Host Cell Factors in HIV Replication: Meta-Analysis of Genome-Wide Studies

We have analyzed host cell genes linked to HIV replication that were identified in nine genome-wide studies, including three independent siRNA screens. Overlaps among the siRNA screens were very modest (<7% for any pairwise combination), and similarly, only modest overlaps were seen in pairwise comparisons with other types of genome-wide studies. Combining all genes from the genome-wide studies together with genes reported in the literature to affect HIV yields 2,410 protein-coding genes, or fully 9.5% of all human genes (though of course some of these are false positive calls). Here we report an “encyclopedia” of all overlaps between studies (available at http://www.hostpathogen.org), which yielded a more extensively corroborated set of host factors assisting HIV replication. We used these genes to calculate refined networks that specify cellular subsystems recruited by HIV to assist in replication, and present additional analysis specifying host cell genes that are attractive as potential therapeutic targets.

[1]  P. Earl,et al.  Folding, interaction with GRP78-BiP, assembly, and transport of the human immunodeficiency virus type 1 envelope protein , 1991, Journal of virology.

[2]  W. Sundquist,et al.  Crystal Structure of Human Cyclophilin A Bound to the Amino-Terminal Domain of HIV-1 Capsid , 1996, Cell.

[3]  M. Rosbash,et al.  The importin-beta family member Crm1p bridges the interaction between Rev and the nuclear pore complex during nuclear export , 1997, Current Biology.

[4]  E. De Clercq,et al.  Bicyclams, a class of potent anti-HIV agents, are targeted at the HIV coreceptor fusin/CXCR-4. , 1997, Antiviral research.

[5]  Ping Wei,et al.  A Novel CDK9-Associated C-Type Cyclin Interacts Directly with HIV-1 Tat and Mediates Its High-Affinity, Loop-Specific Binding to TAR RNA , 1998, Cell.

[6]  Bertrand Friguet,et al.  Antiviral Activity of the Proteasome on Incoming Human Immunodeficiency Virus Type 1 , 1998, Journal of Virology.

[7]  R. Roeder,et al.  Isolation of cDNAs encoding novel transcription coactivators p52 and p75 reveals an alternate regulatory mechanism of transcriptional activation , 1998, The EMBO journal.

[8]  A. Zolotukhin,et al.  Nucleoporins Nup98 and Nup214 Participate in Nuclear Export of Human Immunodeficiency Virus Type 1 Rev , 1999, Journal of Virology.

[9]  D. Rose,et al.  A role for RNA helicase A in post-transcriptional regulation of HIV type 1. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[10]  Wesley I. Sundquist,et al.  Tsg101 and the Vacuolar Protein Sorting Pathway Are Essential for HIV-1 Budding , 2001, Cell.

[11]  Paul Shinn,et al.  HIV-1 Integration in the Human Genome Favors Active Genes and Local Hotspots , 2002, Cell.

[12]  D. McDonald,et al.  Visualization of the intracellular behavior of HIV in living cells , 2002, The Journal of cell biology.

[13]  A. Hopkins,et al.  The druggable genome , 2002, Nature Reviews Drug Discovery.

[14]  F. Bushman,et al.  Human Immunodeficiency Virus cDNA Metabolism: Notable Stability of Two-Long Terminal Repeat Circles , 2002, Journal of Virology.

[15]  Phillip D Zamore,et al.  RNAi: nature abhors a double-strand. , 2002, Current opinion in genetics & development.

[16]  A. Cochrane,et al.  Positive and Negative Modulation of Human Immunodeficiency Virus Type 1 Rev Function by cis and trans Regulators of Viral RNA Splicing , 2002, Journal of Virology.

[17]  Gary D. Bader,et al.  An automated method for finding molecular complexes in large protein interaction networks , 2003, BMC Bioinformatics.

[18]  W. Sundquist,et al.  The Protein Network of HIV Budding , 2003, Cell.

[19]  Shawn M. Burgess,et al.  Transcription Start Regions in the Human Genome Are Favored Targets for MLV Integration , 2003, Science.

[20]  Roger D. Kornberg,et al.  Association of the Mediator complex with enhancers of active genes , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[21]  Brad T. Sherman,et al.  DAVID: Database for Annotation, Visualization, and Integrated Discovery , 2003, Genome Biology.

[22]  Zeger Debyser,et al.  HIV-1 Integrase Forms Stable Tetramers and Associates with LEDGF/p75 Protein in Human Cells* , 2003, The Journal of Biological Chemistry.

[23]  M. Weitzman,et al.  Roles of host cell factors in circularization of retroviral dna. , 2003, Virology.

[24]  E. De Clercq,et al.  LEDGF/p75 Is Essential for Nuclear and Chromosomal Targeting of HIV-1 Integrase in Human Cells* , 2003, Journal of Biological Chemistry.

[25]  Pamela A Silver,et al.  Human cell proteins and human immunodeficiency virus DNA integration. , 2004, Frontiers in bioscience : a journal and virtual library.

[26]  Serge Batalov,et al.  The promise of genomics to identify novel therapeutic targets , 2004, Expert opinion on therapeutic targets.

[27]  K. Jeang,et al.  Requirement of DDX3 DEAD Box RNA Helicase for HIV-1 Rev-RRE Export Function , 2004, Cell.

