Edward P. Browne's research while affiliated with University of North Carolina at Chapel Hill and other places
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Publications (73)
Antiretroviral therapy (ART) halts HIV replication; however, cellular / immue cell viral reservoirs persist despite ART. Understanding the interplay between the HIV reservoir, immune perturbations, and HIV-specific immune responses on ART may yield insights into HIV persistence. A cross-sectional study of peripheral blood samples from 115 people wi...
Antiretroviral therapy (ART) halts HIV replication; however, cellular / immue cell viral reservoirs persist despite ART. Understanding the interplay between the HIV reservoir, immune perturbations, and HIV-specific immune responses on ART may yield insights into HIV persistence. A cross-sectional study of peripheral blood samples from 115 people wi...
Although antiretroviral therapy (ART) is effective at suppressing HIV replication, a viral reservoir persists that can reseed infection if ART is interrupted. Curing HIV will require elimination or containment of this reservoir, but the size of the HIV reservoir is highly variable between individuals. To evaluate the size of the HIV reservoir, seve...
Despite the success of antiretroviral therapy, human immunodeficiency virus (HIV) cannot be cured because of a reservoir of latently infected cells that evades therapy. To understand the mechanisms of HIV latency, we employed an integrated single-cell RNA sequencing (RNA-seq) and single-cell assay for transposase-accessible chromatin with sequencin...
HIV can enter a state of transcriptional latency in CD4 T cells, allowing the virus to evade the host immune system and persist during antiretroviral therapy. Thus, understanding the mechanisms that drive HIV latency, and developing strategies to reactivate viral expression in latently infected cells, are key goals for achieving a cure for HIV. The...
Antiretroviral therapy (ART) halts HIV replication; however, cellular / immue cell viral reservoirs persist despite ART. Understanding the interplay between the HIV reservoir, immune perturbations, and HIV-specific immune responses on ART may yield insights into HIV persistence. A cross-sectional study of peripheral blood samples from 115 people wi...
Although antiretroviral therapy (ART) is highly effective at suppressing HIV replication, a viral reservoir persists that can reseed infection if ART is interrupted. Curing HIV will require elimination or functional containment of this reservoir, but the size of the HIV reservoir is highly variable between individuals. To evaluate the overall size...
Background:
HIV infection remains incurable due to the persistence of a viral reservoir despite antiretroviral therapy (ART). Cannabis (CB) use is prevalent amongst people with HIV (PWH), but the impact of CB on the latent HIV reservoir has not been investigated.
Methods:
Peripheral blood cells from a cohort of PWH who use CB and a matched cohor...
Antiretroviral therapy (ART) has dramatically improved the prognosis for people living with HIV-1, but a cure remains elusive. The largest barrier to a cure is the presence of a long-lived latent reservoir that persists within a heterogenous mix of cell types and anatomical compartments. Efforts to eradicate the latent reservoir have primarily focu...
A promising strategy to cure HIV‐infected individuals is to use latency reversing agents (LRAs) to reactivate latent viruses, followed by host clearance of infected reservoir cells. However, reactivation of latent proviruses within infected cells is heterogeneous and often incomplete. This fact limits strategies to cure HIV which may require comple...
A promising strategy to cure HIV infected individuals is to use latency reversing agents (LRAs) to reactivate latent viruses, followed by host clearance of infected reservoir cells. However, reactivation of latent proviruses within infected cells is heterogeneous and often incomplete. This fact limits strategies to cure HIV which may require comple...
Transcriptional silencing of latent HIV-1 proviruses entails complex and overlapping mechanisms that pose a major barrier to in vivo elimination of HIV-1. We developed a new latency CRISPR screening strategy, called Latency HIV-CRISPR which uses the packaging of guideRNA-encoding lentiviral vector genomes into the supernatant of budding virions as...
HIV infection remains incurable due to the persistence of a viral reservoir during antiretroviral therapy. Cannabis (CB) use is prevalent amongst people with HIV (PWH), but the impact of CB on the latent HIV reservoir has not been investigated. Peripheral CD4 and CD8 T cells from a cohort of CB-using PWH and a matched cohort of non-users on antiret...
HIV reservoirs are extremely stable and pose a tremendous challenge to clear HIV infection. Here, we demonstrate that activation of ISR/ATF4 signaling reverses HIV latency, which also selectively eliminates HIV+ cells in primary CD4+ T cell model of latency without effect on HIV-negative CD4+ T cells. The reduction of HIV+ cells is associated with...
