The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.
Nuclear pore blockade reveals that HIV-1 completes reverse transcription and uncoating in the nucleus
Open accessAbstract
Retroviral infection involves the reverse transcription of the viral RNA genome into DNA, which is subsequently integrated into the host cell genome. Human immunodeficiency virus type 1 (HIV-1) and other lentiviruses mediate the infection of non-dividing cells through the ability of the capsid protein 1 to engage the cellular nuclear import pathways of the target cell and mediate their nuclear translocation through components of the nuclear pore complex 2-4. Although recent studies have observed the presence of the capsid protein in the nucleus during infection 5-8, reverse transcription and disassembly of the viral core have conventionally been considered to be cytoplasmic events. Here, we use an inducible nuclear pore complex blockade to monitor the kinetics of HIV-1 nuclear import and define the biochemical staging of these steps of infection. Surprisingly, we observe that nuclear import occurs with relatively rapid kinetics (<5 h) and precedes the completion of reverse transcription in target cells, demonstrating that reverse transcription is completed in the nucleus. We also observe that HIV-1 remains susceptible to the capsid-destabilizing compound PF74 following nuclear import, revealing that uncoating is completed in the nucleus. Additionally, we observe that certain capsid mutants are insensitive to a Nup62-mediated nuclear pore complex blockade in cells that potently block infection by wild-type capsid, demonstrating that HIV-1 can use distinct nuclear import pathways during infection. These studies collectively define the spatio-temporal staging of critical steps of HIV-1 infection and provide an experimental system to separate and thereby define the cytoplasmic and nuclear stages of infection by other viruses.
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“Beyond its structural role, CA participates in multiple stages of the viral replication cycle, including reverse transcription (RT), cytoplasmic transport via microtubules, uncoating of the viral pre-integration complex, nuclear import, integration, and viral assembly (12, 13).”
From Research progress on HIV-1 structural proteins and antiviral therapies (2026) · cites this paper as [12]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“However, using HIV-1 as a model, it has now been established that reverse transcription begins in the cytoplasm and is completed within the intact CA in the nucleus (Fig. 5).”
From Beyond reverse transcription: molecular mechanisms and emerging paradigms in retroviral replication (2026) · cites this paper as Dharan et al. 2020
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Recent studies have shown that in HIV-1, the intact CA containing the reverse transcription complex, which includes dimerized RNA, RT, CA, NC, IN, Vpr, and host factors such as APOBEC3G gains access to the nucleus (Fig. 5) (Burdick et al. 2020, Dharan et al. 2020, Selyutina et al. 2020, Li et al. 2021, Müller et al. 2021).”
From Beyond reverse transcription: molecular mechanisms and emerging paradigms in retroviral replication (2026) · cites this paper as Dharan et al. 2020
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In the citing paper
“some recent studies report the presence of intact CA and CA-like structures inside the nucleus, challenging the prevailing notions about retroviral CA uncoating”
From Beyond reverse transcription: molecular mechanisms and emerging paradigms in retroviral replication (2026) · cites this paper as Dharan et al. 2020
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In the citing paper
“uncoating occurs near the integration site ~1.5 hours before integration due to the mounting physical pressure exerted by the newly reverse transcribed DNA”
From Beyond reverse transcription: molecular mechanisms and emerging paradigms in retroviral replication (2026) · cites this paper as Dharan et al. 2020
Experimental — accuracy not yet measured
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In contrast to this, HIV-1 PICs have been found to contain CA molecules; furthermore, some recent studies report the presence of intact CA and CA-like structures inside the nucleus, challenging the prevailing notions about retroviral CA uncoating (Burdick et al. 2020, Dharan et al. 2020, Selyutina et al. 2020, Müller et al. 2021).”
