Cited by 1,449HIV Research and TreatmentVirus-based gene therapy researchHIV/AIDS drug development and treatment

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Identification of Host Proteins Required for HIV Infection Through a Functional Genomic Screen

Brass, Abraham L., Dykxhoorn, Derek M., Benita, Yair, Yan, Nan, Engelman, Alan, Xavier, Ramnik J., Lieberman, Judy, Elledge, Stephen J.·2008·Science

DOI 10.1126/science.1152725

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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 factors exploited by retroviruses
Goff, S. P. (2007) · Nature Reviews Microbiology · doi:10.1038/nrmicro1541 · Cited by 247

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A Genome-wide RNAi screening method to discover novel genes involved in virus infection
Panda, D., & Cherry, S. (2015) · Methods · doi:10.1016/j.ymeth.2015.07.002 · Cited by 7
“In recent years a number of studies have reported genome-wide RNAi screen for viruses identifying hundreds of novel players in the virus–host interface [3–17].”
Identify Potential Regulators in HIV-1 Latency by Joint microRNA and mRNA Analysis
Yang, Z.-X., Yang, J., Wang, J., Lu, X.-Y., Jin, C., Xie, T.-S., & Wu, N. (2015) · Cellular Physiology and Biochemistry · doi:10.1159/000430121 · Cited by 7
Knockdown of the host cellular protein transportin 3 attenuates prototype foamy virus infection
Ali, M. K., Kim, J., Hamid, F. B., & Shin, C. (2015) · Bioscience Biotechnology and Biochemistry · doi:10.1080/09168451.2015.1008973 · Cited by 7
Sorting Nexin 6 Enhances Lamin A Synthesis and Incorporation into the Nuclear Envelope
González-Granado, J., Navarro-Puche, A., Molina-Sánchez, P., Blanco-Berrocal, M., Viana, R., de Mora, J. D., & Andrés, V. (2014) · PLoS ONE · doi:10.1371/journal.pone.0115571 · Cited by 7
“Retrograde transport is altered in a number of human infectious diseases [27, 28], as well as in Alzheimer’s disease [29], cancer [30], and possibly in osteoporosis [31].”
Background
Validation of host factors of HIV integration as novel drug targets for anti-HIV therapy
Debyser, Z., Desimmie, B. A., Taltynov, O., Demeulemeester, J., & Christ, F. (2014) · MedChemComm · doi:10.1039/c3md00302g · Cited by 4
ACSM4 Polymorphisms Are Associated With Rapid AIDS Progression in HIV-Infected Patients
Guzmán-Fulgencio, M., Jiménez, J. L., Jiménez-Sousa, M., Bellón, J., García-Álvarez, M., Soriano, V., Gijón-Vidaurreta, P., Bernal-Morell, E., Viciana, P., Muñoz-Fernández, M. A., et al. (2014) · Journal of Acquired Immune Deficiency Syndromes · doi:10.1097/qai.0b013e3182a990e2 · Cited by 7
HIV-1 Infection Is Blocked at an Early Stage in Cells Devoid of Mitochondrial DNA
Lu, G., Matsuura, S., Barrientos, A., & Scott, W. (2013) · PLoS ONE · doi:10.1371/journal.pone.0078035 · Cited by 7
New in silico and conventional in vitro approaches to advance HIV drug discovery and design
Maga, G., Veljković, N., Crespan, E., Spadari, S., Prljic, J., Perović, V., Glišić, S., & Veljković, V. (2012) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2013.741118 · Cited by 5
“Moreover, genome-wide approaches analyzing host factors required for successful HIV-1 replication in infected cells identified more than 1000 cellular proteins which contribute to HIV-1 entry, replication and viral particle assembly, providing a plethora of novel potential targets for anti-HIV therapy [2].”
Background
Shared Molecular Strategies of the Malaria Parasite P. falciparum and the Human Virus HIV-1
Wuchty, S., Siwo, G., & Ferdig, M. T. (2011) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m111.009035 · Cited by 7
Targeting a host element as a strategy to block HIV replication: is it nice to fool with Mother Nature?
Lederman, M., & Esté, J. (2009) · Current Opinion in HIV and AIDS · doi:10.1097/coh.0b013e3283207b07 · Cited by 7