Transcriptional silencing of latent HIV-1 proviruses entails complex and overlapping mechanisms and are a major barrier to in vivo elimination of HIV-1. We developed a new latency CRISPR screening strategy, called Latency HIV-CRISPR, which uses the packaging of guideRNA-encoding lentiviral vector genomes into the supernatant of budding virions as a...
Despite the success of antiretroviral therapy, HIV cannot be cured because of a reservoir of latently infected cells that evades therapy. To understand the mechanisms of HIV latency, we employed an integrated single-cell RNA-seq/ATAC-seq approach to simultaneously profile the transcriptomic and epigenomic characteristics of ~4000 latently infected...
Dimension reduction (DR) algorithms project data from high dimensions to lower dimensions to enable visualization of interesting high-dimensional structure. DR algorithms are widely used for analysis of single-cell transcriptomic data. Despite widespread use of DR algorithms such as t-SNE and UMAP, these algorithms have characteristics that lead to...
Approximately 70% of the HIV-1 latent reservoir originates from infections of CD4 T cells that occur in the months near the time of ART initiation, raising the possibility that interventions during this period might prevent reservoir seeding and reduce reservoir size. We identify class 1 histone deacetylase inhibitors (HDACi) as potent agents of la...
Background:
Antiretroviral therapy (ART) effectively suppresses HIV-1 (HIV) replication to an undetectable level in the periphery; however, the treatment is life-long and HIV reservoirs cannot be eliminated by ART alone in people living with HIV (PLWH). The major obstacle that impedes HIV eradication in ART-treated PLWH is the latent viral reservo...
Latency reversal strategies for HIV cure using inhibitor of apoptosis protein (IAP) antagonists (IAPi) induce unprecedented levels of latent reservoir expression without immunotoxicity during suppressive antiretroviral therapy (ART). However, full targeting of the reservoir may require combinatorial approaches. A Jurkat latency model screen for IAP...
The eradication of HIV infection is difficult to achieve due to stable viral reservoirs. Here, we show that crotonylation enhances AZD5582-induced noncanonical NF-κB (ncNF-κB) signaling, further augmenting HIV latency reversal in Jurkat and U1 cell line models of latency, HIV latently infected primary CD4+ T cells and resting CD4+ T cells isolated...
All known recently emerged human coronaviruses probably originated in bats1. Here we used a single experimental platform based on human lung-only mice (LoM) to demonstrate efficient in vivo replication of all recently emerged human coronaviruses (SARS-CoV, MERS-CoV and SARS-CoV-2) and two highly relevant endogenous pre-pandemic SARS-like bat corona...
Transcriptional silencing of HIV in CD4 T cells generates a reservoir of latently infected cells that can reseed infection after interruption of therapy. As such, these cells represent the principal barrier to curing HIV infection, but little is known about their characteristics. To further our understanding of the molecular mechanisms of latency,...
Although immune checkpoint inhibitors (ICIs), such as anti–programmed cell death protein–1 (PD-1), can deliver durable antitumor effects, most patients with cancer fail to respond. Recent studies suggest that ICI efficacy correlates with a higher load of tumor-specific neoantigens and development of vitiligo in patients with melanoma. Here, we repo...
Toll-like receptors (TLRs) are key pathogen sensing receptors that respond to diverse microbial ligands, and trigger both innate and adaptive immune responses to infection. Since their discovery, a growing body of evidence has pointed to an important role for TLRs in retroviral infection and pathogenesis. These data suggest that multiple TLRs contr...
All known recently emerged human coronaviruses likely originated in bats. Here, we used a single experimental platform based on human lung-only mice (LoM) to demonstrate efficient in vivo replication of all recently emerged human coronaviruses (SARS-CoV, MERS-CoV, SARS-CoV-2) and two highly relevant endogenous pre-pandemic SARS-like bat coronavirus...
Transcriptional silencing of HIV generates a reservoir of latently infected cells, but the mechanisms that lead to this outcome are not well understood. We characterized a primary cell model of HIV latency, and observed that latency is a stable, heritable viral state that is rapidly reestablished after stimulation. Using Assay of Transposon-Accessi...
Host protein folding stress responses can play important roles in RNA virus replication and evolution. Prior work suggested a complicated interplay between the cytosolic proteostasis stress response, controlled by the transcriptional master regulator heat shock factor 1 (HSF1), and human immunodeficiency virus-1 (HIV-1). We sought to uncouple HSF1...