From Beyond reverse transcription: molecular mechanisms and emerging paradigms in retroviral replication (2026) · cites this paper as Dharan et al. 2020
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Thus, for at least HIV-1, once the CA is inside the nucleus, reverse transcription and PIC formation are completed, and uncoating occurs near the integration site ~1.5 hours before integration due to the mounting physical pressure exerted by the newly reverse transcribed DNA (Fig. 5) (Rankovic et al. 2017, Burdick et al. 2020, Dharan et al. 2020, Li et al. 2021, Müller et al. 2021, Yu et al. 2022)”
From Beyond reverse transcription: molecular mechanisms and emerging paradigms in retroviral replication (2026) · cites this paper as Dharan et al. 2020
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Citations
Cites
A quantitative assay for HIV DNA integration in vivo
Butler, S. L., Hansen, M. S., & Bushman, F. D. (2001) · Nature Medicine · doi:10.1038/87979 · Cited by 695
HIV-1 Reverse TranscriptionPreprint
Hu, W.-S., & Hughes, S. H. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006882 · Cited by 597
Redesigning an FKBP–ligand interface to generate chemical dimerizers with novel specificity
Clackson, T., Yang, W., Rozamus, L. W., Hatada, M., Amara, J. F., Rollins, C. T., Stevenson, L. F., Magari, S. R., Wood, S. A., Courage, N. L., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.18.10437 · Cited by 558
Schaller, T., Ocwieja, K. E., Rasaiyaah, J., Price, A. J., Brady, T. L., Roth, S. L., Hué, S., Fletcher, A. J., Lee, K., KewalRamani, V. N., et al. (2011) · PLoS Pathogens · doi:10.1371/journal.ppat.1002439 · Cited by 470
Flexible Use of Nuclear Import Pathways by HIV-1
Lee, K., Ambrose, Z., Martin, T. D., Öztop, I., Mulky, A., Julias, J. G., Vandegraaff, N., Baumann, J. G., Wang, R., Yuen, W., et al. (2010) · Cell Host & Microbe · doi:10.1016/j.chom.2010.02.007 · Cited by 451
HIV-1 capsid: the multifaceted key player in HIV-1 infection
Campbell, E. M., & Hope, T. J. (2015) · Nature Reviews Microbiology · doi:10.1038/nrmicro3503 · Cited by 430
Self-citationHIV-1 uncoats in the nucleus near sites of integration
Burdick, R. C., Li, C., Munshi, M., Rawson, J. M. O., Nagashima, K., Hu, W.-S., & Pathak, V. K. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1920631117 · Cited by 313
Complementary assays reveal a relationship between HIV-1 uncoating and reverse transcription
Hulme, A. E., Perez, O., & Hope, T. J. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1014522108 · Cited by 276
Structural basis of HIV-1 capsid recognition by PF74 and CPSF6
Bhattacharya, A., Alam, S. L., Fricke, T., Zadrozny, K. K., Sędzicki, J., Taylor, A. B., Demeler, B., Pornillos, O., Ganser‐Pornillos, B. K., Diaz‐Griffero, F., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1419945112 · Cited by 270
Wu, X., Anderson, J. L., Campbell, E. M., Joseph, A. M., & Hope, T. J. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0510483103 · Cited by 265
Self-citation
Cited by
Sorted by citations
Cone-shaped HIV-1 capsids are transported through intact nuclear pores
Žíla, V., Margiotta, E., Turoňová, B., Müller, T. G., Zimmerli, C. E., Mattei, S., Allegretti, M., Börner, K., Rada, J., Müller, B., et al. (2021) · Cell · doi:10.1016/j.cell.2021.01.025 · Cited by 361
HIV-1 cores retain their integrity until minutes before uncoating in the nucleus
Li, C., Burdick, R. C., Nagashima, K., Hu, W.-S., & Pathak, V. K. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2019467118 · Cited by 168
“We and others have recently reported that time-of-addition assays with capsid inhibitors PF74 and GS-CA1 (25, 30, 54) inhibited viral replication and resulted in disassembly of nuclear viral cores (25), supporting the view that premature un-coating of the viral core prevents formation of a functional PIC that can inte…”
InfluentialLiquid Biomolecular Condensates and Viral Lifecycles: Review and Perspectives
Etibor, T. A., Yamauchi, Y., & Amorim, M. J. (2021) · Viruses · doi:10.3390/v13030366 · Cited by 134
“The viral lifecycle of HIV is complex, the +ssRNA is reverse transcribed to cDNA, the cDNA is integrated in the genome, and upon being transcribed, both mRNAs and genomic RNA are transported to the cytosol [205,206] to produce viral proteins Gag polyprotein precursor (also known as Pr55Gag), GagPol polyprotein precurs…”
BackgroundMüller, T. G., Žíla, V., Peters, K., Schifferdecker, S., Stanić, M., Lucic, B., Laketa, V., Lušić, M., Müller, B., & Kräusslich, H. (2021) · eLife · doi:10.7554/elife.64776 · Cited by 129
HIV-1 Maturation: Lessons Learned from Inhibitors
Kleinpeter, A. B., & Freed, E. O. (2020) · Viruses · doi:10.3390/v12090940 · Cited by 106
“Although early models proposed that the capsid uncoats soon after membrane fusion, accumulating evidence now suggests that upon release into the cytoplasm, the capsid remains intact, or nearly intact, as it traffics to the nuclear envelope [35,36] and into the nucleus [37,38] (Figure 1).”
Background
Metadata
- Authors
- Dharan, A., Bachmann, N., Talley, S., Zwikelmaier, V., & Campbell, E. M.
- Affiliations
- Loyola University Chicago (US)
- Corresponding author
- Campbell, Edward M.
- Venue
- Nature Microbiology
- Published
- 2020-06-01
- Volume
- 5
- Issue
- 9
- Pages
- 1088-1095
- ISSN
- 2058-5276 (ISSN-L)
- PMC
- PMC9286700
- OpenAlex
- W3031494023
- Cited by
- 223
- References
- 30
- Citations by year
- 2026: 21 · 2025: 36 · 2024: 40 · 2023: 26 · 2022: 26 · 2021: 53 · 2020: 21
- FWCI
- 16.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Microbiology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases (R21 AI139009)
- Topics
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
- Keywords
- HIV-1, reverse transcription, viral uncoating, nuclear import, nuclear pore complex, capsid protein, Nup62, capsid mutants, lentiviral infection
- MeSH terms
- Capsid, Cell Nucleus, Cytoplasm, HeLa Cells, Humans, Indoles, Macrophages, Phenylalanine, Virus Replication, CD4-Positive T-Lymphocytes, HIV-1, HIV Infections, Active Transport, Cell Nucleus, Nuclear Pore, Capsid Proteins, Reverse Transcription, Host-Pathogen Interactions, HEK293 Cells
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