A5011006647- HIV Research and Treatment
- Herpesvirus Infections and Treatments
- Mosquito-borne diseases and control
- Immune Cell Function and Interaction
- Cytomegalovirus and herpesvirus research
- Insect symbiosis and bacterial influences
- Viral Infections and Vectors
- T-cell and B-cell Immunology
- Respiratory viral infections research
- Genomics and Phylogenetic Studies
- HIV/AIDS drug development and treatment
- interferon and immune responses
- Viral Infections and Immunology Research
- Inflammasome and immune disorders
- CRISPR and Genetic Engineering
- Poxvirus research and outbreaks
- NF-κB Signaling Pathways
- Viral gastroenteritis research and epidemiology
- Tracheal and airway disorders
- Bioinformatics and Genomic Networks
- vaccines and immunoinformatics approaches
- Polyamine Metabolism and Applications
- Genomics and Rare Diseases
- Hedgehog Signaling Pathway Studies
- Cell death mechanisms and regulation
Ragon Institute of MGH, MIT and Harvard
2017-2024
Massachusetts General Hospital
2024
Broad Institute
2010-2018
Massachusetts Institute of Technology
2011-2015
Harvard University
2004-2008
Boston Children's Hospital
2007
Sanford Burnham Prebys Medical Discovery Institute
2003-2005
Discovery Institute
2003
Deep sequencing technologies have the potential to transform study of highly variable viral pathogens by providing a rapid and cost-effective approach sensitively characterize rapidly evolving quasispecies. Here, we report on high-throughput whole HIV-1 genome deep platform that combines 454 pyrosequencing with novel assembly variant detection algorithms. In one subject combined these genetic data detailed immunological analyses comprehensively evaluate evolution immune escape during acute...
Simian immunodeficiency viruses of sooty mangabeys (SIVsm) are the source multiple, successful cross-species transmissions, having given rise to HIV-2 in humans, SIVmac rhesus macaques, and SIVstm stump-tailed macaques. Cellular assays phylogenetic comparisons indirectly support a role for TRIM5α, product TRIM5 gene, suppressing interspecies transmission emergence retroviruses nature. Here, we investigate vivo directly, focusing on primate between outbred hosts. Specifically, retrospectively...
The TRIM family proteins share a conserved arrangement of three adjacent domains, an N-terminal RING domain, followed by one or two B-boxes and coiled-coil, which constitutes the tripartite-motif for is named. However, C-termini vary, include at least nine evolutionarily distinct, unrelated protein domains. Antiviral restriction factor TRIM5α has C-terminal B30.2/SPRY major determinant viral target specificity. Here, we describe evolution cyclophilin-A encoding exon downstream TRIM5 locus...
Viruses diversify over time within hosts, often undercutting the effectiveness of host defenses and therapeutic interventions. To design successful vaccines therapeutics, it is critical to better understand viral diversification, including comprehensively characterizing genetic variants in intra-host populations modeling changes from transmission through course infection. Massively parallel sequencing technologies can overcome cost constraints older methods obtain high sequence coverage...
Mutationally constrained epitopes of variable pathogens represent promising targets for vaccine design but are not reliably identified by sequence conservation. In this study, we employed structure-based network analysis, which applies theory to HIV protein structure data quantitate the topological importance individual amino acid residues. Mutation residues at important positions disproportionately impaired viral replication and occurred with high frequency in presented protective human...
Many important bacterial virulence factors act as mimics of mammalian proteins to subvert normal host cell processes. To identify protein components the innate immune signaling pathway, we searched genome database for with homology Toll/interleukin-1 receptor (TIR) domain Toll-like receptors (TLRs) and their adaptor proteins. A previously uncharacterized gene, which have named tlpA (for TIR-like A), was identified in Salmonella enterica serovar Enteritidis that is predicted encode a...
Retroviral restriction factor TRIM5alpha exhibits a high degree of sequence variation among primate species. It has been proposed that this diversity is the cumulative result ancient, lineage-specific episodes positive selection. Here, we describe contribution within-species to evolution TRIM5alpha. Sampling within two geographically distinct Old World monkey species revealed extensive polymorphism, including individual polymorphisms predate speciation (shared polymorphism). In some...
Genes encoding proteins with PYRIN/PAAD/DAPIN domains, a nucleotide binding fold (NACHT), and leucine rich repeats have recently been recognized as important mediators in autoimmune inflammatory disorders. Here we characterize the expression function of member PYRIN NACHT domain (PAN) family, PAN1 (also known NALP2 PYPAF2). protein is regulated by lipopolysaccharide (LPS) interferons (IFNbeta IFNgamma) THP-1 macrophage cells. In gene transfection studies manifests an inhibitory influence on...