A hallmark of human immunodeficiency type-1 (HIV) infection is the integration of the viral genome into host chromatin, resulting in a latent reservoir that persists despite antiviral therapy or immune response. Thus, key priorities towards eradication of HIV infection are to understand the mechanisms that allow HIV latency and to develop latency r...
Long-lasting, latently infected resting CD4+ T cells are the greatest obstacle to obtaining a cure for HIV infection, as these cells can persist despite decades of treatment with antiretroviral therapy (ART). Estimates indicate that more than 70 years of continuous, fully suppressive ART are needed to eliminate the HIV reservoir1. Alternatively, in...
In the version of this article initially published, the bottom plot in Fig. 5b was aligned incorrectly with the plots above, and the following authors (and their affiliations) were missing from the complete list of authors at the end of the text: H. Michael Belmont (Department f Medicine, Division of Rheumatology, New York University School of Medi...
Lupus nephritis is a potentially fatal autoimmune disease for which the current treatment is ineffective and often toxic. To develop mechanistic hypotheses of disease, we analyzed kidney samples from patients with lupus nephritis and from healthy control subjects using single-cell RNA sequencing. Our analysis revealed 21 subsets of leukocytes activ...
Background
Lupus nephritis is a potentially fatal autoimmune disease, whose current treatment is ineffective and often toxic. In 2014, the National Institute of Health (NIH), industry and non-profit organizations joined their efforts with the AMP project, whose goal is to identify new diagnostic and therapeutic targets through a better understandin...
Targeting immune checkpoint pathways, such as programmed death ligand-1 (PD-L1, also known as CD274 or B7-H1) or its receptor programmed cell death-1 (PD-1) has shown improved survival for patients with numerous types of cancers, not limited to lung cancer, melanoma, renal cell carcinoma, and Hodgkin lymphoma. PD-L1 is a co-inhibitory molecule whos...
Specialized immune cell subsets are involved in autoimmune disease, cancer immunity, and infectious disease through a diverse range of functions mediated by overlapping pathways and signals. However, subset-specific responses may not be detectable in analyses of whole blood samples, and no efficient approach for profiling cell subsets at high throu...
A detailed understanding of the mechanisms that establish or maintain the latent reservoir of HIV will guide approaches to eliminate persistent infection. We used a cell line and primary cell models of HIV latency to investigate viral RNA (vRNA) expression and the role of the host transcriptome using single-cell approaches. Single-cell vRNA quantit...
Background:
Detailed molecular analyses of cells from rheumatoid arthritis (RA) synovium hold promise in identifying cellular phenotypes that drive tissue pathology and joint damage. The Accelerating Medicines Partnership RA/SLE Network aims to deconstruct autoimmune pathology by examining cells within target tissues through multiple high-dimensio...
Lupus nephritis is a potentially fatal autoimmune disease, whose current treatment is ineffective and often toxic. To gain insights into disease mechanisms, we analyzed kidney samples from lupus nephritis patients and healthy controls using single-cell RNA-seq. Our analysis revealed 21 subsets of leukocytes active in disease, including multiple pop...
The leading strategy towards eradication of human immunodeficiency virus (HIV) infection is the depletion of viral reservoirs through reversal of viral latency, followed by clearance of persistently infected cells. To date, a latency reversing agent (LRA) that reactivates a majority of the quiescent provirus population, without significant off-targ...
The latent HIV reservoir is diverse, but most studies of HIV latency have used bulk cell assays. Here we characterized cell line and primary cell models of HIV latency with single cell qPCR (sc-qPCR) for viral RNA (vRNA), and single cell RNAseq (scRNAseq). sc-qPCR revealed distinct populations of cells transcribing vRNA across a wide range of level...
Background
Detailed molecular analyses of cells from rheumatoid arthritis (RA) synovium hold promise in identifying cellular phenotypes that drive tissue pathology and joint damage. The Accelerating Medicines Partnership (AMP) RA/SLE network aims to deconstruct autoimmune pathology by examining cells within target tissues through multiple high-dime...
OBJECTIVE
There is a critical need to define the cells that mediate tissue damage in lupus nephritis. Here we aimed to establish a protocol to preserve lupus nephritis kidney biopsies and urine cell samples obtained at multiple clinical sites for subsequent isolation and transcriptomic analysis of single cells.
METHODS
Fresh and cryopreserved kidn...
