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Identification of Host Proteins Required for HIV Infection Through a Functional Genomic Screen
Abstract
HIV-1 exploits multiple host proteins during infection. We performed a large-scale small interfering RNA screen to identify host factors required by HIV-1 and identified more than 250 HIV-dependency factors (HDFs). These proteins participate in a broad array of cellular functions and implicate new pathways in the viral life cycle. Further analysis revealed previously unknown roles for retrograde Golgi transport proteins (Rab6 and Vps53) in viral entry, a karyopherin (TNPO3) in viral integration, and the Mediator complex (Med28) in viral transcription. Transcriptional analysis revealed that HDF genes were enriched for high expression in immune cells, suggesting that viruses evolve in host cells that optimally perform the functions required for their life cycle. This effort illustrates the power with which RNA interference and forward genetics can be used to expose the dependencies of human pathogens such as HIV, and in so doing identify potential targets for therapy.
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“Host proteins with potential functions in the viral lifecycle have also been identified using siRNA-based screens (125-127).”
From Role of host tRNAs and aminoacyl-tRNA synthetases in retroviral replication (2019) · cites this paper as [127]
In the citing paper
“| Mixed pattern of regulation upon HIV-1 infection | GlyRS | 127 |”
From Role of host tRNAs and aminoacyl-tRNA synthetases in retroviral replication (2019) · cites this paper as [127]
In the citing paper
“The five ARSs listed exhibit a significant decrease (Ն16-fold) in transcript levels.”
From Role of host tRNAs and aminoacyl-tRNA synthetases in retroviral replication (2019) · cites this paper as [127]
In the citing paper
“| Levels of transcripts decrease upon HIV-1 infection b | EPRS a , TyrRS, MetRS a , HisRS, PheRS | 127 |”
From Role of host tRNAs and aminoacyl-tRNA synthetases in retroviral replication (2019) · cites this paper as [127]
In the citing paper
“| Levels of transcripts increase upon HIV-1 infection | AsnRS, CysRS | 127 |”
From Role of host tRNAs and aminoacyl-tRNA synthetases in retroviral replication (2019) · cites this paper as [127]
In the citing paper
“Five other ARSs, AlaRS, IleRS, LysRS, ValRS, and GlnRS, exhibit a moderate decrease (ϳ4fold) in HIV-1-infected cells.”
From Role of host tRNAs and aminoacyl-tRNA synthetases in retroviral replication (2019) · cites this paper as [127]
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Host factors exploited by retroviruses
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ZBTB2 increases PDK4 expression by transcriptional repression of RelA/p65
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“Screening data was compared for overlap with published hit lists for cell cycle regulators [36, 37] , host regulators of HIV infection [38] [39] [40] , and interferon stimulated genes (ISGs) [41] .”
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BackgroundSelf-citationNew insights into retroviral Gag–Gag and Gag–membrane interactions
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BackgroundIdentifying proteins controlling key disease signaling pathways
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“Identifying proteins controlling key disease signaling pathways Anthony Gitter 1∗ and Ziv Bar-Joseph 1 1School of Computer Science, Carnegie Mellon University, 5000 Forbes Avenue, Pittsburgh, PA 15213, USA Supplementary Information”
BackgroundFrom promoting to inhibiting: diverse roles of helicases in HIV-1 Replication
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Identification of Cellular Proteins Required for Replication of Human Immunodeficiency Virus Type 1
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“Interestingly, in previous studies solely using siRNA or shRNA to identify cellular proteins required for HIV-1 replication [4-7], Brass et al.”
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“Although a recent genome-wide siRNA screen uncovered a number of cellular genes that contribute to various stages of HIV infection, it was notable that only a few additional factors were described that are associated with either viral DNA synthesis or integration [17].”
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“The 54 CTDGs identified in this study include 10 genes with a reported link to HIV-1 replication: ARPC1A acts at a preintegration step and at viral budding [47, 48 ]; CARD6 is involved in NF-kB activation [56]; SKP2 and granulin are involved in Tat function [57,58]; deoyhypusine synthase is involved in Rev function [5…”
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“Three independent siRNAscreening studies have identified hundreds of host factors that are critical for HIV-1 replication, which were not previously known to be required by the virus.([37-40]) In addition to identification of new anti-HIV targets and combinations of multiple anti-HIV siRNAs, there have also been conce…”
BackgroundChinn, L. W., Tang, M., Kessing, B. D., Lautenberger, J. A., Troyer, J. L., Malasky, M., MCINTOSH, C. E., Kirk, G. D., Wolinsky, S. M., Buchbinder, S., et al. (2010) · The Journal of Infectious Diseases · doi:10.1086/657322 · Cited by 28
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“…engendered a new paradigm for HIV-host interactions – that HIV not only exploits many host factors for the successful completion of the life cycle (Brass et al., 2008; König et al., 2008), it also exploits several key host factors that are critical for subversion of innate immune responses in…”
BackgroundSelf-citationsiRNA Genome Screening Approaches to Therapeutic Drug Repositioning
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“21,121 Genome wide 273 Multiple pathways [97]”
BackgroundReduced Cellular Susceptibility to In Vitro HIV Infection Is Associated with CD4+ T Cell Quiescence
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“, all of them using microplate-based assays. In addition, several research groups have recently published studies identifying the host proteins required for HIV infection using similar microplate-based approaches”
BackgroundPotential roles for cellular cofactors in hepatitis C virus replication complex formation
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1,3‐Diazepine: A privileged scaffold in medicinal chemistry
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BackgroundHigh-Throughput HIV–Cell Fusion Assay for Discovery of Virus Entry Inhibitors
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“receptors and coreceptors are required for virus entry (6).”
BackgroundA role for the host coatomer and KDEL receptor in early vaccinia biogenesis
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“Culturing of TZM-b1 cells and propagation of HIV-IIIB have been described (25).”
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Dynamic Oligomerization of Integrase Orchestrates HIV Nuclear Entry
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BackgroundSpironolactone and XPB: An Old Drug with a New Molecular Target
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BackgroundInfluential
Metadata
- Authors
- Brass, A. L., Dykxhoorn, D. M., Benita, Y., Yan, N., Engelman, A., Xavier, R. J., Lieberman, J., & Elledge, S. J.
- Affiliations
- Brigham and Women's Hospital (US)
- ORCID
- Venue
- Science
- Published
- 2008-02-15
- Volume
- 319
- Issue
- 5865
- Pages
- 921-926
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2145848202
- Cited by
- 1,449
- References
- 0
- Citations by year
- 2026: 12 · 2025: 18 · 2024: 26 · 2023: 28 · 2022: 38 · 2021: 38 · 2020: 52 · 2019: 59 · 2018: 71 · 2017: 53 · 2016: 62 · 2015: 96 · 2014: 90 · 2013: 150 · 2012: 148
- FWCI
- 57.05
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of Allergy and Infectious Diseases (U19AI056900, AI052014, AI 062773, R01AI062773, R01AI052014, P30AI060354)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK040561)
- Topics
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
- Keywords
- HIV-1, host factors, host-virus interaction, Rab6, viral entry, karyopherins, TNPO3, viral integration, Mediator complex, MED28, viral transcription, antiviral drug targets
- MeSH terms
- Cytoskeletal Proteins, Humans, Proteins, Transcription, Genetic, Virus Replication, HIV-1, HIV Infections, Virus Integration, Computational Biology, rab GTP-Binding Proteins, Genomics, Karyopherins, Vesicular Transport Proteins, RNA Interference, RNA, Small Interfering, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, Virus Internalization, Human Immunodeficiency Virus Proteins, Host-Pathogen Interactions, Mediator Complex
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