A5072914179- HIV Research and Treatment
- Virus-based gene therapy research
- HIV/AIDS drug development and treatment
- RNA Research and Splicing
- Nuclear Structure and Function
- Muscle Physiology and Disorders
- Immune Cell Function and Interaction
- RNA Interference and Gene Delivery
- HIV/AIDS Research and Interventions
- Cytomegalovirus and herpesvirus research
- T-cell and B-cell Immunology
- Veterinary Oncology Research
- T-cell and Retrovirus Studies
- RNA modifications and cancer
- Hepatitis B Virus Studies
- CRISPR and Genetic Engineering
- Infectious Diseases and Mycology
- Viral Infections and Immunology Research
- Viral Infectious Diseases and Gene Expression in Insects
- Animal Disease Management and Epidemiology
- Heat shock proteins research
- Parvovirus B19 Infection Studies
- Psoriasis: Treatment and Pathogenesis
- Mesenchymal stem cell research
- HIV-related health complications and treatments
University College London
2015-2025
Medical Research Council
2006-2014
MRC Laboratory for Molecular Cell Biology
2009-2012
London Centre for Nanotechnology
2012
Columbia University
1999-2001
Howard Hughes Medical Institute
1999-2001
UCL Australia
2000
Royal Holloway University of London
1995-1999
Guy's Hospital
1994-1997
ABSTRACT To examine the early events of life cycle human immunodeficiency virus type 1 (HIV-1), we analyzed intracellular complexes mediating reverse transcription isolated from acutely infected cells. Partial purification (RTCs) by equilibrium density fractionation and velocity sedimentation indicated that two species RTCs are formed but only one is able to synthesize DNA. Most capsid, matrix, transcriptase (RT) proteins dissociate complex soon after cell infection, Vpr remains associated...
Canine transmissible venereal tumor (CTVT) is the oldest known somatic cell lineage. It a cancer that propagates naturally in dogs. We sequenced genomes of two CTVT tumors and found has acquired 1.9 million substitution mutations bears evidence exposure to ultraviolet light. remarkably stable lacks subclonal heterogeneity despite thousands rearrangements, copy-number changes, retrotransposon insertions. More than 10,000 genes carry nonsynonymous variants, 646 have been lost. first arose dog...
Significance Transportin 3 (Tnpo3) was shown to orchestrate nuclear import of splicing factors over a decade ago, but how it recognizes these cargoes remained unknown. Furthermore, the recently discovered role for Tnpo3 as cofactor HIV-1 replication requires mechanistic clarification. We show that associates with wide range proteins involved in mRNA metabolism, majority which contain serine/arginine-rich domains. Using X-ray crystallography we determined three-dimensional structures its key...
The HIV/AIDS pandemic is a major global health threat and understanding the detailed molecular mechanisms of HIV replication critical for development novel therapeutics. To replicate, HIV-1 must access nucleus infected cells integrate into host chromosomes, however little known about events occurring post-nuclear entry but before integration. Here we show that karyopherin Transportin 3 (Tnp3) promotes integration in different cell types. Furthermore Tnp3 binds viral capsid proteins tRNAs...
Latency allows HIV-1 to persist in long-lived cellular reservoirs, preventing virus eradication. We have previously shown that the heat shock protein 90 (Hsp90) is required for gene expression and mediates greater replication conditions of hyperthermia. Here we report specific inhibitors Hsp90 such as 17-(N-allylamino)-17-demethoxygeldanamycin AUY922 prevent reactivation CD4+ T cells. A single modification at position 19 abolished this activity, supporting specificity target. tested impact...
ABSTRACT To examine the early events in life cycle of Moloney murine leukemia virus (MoMLV), we analyzed intracellular complexes mediating reverse transcription. Partial purification transcription (RTCs) by equilibrium density fractionation and velocity sedimentation indicated that three distinct species are formed shortly after cell infection. Only one these is able to start complete cytoplasm. This RTC composed at least viral genome, capsid, integrase, transcriptase proteins. The becomes...
Abstract Background Nuclear import of the HIV-1 reverse transcription complex (RTC) is critical for infection non dividing cells, and importin 7 (imp7) has been implicated in this process. To further characterize function imp7 replication we generated cell lines stably depleted used them conjunction with infection, cellular fractionation pull-down assays. Results Imp7 depletion impaired but did not significantly affect HIV-2, simian immunodeficiency virus (SIVmac), or equine infectious...
Targeting host factors is a complementary strategy for the development of new antiviral drugs. We screened library isoxazolidine and isoxazole sulfonamides found four compounds that inhibited HIV‐1 infection in human CD4+ lymphocytic T cells with no toxicity at IC 90 concentrations. Structure‐activity relationship showed benzyl halo‐substituted aromatic ring on heterocycle scaffold were critical antiretroviral activity. The size position incorporated halogen had marked effect sulfonamide...