The human immune system consists of many specialized cell subsets that simultaneously carry out a diverse range of functions using overlapping pathways and signals. Subset-specific immune profiling can resolve immune activity in autoimmune disease, cancer immunity, and infectious disease that may not be discoverable or detectable in analyses of cru...
Background and aims
Despite treatments, a substantial proportion of lupus nephritis (LN) patients progress to end stage renal disease and death. Detailed transcriptomic analyses of LN kidneys may identify new therapeutic targets. Our goal is to demonstrate the feasibility of single cell and low-input transcriptomic analyses of LN kidney and urine c...
Humans encode seven APOBEC3 proteins (A-H), with A3G, 3F and 3H as the major factors restricting HIV-1 replication. HIV-1, however, encodes Vif, which counteracts A3 proteins by chaperoning them to the proteasome where they are degraded. Vif polymorphisms found in HIV-1s isolated from infected patients have varying anti-A3G potency when assayed in...
Type 1 interferons such as interferon-alpha (IFNα) inhibit replication of Human immunodeficiency virus (HIV-1) by upregulating the expression of genes that interfere with specific steps in the viral life cycle. This pathway thus represents a potential target for immune-based therapies that can alter the dynamics of host-virus interactions to benefi...
Diversity reigns in antibody responses
During the course of an immune response, B cells specific for an invading pathogen divide. The antibodies they produce increase in affinity via somatic mutation in specialized lymph node structures called germinal centers. Tas et al. used multiphoton microscopy and sequencing to determine how different B cell...
Dynamical systems are frequently used to model biological systems. When these
models are fit to data it is necessary to ascertain the uncertainty in the
model fit. Here we develop prediction deviation, a metric of uncertainty that
determines the extent to which observed data have constrained the model's
predictions. Prediction deviation is calculat...
Type 1 interferons such as interferon-alpha (IFNa) inhibit replication of Human immunodeficiency virus (HIV-1) by upregulating the expression of genes that interfere with specific steps in the viral life cycle. This pathway thus represents a potential target for immune-based therapies that can alter the dynamics of host- virus interactions to benef...
Unlabelled:
Interleukin-1 beta (IL-1β) is an inflammatory cytokine that is secreted in response to inflammasome activation by innate microbe-sensing pathways. Although some retroviruses can trigger IL-1β secretion through the DNA-sensing molecule IFI16, the effect of IL-1β on the course of infection is unknown. To test whether IL-1β secretion affe...
The apolipoprotein B editing complex 3 (A3) cytidine deaminases are among the most highly evolutionarily selected retroviral restriction factors, both in terms of gene copy number and sequence diversity. Primate genomes encode seven A3 genes, and while A3F and 3G are widely recognized as important in the restriction of HIV, the role of the other ge...
Early events during retroviral infection play a critical role in determining the course of infection and pathogenesis, but the mechanisms that regulate this phase of infection are poorly understood. Toll-like receptor 7 (TLR7) is required for promoting germinal center reactions and virus-specific neutralizing antibodies at later timepoints post inf...
Background: Acute HIV infection is characterized by a high viremia accompanied by a powerful wave of pro-inflammatory cytokines that affects the subsequent course of infection and pathogenesis. Thus, understanding the mechanisms that regulate cytokine secretion and viremia is a key priority. The innate immune receptor TLR7 has been identified a ret...
The discovery of host-encoded gene products that sense molecular patterns in infectious microbes, and the demonstration of their role in triggering innate and adaptive immune responses, has been a key milestone in our understanding of immunology. Twenty-three years after Janeway first outlined the fundamental concepts of the 'pattern recognition' m...
Heparin covalently attached to a water-insoluble resin suspended in HIV-infected aqueous buffer or whole blood captures the virus; subsequent physical separation of the immobilized heparin reduced the viral titers by over 80 and 50%, respectively. The detoxification concept has been validated by both circulating an HIV-1 solution through a column p...
The development of vaccines that can enhance immunity to viral pathogens is an important goal. However, the innate molecular pathways that regulate the strength and quality of the immune response remain largely uncharacterized. To define the role of Toll-like receptor (TLR) signaling in control of a model retroviral pathogen, Friend virus (FV), I g...