Identifying host targets for drug development with knowledge from genome-wide studies: lessons from HIV-AIDS.
Winkler, C. (2008) · Cell Host and Microbe · doi:10.1016/j.chom.2008.04.001 · Cited by 7
Network-Based Analysis of OMICs Data to Understand the HIV-Host Interaction
Ivanov, S., Lagunin, A., Filimonov, D., & Tarasova, O. (2020) · doi:10.20944/preprints202004.0514.v1 · Cited by 7
“The difficulty in the creation of anti-HIV vaccine can be explained by the fact that people do not develop natural, protective immunity to HIV infection, whereas almost all successful vaccines were developed for diseases for which natural immunity exists (Brett-Major et al., 2017).”
BackgroundInfluential
HIV-1 Rev function and RNA nuclear-cytoplasmic export.
Cochrane, A. (2014) · Methods in molecular biology · doi:10.1007/978-1-62703-670-2_9 · Cited by 7
Prevention of Human Immunodeficiency Virus Type 1 Transmission by Pharmaceuticals Targeted to Host Proteins Required for Virus Infection? Consideration of Farnesyl Thiosalicylic Acid, a Ras Inhibitor
Neurath, A., & Lackman-Smith, C. (2010) · doi:10.4172/jaa.1000010 · Cited by 7
“…targeted to host proteins (in addition to CD4, CCR5 and CXCR4) required for virus infection (Kellam, 2006; Zhang et al., 2007; Nguyen et al., 2007; Konig et al., 2008; Ptak et al., 2008; Zhou et al., 2008; Loo and Gale, 2008; Goff, 2008; Brass et al., 2008; Bushman et al., 2009; Fu et al., 2009).”
Background
Deep analysis of the major histocompatibility complex genetic associations using covariate analysis and haploblocks unravels new mechanisms for the molecular etiology of Elite Control in AIDS
Rahmouni, M., Clerc, S. L., Spadoni, J.-L., Labib, T., Tison, M., Medina-Santos, R., Bensussan, A., Tamouza, R., Deleuze, J., & Zagury, J. (2025) · BMC Immunology · doi:10.1186/s12865-024-00680-6 · Cited by 6
“Its down-regulation has been associated with impairment of HIV-1 replication [26, 27], but on the opposite, it is not certain that its overexpression will increase HIV-1 replication.”
Determinants of Retroviral Integration and Implications for Gene Therapeutic MLV—Based Vectors and for a Cure for HIV-1 Infection
Pellaers, E., Bhat, A., Christ, F., & Debyser, Z. (2022) · Viruses · doi:10.3390/v15010032 · Cited by 8
“Examples of such factors are the ran–binding protein 2 (RANBP2, also called Nup358) [149], transportin SR2 (TRN–SR2, also called transportin 3) [150,151], nucleoporin 153 (Nup153) [149–151] and transportin 1 (TRN–1) [152].”
Background
Attenuated Negative Feedback in Monocyte-Derived Macrophages From Persons Living With HIV: A Role for IKAROS
Faia, C., Plaisance‐Bonstaff, K., Vittori, C., Wyczechowska, D. D., Lassak, A., Meyaski‐Schluter, M., Reiss, K., & Peruzzi, F. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.785905 · Cited by 6
“Interestingly, NCOR2 was identified as one of the host genes necessary for HIV infection, also called HIV-dependency factors (72), and two SNPs on the NCOR2 gene were found to be associated with HIV transmission in a high throughput genomewide analysis (73).”
Background
The role of Pannexin-1 channels and extracellular ATP in the pathogenesis of the human immunodeficiency virus
D'Amico, D., Valdebenito, S., & Eugenin, E. (2021) · Purinergic Signalling Purinergic Signalling · doi:10.1007/s11302-021-09817-3 · Cited by 6
A Flexible, Pooled CRISPR Library for Drug Development Screens
Blanck, M., Budnik-Zawilska, M., Lenger, S. R., McGonigle, J. E., Martin, G. R. A., le Sage, C., Lawo, S., Pemberton, H. N., Tiwana, G. S., Sorrell, D. A., et al. (2020) · The CRISPR Journal · doi:10.1089/crispr.2019.0066 · Cited by 7
Viral protein X unlocks the nuclear pore complex through a human Nup153-dependent pathway to promote nuclear translocation of the lentiviral genome