Gut-associated lymphoid tissues are enriched in CCR6+ Th17-polarized CD4+ T cells that contribute to HIV-1 persistence during antiretroviral therapy (ART). This raises the need for Th17-targeted immunotherapies. In an effort identify mechanisms governing permissiveness/persistence gut-homing Th17 cells, we analyzed transcriptome of versus CCR6– exposed inducer retinoic acid (RA) and performed functional validations colon biopsies HIV-infected individuals receiving ART (HIV+ART). Although...
The canine transmissible venereal tumor (CTVT) is a clonally cancer that regresses spontaneously or after treatment with vincristine, but we know little about the regression mechanisms. We performed global transcriptional, methylation, and functional pathway analyses on serial biopsies of vincristine-treated CTVTs found occurs in sequential steps; activation innate immune system host epithelial tissue remodeling followed by infiltration tumor, arrest cell cycle, repair damage. identified...
HIV-1 capsid influences viral uncoating and nuclear import. Some is detected in the nucleus but it unclear if has any function. We reported that antibiotic Coumermycin-A1 (C-A1) inhibits integration a mutation confers resistance to C-A1, suggesting might affect post-nuclear entry steps. Here we report C-A1 capsid-dependent way. Using molecular docking, identify an extended binding pocket delimited by two adjacent monomers where predicted bind. Isothermal titration calorimetry confirmed binds...
Infection of non-dividing cells is a biological property HIV-1 crucial for virus transmission and AIDS pathogenesis. This depends on nuclear import the intracellular reverse transcription pre-integration complexes (RTCs/PICs). To identify cellular factors involved in RTCs, cytosolic extracts were fractionated by chromatography activity examined assay. A near-homogeneous fraction was obtained, which active inducing purified labeled RTCs. The contained tRNAs, mostly with defective 3′ CCA ends....
Chemical genetics is an emerging approach to investigate the biology of host-pathogen interactions. We screened several inhibitors ATP-dependent DNA motors and detected gyrase B inhibitor coumermycin A1 (C-A1) as a potent antiretroviral. C-A1 inhibited HIV-1 integration gene expression from acutely infected cell, but two activities mapped distinct targets. Target discovery identified Hsp90 target affecting viral expression. Chromatin immunoprecipitation revealed that associates with promoter...
HIV-infected individuals may experience fever episodes. Fever is an elevation of the body temperature accompanied by inflammation. It usually beneficial for host through enhancement immunological defenses. In cultures, transient non-physiological heat shock (42-45°C) and Heat Shock Proteins (HSPs) modulate HIV-1 replication, poorly defined mechanisms. The effect physiological hyperthermia (38-40°C) on infection has not been extensively investigated. Here, we show that culturing primary CD4+...
Among CD4+ T cells, helper 17 (Th17) cells are particularly susceptible to HIV-1 infection and depleted from mucosal sites, which causes damage the gut barrier, resulting in a microbial translocation-induced systemic inflammation, hallmark of disease progression. Furthermore, proportion latently infected Th17 persist long term gastrointestinal lymphatic tract where low-level transcription is observed. This residual viremia contributes chronic immune activation. Thus, key players HIV...
ABSTRACT Retroviruses copy their RNA genome into a DNA molecule, but little is known of the structure complex mediating reverse transcription in vivo. We used confocal and electron microscopy to study human immunodeficiency virus type 1 (HIV-1) intracellular complexes (RTCs). Cytoplasmic extracts were prepared 3, 4, 16 h after acute infection by Dounce homogenization hypotonic buffer. RTCs purified velocity sedimentation, followed density fractionation linear sucrose gradients dialysis large...
Understanding how lentiviruses can infect terminally differentiated, non-dividing cells has proven a very complex and controversial problem. It is, however, problem worth investigating, for it is central to HIV-1 transmission AIDS pathogenesis. Here I shall attempt summarise what our current understanding infection of cells. In some cases also make sense controversies in the field advance one or two modest proposals.
To date, no immunization of humans or animals has elicited broadly neutralizing sera able to prevent HIV-1 transmission; however, elicitation broad and potent heavy chain only antibodies (HCAb) previously been reported in llamas. In this study, the anti-HIV immune responses immunized llamas were studied via deep sequencing analysis using monoclonal HCAbs as a guides. Distinct antibody lineages identified each animal, including two defined by novel (as variable regions called VHH) robotic...
In eukaryotes, tRNAs are transcribed in the nucleus and exported to cytosol, where they deliver amino acids ribosomes for protein translation. This nuclear-cytoplasmic movement was believed be unidirectional. However, active shuttling of tRNAs, named tRNA retrograde transport, between cytosol has been discovered. pathway is conserved suggesting a fundamental function; however, little known about its role human cells. Here we report that, cells, oxidative stress triggers which rapid,...
Environmental influences have profound yet reversible effects on the behavior of resident cells. Earlier data indicated that amount muscle formed from implanted myogenic cells is greatly augmented by prior irradiation (18 Gy) host mouse muscle. Here we confirm this phenomenon, showing it varies between strains. However, unclear whether due to secretion proliferative factors or reduction antiproliferative agents. To investigate further, exploited observation immortal C2 C12 cell line forms...