A5084515990- HIV Research and Treatment
- SARS-CoV-2 and COVID-19 Research
- HIV/AIDS drug development and treatment
- interferon and immune responses
- Mosquito-borne diseases and control
- Hepatitis C virus research
- Hepatitis B Virus Studies
- Reproductive tract infections research
- Cytomegalovirus and herpesvirus research
- Biochemical and Molecular Research
- Syphilis Diagnosis and Treatment
- Respiratory viral infections research
- Viral Infections and Vectors
- Animal Virus Infections Studies
- Viral Infections and Immunology Research
- Bacteriophages and microbial interactions
- Viral gastroenteritis research and epidemiology
- Calpain Protease Function and Regulation
- T-cell and Retrovirus Studies
- COVID-19 Clinical Research Studies
- SARS-CoV-2 detection and testing
- Animal Disease Management and Epidemiology
- Inflammasome and immune disorders
- Virology and Viral Diseases
- CRISPR and Genetic Engineering
University of Missouri
2014-2024
Washington University in St. Louis
2019-2024
Emory University
2019
National University of San Marcos
2014
University of Washington
2006-2012
Asociación para la Conservación de la Cuenca Amazónica
2009
National Institutes of Health
2007
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) variants govern transmissibility, responsiveness to vaccination, and disease severity. In a screen for new models of SARS-CoV-2 infection, we identify human H522 lung adenocarcinoma cells as naturally permissive infection despite complete absence angiotensin-converting enzyme (ACE2) expression. Remarkably, requires the E484D S variant; viruses expressing wild-type are not infectious. Anti-S monoclonal antibodies...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes a number of strategies to modulate viral and host mRNA translation. Here, we used ribosome profiling in SARS-CoV-2-infected model cell lines primary airway cells grown at an air-liquid interface gain deeper understanding the translationally regulated events response virus replication. We found that SARS-CoV-2 mRNAs dominate cellular pool but are not more efficiently translated than mRNAs. utilized highly efficient...
ABSTRACT A critical determinant for early post-entry events, the HIV-1 capsid (CA) protein forms conical core when it rearranges around dimeric RNA genome and associated viral proteins. Although mutations in CA have been reported to alter innate immune sensing of HIV-1, a direct link between stability nucleic acids has not established. Herein, we assessed how manipulating lattice through chemical genetic approaches affects recognition HIV-1. We found that destabilization resulted potent...
To determine whether the 23S rRNA mutation that confers macrolide resistance is present in >1 Treponema pallidum strain, 58 isolates collected between 2001 and 2005 were screened for this an unrelated sequence distinguishes strains. The odds of identifying a macrolide-resistant strain increased over time (P=.006). In subjects who had received macrolides previous year, relative risk harboring resistant was 2.2 (95% confidence interval, 1.1-4.4; P=.02). strains not identical. These findings...
Although the three Treponema pallidum subspecies (T. subsp. pallidum, T. pertenue, and endemicum), paraluiscuniculi, unclassified Fribourg-Blanc treponeme cause clinically distinct diseases, these pathogens are genetically antigenically highly related able to persistent infection. Recent evidence suggests that putative surface-exposed variable antigen TprK plays an important role in both treponemal immune evasion persistence. tprK heterogeneity is generated by nonreciprocal gene conversion...
Technical limitations in simultaneous microscopic visualization of RNA, DNA, and proteins HIV have curtailed progress this field. To address need we develop a microscopy approach, multiplex immunofluorescent cell-based detection RNA Protein (MICDDRP), which is based on branched DNA situ hybridization technology. MICDDRP enables single-cell (a) spliced unspliced (b) cytoplasmic nuclear (c) Gag. We use to visualize incoming capsid cores containing and/or nascent follow reverse transcription...
A large number of human immunodeficiency virus 1 (HIV-1) integrase (IN) alterations, referred to as class II substitutions, exhibit pleiotropic effects during replication. However, the underlying mechanism for phenotype is not known. Here we demonstrate that all tested IN substitutions compromised IN-RNA binding in virions by one three distinct mechanisms: (i) markedly reducing levels thus precluding formation complexes with viral RNA; (ii) adversely affecting functional multimerization and...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of disease 2019 (COVID-19) pandemic, is continuing to cause immense and social economic disruptions. Conventional assays that monitor SARS-CoV-2 growth in cell culture rely on costly time-consuming RNA extraction procedures, hampering progress basic research development effective therapeutics. Here, we developed a simple quantitative real-time PCR assay supernatants does not necessitate as accurate sensitive...
BackgroundFlaviviruses such as Zika cause sporadic pandemic outbreaks worldwide. There is an urgent need for anti-Zika virus (ZIKV) drugs to prevent mother-to-child transmission of ZIKV, new infections in high-risk populations, and the infection medical personnel ZIKV-affected areas.MethodsHere, we showed that small molecule 6-deoxyglucose-diphyllin (DGP) exhibited anti-ZIKV activity both vitro vivo. DGP potently blocked ZIKV across all human monkey cell lines tested. also displayed...
ABSTRACT Sterile alpha motif- and histidine/aspartic acid domain-containing protein 1 (SAMHD1) limits HIV-1 replication by hydrolyzing deoxynucleoside triphosphates (dNTPs) necessary for reverse transcription. Nucleoside transcriptase inhibitors (NRTIs) are components of anti-HIV therapies. We report here that SAMHD1 cleaves NRTI (TPs) at significantly lower rates than dNTPs depletion from monocytic cells affects the susceptibility infections to NRTIs in complex ways depend not only on...
Despite the availability of effective vaccines and treatments, HBV remains a significant global health concern, with more than 240 million individuals chronically infected. Current treatments are highly at controlling viral replication disease progression but rarely cure infections. Therefore, much emphasis is being placed on finding therapeutics new drug targets, such as gene expression, covalently closed circular DNA formation stability, capsid formation, host immune modulators, ultimate...
