Cited by 162HIV Research and TreatmentVirus-based gene therapy researchHIV/AIDS drug development and treatment

HIV-1 replication complexes accumulate in nuclear speckles and integrate into speckle-associated genomic domains

Open access
Francis, Ashwanth C., Marin, Mariana, Singh, Parmit K., Achuthan, Vasudevan, Prellberg, Mathew J., Palermino-Rowland, Kristina, Lan, Shuiyun, Tedbury, Philip R. +3 more·2020·Nature Communications

Abstract

The early steps of HIV-1 infection, such as uncoating, reverse transcription, nuclear import, and transport to integration sites are incompletely understood. Here, we imaged nuclear entry and transport of HIV-1 replication complexes in cell lines, primary monocyte-derived macrophages (MDMs) and CD4 + T cells. We show that viral replication complexes traffic to and accumulate within nuclear speckles and that these steps precede the completion of viral DNA synthesis. HIV-1 transport to nuclear speckles is dependent on the interaction of the capsid proteins with host cleavage and polyadenylation specificity factor 6 (CPSF6), which is also required to stabilize the association of the viral replication complexes with nuclear speckles. Importantly, integration site analyses reveal a strong preference for HIV-1 to integrate into speckle-associated genomic domains. Collectively, our results demonstrate that nuclear speckles provide an architectural basis for nuclear homing of HIV-1 replication complexes and subsequent integration into associated genomic loci.

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Crossref · 10.1038/s41467-020-17256-8

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  • Under normal infection conditions, HIV-1 pre-integration complexes colocalize with nuclear speckles and strongly favor SPADs for integration while avoiding LADs.

    “Under normal infection conditions, HIV-1 PICs colocalized with nuclear speckles and strongly favoured SPADs for integration while avoiding LADs84.”

    From Structure and function of retroviral integrase (2022) · cites this paper as [84]

    The Results section (‘HIV-1 integrates into speckle-associated genomic DNA’; page unavailable) reports that HIV-1 replication complexes accumulate in nuclear speckles and that integration strongly favors SPADs across cell types. The Discussion mentions LAD association for recurrent integration genes in the absence of CA–CPSF6 interaction, but does not establish that HIV-1 avoids LADs under normal infection conditions. (LLM, conf=0.86)

    Experimental — accuracy not yet measured
  • CPSF6 plays a critical role in regulating nuclear pre-integration complex incursion.

    “In addition to its role in nuclear import, CPSF6 plays a critical role in regulating nuclear PIC incursion.”

    From Structure and function of retroviral integrase (2022) · cites this paper as [84]

    The Results section (“Relocation outside of NSs diminishes nuclear VRC stability”; page unavailable) suggests that CPSF6 is involved in transporting HIV-1 viral replication complexes to nuclear speckles. The Discussion (page unavailable) is more cautious: it says CPSF6 and/or other factors may tether the complexes there. These passages support a role in intranuclear positioning, but not the stronger assertion that CPSF6 itself plays a critical role in regulating nuclear PIC incursion. (LLM, conf=0.81)

    Experimental — accuracy not yet measured
  • In CPSF6 knockout cells, pre-integration complexes congregate at the nuclear periphery and target LADs for integration while losing the preference for SPADs.

    “In CPSF6 knockout cells, PICs congregated at the nuclear periphery and uncharacteristically targeted LADs for integration while losing the preference for SPADs84,85.”

    From Structure and function of retroviral integrase (2022) · cites this paper as [84]

    The Results section ('HIV-1 integrates into speckle-associated genomic DNA'; page unavailable) reports that HIV-1 disfavored SPAD integration in CPSF6-knockout cells. The Discussion (page unavailable) says CPSF6-negative recurrent integration genes associate with LADs at the nuclear periphery, citing a prior report. These passages do not establish that pre-integration complexes congregated at the nuclear periphery in knockout cells or that knockout cells broadly targeted LADs for integration. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 1

  1. [16]Hulme AE Kelley Z Foley D Hope TJ Complementary assays reveal a low level of CA associated with nuclear HIV-1 viral complexes J. Virol. 2015 89 5350 5361 25741002 PMC4442523

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Authors
Francis, A. C., Marin, M., Singh, P. K., Achuthan, V., Prellberg, M. J., Palermino-Rowland, K., Lan, S., Tedbury, P. R., Sarafianos, S. G., Engelman, A. N., & Melikyan, G. B.
Affiliations
  • Emory University (US)
  • Harvard University (US)
Corresponding author
  • Francis, Ashwanth C.
  • Melikyan, Gregory B.
Venue
Nature Communications
Published
2020-07-14
Volume
11
Issue
1
Pages
3505-3505
ISSN
2041-1723 (ISSN-L)
OpenAlex
W3042510281
Cited by
159
References
75
Citations by year
2026: 15 · 2025: 29 · 2024: 27 · 2023: 20 · 2022: 32 · 2021: 29 · 2020: 7
FWCI
11.73
Type
journal article
Language
en
Open access
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (R01 AI129862, R01 AI052014, R01 AI148382, R01 AI120860, U54 AI150472)
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, nuclear speckles, viral replication complex, viral integration, CPSF6, capsid protein, nuclear transport, monocyte-derived macrophages, CD4+ T cells, nuclear organization, viral uncoating, reverse transcription
MeSH terms
Cell Nucleus, Humans, Microscopy, Fluorescence, Virology, Virus Replication, CD4-Positive T-Lymphocytes, HIV-1, HIV Infections, Virus Integration, Genome, Viral, Capsid Proteins, Host-Pathogen Interactions, HEK293 Cells

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