patients with severe disease, but persisted somewhat in convalescent patients. These results suggest that Tregs may play nefarious roles in COVID-19, v...
Structure-based immunogen design Vaccine design for highly mutable pathogens is hindered by a pau... more Structure-based immunogen design Vaccine design for highly mutable pathogens is hindered by a paucity of conserved immunogenic epitopes. Gaiha et al. employed a structure-based technique using network theory to assign scores to protein structure in order to infer mutational constraints (see the Perspective by McMichael and Carrington). The authors validated the method on proteins with published functional outcomes and then assessed mutational constraints within the HIV proteome. Highly networked residues strongly associated with immune control of HIV infection and may lead to protective immunogens for pathogens for which there is currently no efficient vaccine. Science , this issue p. 480 ; see also p. 438
Recent work (Cohen & Welling, 2016) has shown that generalizations of convolutions, based on grou... more Recent work (Cohen & Welling, 2016) has shown that generalizations of convolutions, based on group theory, provide powerful inductive biases for learning. In these generalizations, filters are not only translated but can also be rotated, flipped, etc. However, coming up with exact models of how to rotate a 3 x 3 filter on a square pixel-grid is difficult. In this paper, we learn how to transform filters for use in the group convolution, focussing on roto-translation. For this, we learn a filter basis and all rotated versions of that filter basis. Filters are then encoded by a set of rotation invariant coefficients. To rotate a filter, we switch the basis. We demonstrate we can produce feature maps with low sensitivity to input rotations, while achieving high performance on MNIST and CIFAR-10.
The relationship between SARS-CoV-2 viral load and risk of disease progression remains largely un... more The relationship between SARS-CoV-2 viral load and risk of disease progression remains largely undefined in coronavirus disease 2019 (COVID-19). We quantified SARS-CoV-2 viral load from participants with a diverse range of COVID-19 severity, including those requiring hospitalization, outpatients with mild disease, and individuals with resolved infection. SARS-CoV-2 plasma RNA was detected in 27% of hospitalized participants and 13% of outpatients diagnosed with COVID-19. Amongst the participants hospitalized with COVID-19, higher prevalence of detectable SARS-CoV-2 plasma viral load was associated with worse respiratory disease severity, lower absolute lymphocyte counts, and increased markers of inflammation, including C-reactive protein and IL-6. SARS-CoV-2 viral loads, especially plasma viremia, were associated with increased risk of mortality. SARS-CoV-2 viral load may aid in the risk stratification of patients with COVID-19 and its role in disease pathogenesis should be further ...
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Papers by Daniel Worrall