ABSTRACT Since the beginning of coronavirus disease 2019 (COVID-19) pandemic, much effort has been dedicated to identifying effective antivirals against severe acute respiratory syndrome 2 (SARS-CoV-2). A number calpain inhibitors show excellent antiviral activities SARS-CoV-2 by targeting viral main protease (M pro ), which plays an essential role in processing polyproteins. In this study, we found that potently inhibited infection a chimeric vesicular stomatitis virus (VSV) encoding spike...
Hepatitis B virus (HBV) RNase H (RNH) is an appealing therapeutic target due to its essential role in viral replication. RNH inhibitors (RNHIs) could help more effectively control HBV infections. Here, we report 3-hydroxypyrimidine-2,4-diones as novel RNHIs with antiviral activity. We synthesized and tested 52 analogs found 4 that inhibit activity infected cells. Importantly, 2 of these compounds inhibited replication the low micromolar range.
Abstract SARS-CoV-2 utilizes a number of strategies to modulate viral and host mRNA translation. Here, we used ribosome profiling in infected model cell lines primary airway cells grown at the air-liquid interface gain deeper understanding translationally regulated events response virus replication. We find that mRNAs dominate cellular pool but are not more efficiently translated than mRNAs. utilized highly efficient ribosomal frameshifting strategy comparison HIV-1, suggesting utilization...
ABSTRACT Established in vitro models for SARS-CoV-2 infection are limited and include cell lines of non-human origin those engineered to overexpress ACE2, the cognate host receptor. We identified human H522 lung adenocarcinoma cells as naturally permissive despite complete absence ACE2. Infection required spike protein, though contrast ACE2-dependent models, alone was not sufficient infection. Temporally resolved transcriptomic proteomic profiling revealed alterations cycle antiviral...
An estimated 240 million are chronically infected with hepatitis B virus (HBV), which can lead to liver disease, cirrhosis, and hepatocellular carcinoma. Currently, HBV treatment options include only nucleoside reverse transcriptase inhibitors the immunomodulatory agent interferon alpha, these treatments generally not curative. New novel mechanisms of action, therefore, highly desired for therapy. The viral core protein (Cp) has gained attention as a possible therapeutic target because its...
Host RNA binding proteins recognize viral and play key roles in virus replication antiviral mechanisms. SARS-CoV-2 generates a series of tiered subgenomic RNAs (sgRNAs), each encoding distinct protein(s) that regulate different aspects replication. Here, for the first time, we demonstrate successful isolation genomic three sgRNAs (N, S, ORF8) from single population infected cells characterize their protein interactomes. Over 500 interactors (including 260 previously unknown) were identified...
RNA viruses are highly successful pathogens and the causative agents for many important diseases. To fully understand replication of these it is necessary to address roles both positive-strand ((+)RNA) negative-strand ((−)RNA), their interplay with viral host proteins. Here we used branched DNA (bDNA) fluorescence in situ hybridization (FISH) stain abundant (+)RNA far less (−)RNA hepatitis C virus (HCV)- Zika virus-infected cells, combined analyses visualization proteins through confocal...
Mov10 is a processing body (P-body) protein and an interferon-stimulated gene that can affect replication of retroviruses, hepatitis B virus, C virus (HCV). The mechanism HCV inhibition by unknown. Here, we investigate the effect on infection determine life cycle steps affected changes in overexpression. overexpression suppresses RNA both infectious subgenomic replicon systems. Additionally, decreases infectivity released unlike control P-body DCP1a has no production or progeny virus....
Host factors that define the cellular tropism of SARS-CoV-2 beyond cognate ACE2 receptor are poorly defined. Here we report replication is restricted at a post-entry step in number ACE2-positive airway-derived cell lines due to tonic activation cGAS-STING pathway mediated by mitochondrial DNA leakage and naturally occurring cGAS STING variants. Genetic pharmacological inhibition type I/III IFN pathways as well overexpression overcome these blocks. knockout primary airway cultures induces ISG...
Transcriptional regulation in Treponema pallidum ssp. is poorly understood, primarily because this organism cannot be cultivated vitro or genetically manipulated. We have recently shown a phase variation mechanism controlling transcription initiation of Subfamily II tpr (T. pallidumrepeat) genes (tprE, tprG and tprJ), group virulence factor candidates. Furthermore, the same study suggested that additional mechanisms might influence level these tprs. The T. genome sequence has revealed few...
Moloney leukemia virus 10 (MOV10) is an RNA helicase that has been shown to affect the replication of several viruses. The effect MOV10 on Hepatitis B (HBV) infection not known and its role this poorly understood. We investigated down-regulation over-expression HBV in a variety cell lines, as well system using competent virus. report down-regulation, siRNA, shRNA, CRISPR/Cas9 gene editing technology, resulted increased levels DNA, pre-genomic RNA, core protein. In contrast, reduced These...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of ongoing COVID-19 pandemic, has infected millions within just a few months and is continuing to spread around globe causing immense disease mortality. Assays monitor SARS-CoV-2 growth depend on time-consuming costly RNA extraction steps, hampering progress in basic research drug development efforts. Here we developed facile Q-RT-PCR assay that bypasses viral steps can replication kinetics from small amount...
We have recently developed the first microscopy-based strategy that enables simultaneous multiplex detection of viral RNA (vRNA), DNA (vDNA), and protein. Here, we used this approach to study kinetics latency reactivation in cells infected with human immunodeficiency virus (HIV). showed transcription nascent vRNA from individual latently integrated reactivated vDNA sites appearing earlier than further demonstrated method can be quantitatively assess efficacy a variety reactivating agents....