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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
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
“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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“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
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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
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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
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Structural basis of HIV-1 capsid recognition by PF74 and CPSF6
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“…that the capsid remains intact in target cells, acting as a container for reverse transcription, driving nuclear import through specific interactions with nuclear pore components, and protecting the contents of the core before uncoating near sites of integration in the nucleus 160–162 .”
Cell-to-cell spread primes the nuclear pore for HIV-1
Nunzio, F. D. (2026) · Cell Host & Microbe · doi:10.1016/j.chom.2026.05.028
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Safaei, Z., & Khalili, K. (2026) · Journal of NeuroVirology · doi:10.1007/s13365-026-01343-5
“Rather than undergoing complete cytoplasmic disassembly, as traditionally proposed, current evidence indicates that the capsid remains largely intact during cytoplasmic trafficking and engages the nuclear pore complex to facilitate nuclear entry (Dharan et al. 2020 ).”
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Brown, A. W., Al-Izzi, S. C., Parker, J. L., Hertel, S., Jacques, D. A., Kusumaatmaja, H., & Morris, R. G. (2026) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2605059123
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“…basis for the single-round infection block in CBR THP-1 cells, we utilized quantitative PCR (qPCR) to measure the levels of late reverse transcription (LRT) products, 2-long terminal repeat (LTR)-containing circles (a surrogate marker of nuclear import [73, 74]), and integrated proviruses (75).”
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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