[28]  M. Llano,et al.  LEDGF/p75 Determines Cellular Trafficking of Diverse Lentiviral but Not Murine Oncoretroviral Integrase Proteins and Is a Component of Functional Lentiviral Preintegration Complexes , 2004, Journal of Virology.

[29]  F. Bushman,et al.  Retroviral DNA Integration: ASLV, HIV, and MLV Show Distinct Target Site Preferences , 2004, PLoS biology.

[30]  Sarah Ng,et al.  The functionally conserved nucleoporins Nup124p from fission yeast and the human Nup153 mediate nuclear import and activity of the Tf1 retrotransposon and HIV-1 Vpr. , 2005, Molecular biology of the cell.

[31]  Paul Shinn,et al.  A role for LEDGF/p75 in targeting HIV DNA integration , 2005, Nature Medicine.

[32]  N. Yokoyama,et al.  DBR1 siRNA inhibition of HIV-1 replication , 2005, Retrovirology.

[33]  F. Bushman,et al.  Modulating target site selection during human immunodeficiency virus DNA integration in vitro with an engineered tethering factor. , 2006, Human gene therapy.

[34]  P. Gregersen,et al.  Overlapping Probabilities of Top Ranking Gene Lists, Hypergeometric Distribution, and Stringency of Gene Selection Criterion , 2006, 2006 International Conference of the IEEE Engineering in Medicine and Biology Society.

[35]  Buu P. Tu,et al.  High-content screening of functional genomic libraries. , 2006, Methods in enzymology.

[36]  S. Yokoyama,et al.  Apolipoprotein A‐I increases association of cytosolic cholesterol and caveolin‐1 with microtubule cytoskeletons in rat astrocytes , 2006, Journal of neurochemistry.

[37]  K. Nagashima,et al.  Proteomic and Biochemical Analysis of Purified Human Immunodeficiency Virus Type 1 Produced from Infected Monocyte-Derived Macrophages , 2006, Journal of Virology.

[38]  Wulin Teo,et al.  An Essential Role for LEDGF/p75 in HIV Integration , 2006, Science.

[39]  Chen Liang,et al.  Association of RNA Helicase A with Human Immunodeficiency Virus Type 1 Particles* , 2006, Journal of Biological Chemistry.

[40]  Sean R. Collins,et al.  Global landscape of protein complexes in the yeast Saccharomyces cerevisiae , 2006, Nature.

[41]  R. König,et al.  A probability-based approach for the analysis of large-scale RNAi screens , 2007, Nature Methods.

[42]  P. Cherepanov LEDGF/p75 interacts with divergent lentiviral integrases and modulates their enzymatic activity in vitro , 2006, Nucleic acids research.

[43]  Jacques Fellay,et al.  A Whole-Genome Association Study of Major Determinants for Host Control of HIV-1 , 2007, Science.

[44]  R. Kornberg The molecular basis of eukaryotic transcription , 2007, Proceedings of the National Academy of Sciences.

[45]  F. Bushman,et al.  Role of PSIP1/LEDGF/p75 in Lentiviral Infectivity and Integration Targeting , 2007, PloS one.

[46]  A. Lackner,et al.  Gastrointestinal disease in simian immunodeficiency virus-infected rhesus macaques is characterized by proinflammatory dysregulation of the interleukin-6-Janus kinase/signal transducer and activator of transcription3 pathway. , 2007, The American journal of pathology.

[47]  Pauline E. Chugh,et al.  Akt inhibitors as an HIV-1 infected macrophage-specific anti-viral therapy , 2008, Retrovirology.

[48]  A. Engelman,et al.  LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration. , 2007, Genes & development.

[49]  S. Goff,et al.  Host proteins interacting with the Moloney murine leukemia virus integrase : Multiple transcriptional regulators and chromatin binding factors , 2016 .

[50]  Amy S. Espeseth,et al.  Genome-scale RNAi screen for host factors required for HIV replication. , 2008, Cell host & microbe.

[51]  R. König,et al.  Global Analysis of Host-Pathogen Interactions that Regulate Early-Stage HIV-1 Replication , 2008, Cell.

[52]  Ruth R. Montgomery,et al.  RNA interference screen for human genes associated with West Nile virus infection , 2008, Nature.

[53]  J. Lieberman,et al.  Identification of Host Proteins Required for HIV Infection Through a Functional Genomic Screen , 2007, Science.

[54]  D. Heckerman,et al.  Central Role of Reverting Mutations in HLA Associations with Human Immunodeficiency Virus Set Point , 2008, Journal of Virology.

[55]  M. Newton,et al.  Drosophila RNAi screen identifies host genes important for influenza virus replication , 2008, Nature.

[56]  S. Goff,et al.  Knockdown Screens to Knockout HIV-1 , 2008, Cell.

[57]  J. Church Identification of Host Proteins Required for HIV Infection Through a Functional Genomic Screen , 2008, Pediatrics.

[58]  J. Luban HIV-1 Infection: Going Nuclear with TNPO3/Transportin-SR2 and Integrase , 2008, Current Biology.

[59]  Zeger Debyser,et al.  Transportin-SR2 Imports HIV into the Nucleus , 2008, Current Biology.

[60]  R. Doms,et al.  Baseline Resistance of Primary Human Immunodeficiency Virus Type 1 Strains to the CXCR4 Inhibitor AMD3100 , 2008, Journal of Virology.

[61]  Donna R. Maglott,et al.  Human immunodeficiency virus type 1, human protein interaction database at NCBI , 2008, Nucleic Acids Res..