Singh, S. P., Raja, S., & Mahalingam, S. (2020) · Molecular Biology of the Cell · doi:10.1091/mbc.e19-08-0438 · Cited by 8
“A genome-wide RNA interference screening suggested the requirement of Nup98, Nup358, and nucleoporin 153 (Nup153) for the nuclear translocation of the HIV-1 genome in nondividing cells (Ebina et al. , 2004; Brass et al. , 2008; König et al. , 2008; Zhou et al. , 2008).”
Kinases: Understanding Their Role in HIV Infection
Martini, W. D., Rahman, R., Ojegba, E., Jungwirth, E., Macias, J., Ackerly, F., Fowler, M. G., Cottrell, J. A., Chu, T., & Chang, S.-L. L. (2019) · World Journal of AIDS · doi:10.4236/wja.2019.93011 · Cited by 6
The mRNA Metabolism in Human Disease
Romão, L. (2019) · Advances in Experimental Medicine and Biology · doi:10.1007/978-3-030-19966-1 · Cited by 6
PATZ1 is required for efficient HIV-1 infection
Aziati, I. D., Yoshida, T., Hamano, A., Maeda, K., Takeuchi, H., & Yamaoka, S. (2019) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2019.04.175 · Cited by 4
A Functional Genomics Approach to Henipavirus Research: The Role of Nuclear Proteins, MicroRNAs and Immune Regulators in Infection and Disease
Stewart, C. R., Deffrasnes, C., Foo, C. H., Bean, A. G. D., & Wang, L. (2017) · Current topics in microbiology and immunology · doi:10.1007/82_2017_28 · Cited by 7
“2008; Brass et al.”
Characterization of two distinct early post-entry blocks to HIV-1 in common marmoset lymphocytes
Pacheco, B., Menéndez‐Arias, L., & Sodroski, J. (2016) · Scientific Reports · doi:10.1038/srep37489 · Cited by 6
The Early Bird Catches the Worm - Can Evolution Teach us Lessons in Fighting HIV?
Schaller, T., & Herold, N. (2016) · Current HIV Research · doi:10.2174/1570162x14999160224094914 · Cited by 8
A Genome-Wide Screen for Machinery Involved in Downregulation of MHC Class I by HIV-1 Nef
Choma, M., Lumb, J. H., Kozik, P., & Robinson, M. (2015) · PLoS ONE · doi:10.1371/journal.pone.0140404 · Cited by 6
Ring finger protein 39 genetic variants associate with HIV-1 plasma viral loads and its replication in cell culture
Lin, Y.-J., Chen, C.-Y., Jeang, K., Liu, X., Wang, J.-H., Hung, C.-H., Tsang, H.-Y., Lin, T.-H., Liao, C.-C., Huang, S.-M., et al. (2014) · Cell & Bioscience · doi:10.1186/2045-3701-4-40 · Cited by 6
“Genome-wide siRNA screening approaches have been conducted to identify host cellular proteins that affect HIV-1 replication [7-10].”
Background
Coregulation of HIV-1 dependency factors in individuals heterozygous to the CCR5-delta32 deletion
Hütter, G., Blüthgen, C., Neumann, M., Reinwald, M., Nowak, D., & Klüter, H. (2013) · AIDS Research and Therapy · doi:10.1186/1742-6405-10-26 · Cited by 6
A Divide and Conquer Approach for Construction of Large-Scale Signaling Networks from PPI and RNAi Data Using Linear Programming
Ozsoy, O. E., & Can, T. (2013) · IEEE/ACM Transactions on Computational Biology & Bioinformatics · doi:10.1109/tcbb.2013.80 · Cited by 6
“To scale for large signaling networks, we propose a divide and conquer-based heuristic, in which a given reference network is divided into smaller subnetworks that are solved separately and the solutions are merged together to form the solution for the large network.”
Method

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: Dykxhoorn, Derek M.
Benita, Yair
Yan, Nan
Engelman, Alan
Xavier, Ramnik J.
Lieberman, Judy
Elledge, Stephen J.
Venue: Science
Publisher: American Association for the Advancement of Science (AAAS)
Published: 2008-02-15
Volume: 319
Issue: 5865
Pages: 921-926
ISSN: 0036-8075 (ISSN-L)
1095-9203
DOI: 10.1126/science.1152725
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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Identification of Host Proteins Required for HIV Infection Through a Functional Genomic Screen

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