Citations
... Several different HIV-encoding plasmids were used to generate infectious particles for analysis. For screening transduced HOS cells for a clone that expresses mCherry upon infection, we used a defective HIV clone that encodes a short half-life GFP cassette (37,38), and packaged the virus using plasmids encoding GagPol (PAX2) and VSV-G (MD2-VSV-G). For replication-competent HIV, we used plasmids for a CXCR4 tropic strain (NL4-3) and a CCR5-tropic strain (NL-AD8), as well as a strain with the gene for heat shock antigen (HSA) within the nef open reading frame (39). ...
... Some points that may be relevant to an explanation of these discrepancies are the quantity and intensity of use of the cannabis by individuals. Other studies have evaluated the effect of cannabis on inflammation in other types of inflammatory diseases [51]. ...
... The combinatorial mechanisms that contribute to HIV-1 transcription and latency have been extensively studied and reviewed [85][86][87][88]. Briefly, the 5 ′ long terminal repeat (LTR) functions as an enhancer and promoter that recruits host cell transcription factors, chromatin remodeling complexes and RNAP II to initiate transcription. ...
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... To address this need, we developed a cell-based assay that uses novel CellRaft technology (28) in combination with a highly sensitive Tat-dependent mCherry reporter cell line to detect HIV infection events, enabling quantification of HIV outgrowth from reactivated CD4 T cells from PWH. CellRafts are nanoliter-sized wells (herein referred to as rafts) arranged in polydimethylsiloxane (PDMS)/polystyrene microarrays that allow single-cell resolution microscopy in addition to extraction of individual rafts for sequencing purposes (29,30). Automated brightfield and fluorescence microscopy scanning of the arrays is enabled by a machine called the AIR system. ...
... HIV latency is a stable and heritable phenomenon, consistent with the notion of an epigenetic program that regulates HIV latency [16]. In particular, removal of activating marks such as H3K9ac and H3K27ac by class 1 histone deacetylases (HDACs) and the addition of repressive H3K9me3 and H3K27me3 marks by histone methyltransferases have been shown to contribute to HIV latency [17][18][19]. ATACseq analysis has also shown that latent proviruses exhibit a "closed" chromatin conformation that likely restricts access by key TFs and RNA Polymerase II (RNAPol2) [16]. ...
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... Three days later, the cultures are examined for enrichment of specific sgRNAs in HIV-1 virions compared to their frequency in genomic DNA by RT-PCR/PCR and deep sequencing 26 . The initial screen identified IFN-induced antiviral factors 26 and has subsequently been modified to identify cellular that promote HIV-1 replication 27 , restrict HIV-1 by targeting the viral capsid 28 , or affect viral latency 29 . In addition, it has been used to identify ISGs restricting HIV-1 in primary CD4 + T cells 30 . ...
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... Conversely, proviral reactivation is characterized by a reduction in HMTs and their corresponding methylation marks as well as increased acetylation at the LTR [52]. A recent study in primary cells also showed that histone deacetylation at the LTR may serve as a "gatekeeping" event in promoting latency establishment [61]. Therefore, the switch between an activating acetylated status and a repressive deacetylated status that enables the deposition of methyl marks is likely pivotal to the formation of the latent reservoir. ...
... Additionally, ATF4 can stimulate the transcription of HIV-1 [113][114][115]. Ex vivo treatment with HA15, which is a selective inducer of the ER stress response, results in HIV-1 reactivation and a significant decrease in reservoir size [116]. These findings raise important questions regarding the impact of selectively activating or inhibiting different parts of the stress response on HIV-1. ...
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... Each of these techniques for dimensionality reduction has a set of parameters that allows fine-grained control over the embedding. The details of loss functions and the transformation of the high dimensional spaces into the lower dimensional embedding is outside the scope of the current discussion as it is well documented elsewhere (e.g., Huang et al., 2022). The DS-Viz method employs the UMAP technique for the dimensionality reduction as it is widely used (for an application in genetics, see Becht et al. (2019)), well documented and flexible in terms of input data (i.e., it can receive a precomputed distance matrix). ...
... The effect of AZD5582 was seen to be potentiated by crotonylation, allowing for superior latency reversal along with significant increases in p52 protein levels (Li et al., 2021). The effects of AZD5582 were also seen to be synergistically enhanced by selective and pan BET domain inhibition in a cell-line model of latency, however this was not seen to consistently result in HIV latency reversal in ex-vivo primary CD4+ T cells (Falcinelli et al., 2022). A recent study, examined the combination of AZD5582 with the DEAD-box polypeptide 3 (DDX3) inhibitor FH1321. ...