Overproduction of the ornithine decarboxylase (ODC) regulatory protein ODC-antizyme has been shown to correlate with cell growth inhibition in a variety different types. Although exact mechanism this is not known, it attributed effect antizyme on polyamine metabolism. Antizyme binds directly ODC, targeting ODC for ubiquitin-independent degradation by 26 S proteasome. We now show that induction also leads cycle cyclin D1. demonstrate capable specific, noncovalent association D1 and...
ABSTRACT Herpes simplex virus 2 (HSV-2), the principal causative agent of recurrent genital herpes, is a highly prevalent viral infection worldwide. Limited information available on amount genomic DNA variation between HSV-2 strains because only two genomes have been determined, HG52 laboratory strain and newly sequenced SD90e low-passage-number clinical isolate strain, each from different geographical area. In this study, we report nearly complete genome sequences 34 strains, 14 which were...
Apoptosis (programmed cell death) plays important roles in many facets of normal mammalian physiology. Host-pathogen interactions have provided evolutionary pressure for apoptosis as a defense mechanism against viruses and microbes, sometimes linking mechanisms with inflammatory responses through NFκB induction. Proteins involved induction commonly contain evolutionarily conserved domains that can serve signatures identification by bioinformatics methods. Using combination public (NCBI)...
ABSTRACT Human respiratory syncytial virus (RSV) is the leading cause of lower tract disease in infants and young children an important pathogen elderly immunocompromised. While population-wide molecular epidemiology studies have shown multiple cocirculating RSV genotypes revealed antigenic genetic change over successive seasons, little known about extent viral diversity course individual infection, origins novel variants, or effect immune pressure on potential immune-escape mutations. To...
The introduction of West Nile virus (WNV) into North America in 1999 is a classic example viral emergence new environment, with its subsequent dispersion across the continent having major impact on local bird populations. Despite importance this epizootic, pattern, dynamics, and determinants WNV spread natural hosts remain uncertain. In particular, it unclear whether encountered barriers to transmission, or an unconstrained manner, if specific lineages were favored over others indicative...
TRIM5alpha is a potent barrier to cross-species retroviral transmission, and TRIM5alphas from different species have divergent antiretroviral specificities. Multiple TRIM5 alleles circulate within rhesus macaque populations. Here we show that they too specificities, highlighting how genotypes contribute protection in an individual or population.
HIV broadly neutralizing antibodies (bnAbs) have been shown to occasionally display unusual virus neutralization profiles with nonsigmoidal slopes and plateaus at <100% against a variety of viruses. The significance incomplete for the ability bnAbs mediate protective effects in vivo, however, is undetermined. In current study, we selected two bnAbs, PGT121 3BNC117, as they incompletely neutralize clade C simian-human immunodeficiency (SHIV) stock (SHIV-327c) 85% 70%, respectively, performed...
Human herpes simplex viruses 1 and 2 (HSV-1 HSV-2) are large-genome DNA that establish a persistent infection in sensory neurons commonly manifest with recurring oral or genital erosions transmit virus. HSV encodes 12 predicted glycoproteins serve various functions, including cellular attachment, entry, egress. Glycoprotein G is currently the target of an antibody test to differentiate HSV-1 from HSV-2; however, this has shown reduced capacity strains East Africa. Until recent availability...
Background. Infection with hepatitis C virus (HCV) is a burgeoning worldwide public health problem, 170 million infected individuals and an estimated 20 deaths in the coming decades. While 6 main genotypes generally distinguish global geographic diversity of HCV, multitude closely related subtypes within these are poorly defined may influence clinical outcome treatment options. Unfortunately, paucity genetic data from many makes time-consuming primer walking limiting step for sequencing...
High throughput sequencing has accelerated the determination of genome sequences for thousands human infectious disease pathogens and dozens their vectors. The scale scope these data are enabling genotype-phenotype association studies to identify genetic determinants pathogen virulence drug/insecticide resistance, phylogenetic track origin spread outbreaks. To maximize utility genomic purposes, it is essential that metadata about pathogen/vector isolate characteristics be collected made...
West Nile virus (WNV) is an arbovirus that was first reported in North America New York 1999 and, by 2003, had spread more than 4000 km to California. However, variation viral genetics associated with not well understood. Herein, we report sequences for 100 WNV isolates made from mosquito pools were collected 2003 2011 as part of routine surveillance the California Mosquito-borne Virus Surveillance System. We performed phylogeographic analyses and demonstrated 5 independent introductions (1...
Retroviral capsid recognition by Trim5 blocks productive infection. Rhesus macaques harbor three functionally distinct alleles: Trim5αQ, Trim5αTFP and Trim5CypA. Despite the high degree of amino acid identity between Trim5αQ alleles, Q/TFP polymorphism results in differential restriction some primate lentiviruses, suggesting these alleles differ how they engage capsids. Simian immunodeficiency virus rhesus (SIVmac) evolved to resist all alleles. Thus, SIVmac provides a unique opportunity...