CPSF6-Dependent Targeting of Speckle-Associated Domains Distinguishes Primate from Nonprimate Lentiviral Integration
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Integration is the defining step of the retroviral life cycle and underlies the inability to cure HIV/AIDS through the use of intensified antiviral therapy. The reservoir of latent, replication-competent proviruses that forms early during HIV infection reseeds viremia when patients discontinue medication. HIV cure research is accordingly focused on the factors that guide provirus formation and associated chromatin environments that regulate transcriptional reactivation, and studies of orthologous infectious agents such as nonprimate lentiviruses can inform basic principles of HIV biology. HIV-1 utilizes the integrase-binding protein LEDGF/p75 and the capsid interactor CPSF6 to target speckle-associated domains (SPADs) for integration. However, the extent to which these two host proteins regulate integration of other lentiviruses is largely unknown. Here, we mapped millions of retroviral integration sites in cell lines that were depleted for LEDGF/p75 and/or CPSF6. Our results reveal that primate lentiviruses uniquely target SPADs for integration in a CPSF6-dependent manner.
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Non-primate lentiviruses show minimal preference for integrating into SPADs, and their capsid proteins do not bind CPSF6.
“Interestingly, non-primate lentiviruses displayed minimal preferences for integrating into SPADs, and the respective capsid proteins did not bind CPSF6 (REF.87).”
From Structure and function of retroviral integrase (2022) · cites this paper as [87]
Genic proviruses formed when LEDGF/p75 was absent clustered near transcription start sites.
“The genic proviruses that did form under these conditions uncharacteristically congregated around transcription start sites87,99–101.”
From Structure and function of retroviral integrase (2022) · cites this paper as [87]
Recent work uncovered surprising differences in mechanisms targeting retroviral integration, even within a single genus.
“Recent work uncovered surprising differences between mechanisms involved in targeting retroviral integration, even within a single genus87.”
From Structure and function of retroviral integrase (2022) · cites this paper as [87]
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Virus–Host Interactions in Retrovirus Integration
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Self-citation(2018) · Elsevier eBooks · doi:10.1016/c2014-0-03142-5 · Cited by 12 · see citing works
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Multivalent interactions essential for lentiviral integrase function
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CPSF6 promotes HIV-1 preintegration complex function
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Taylor, I. A., & Fassati, A. (2023) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjad076 · Cited by 8 · see citing works
Aquarius helicase facilitates HIV-1 integration into R-loop enriched genomic regions
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Luchsinger, C., Dai, A. Z., Yalamanchili, H. K., Balakrishnan, A., Huang, K.-L., Bertelli, C., Cui, B., Lorenzo-Redondo, R., Wagner, E. J., & Diaz‐Griffero, F. (2025) · mBio · doi:10.1128/mbio.02865-25 · Cited by 1 · see citing works
HIV-1 uncoating location dictates sites of integration
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Human immunodeficiency virus-1 induces and targets host genomic R-loops for viral genome integrationPreprint
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The role of LEDGF in transcription is exploited by HIV-1 to position integrationPreprint
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Hultquist, J. F., Cornish, D., Jackson-Jones, K. A., Ling-Hu, T., Simons, L. M., Cisneros, W. J., Kuffour, E. O., Agnes, F., Lee, Y., Bieniasz, P. D., et al. (2024) · Research Square · doi:10.21203/rs.3.rs-5099896/v1 · Cited by 1 · see citing works
Rheinberger, M., Costa, A., Kampmann, M., Glavaš, D., Shytaj, I. L., Penzo, C., Tibroni, N., Fackler, O., Vlahoviček, K., Lucic, B., et al. (2022) · SSRN Electronic Journal · doi:10.2139/ssrn.4142784
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In situ chromatin dynamics and HIV-1 nuclear traffickingPreprint
Hou, Z., Shen, Y., Chen, L., Shen, J., Stuart, D. I., & Zhang, P. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.12.693995
Relationship between the distribution of LEDGF along genes and positions of HIV-1 DNA integration
Pathak, R., Esnault, C., Radhakrishnan, R., Singh, P. K., Zhang, H., Dale, R., Anand, A., Mitra, A., Bedwell, G. J., Engelman, A., et al. (2026) · mBio · doi:10.1128/mbio.00090-26 · Cited by 2 · see citing works
Self-citationIdentification of specific phylogenetic properties of HIV-1 M and O integrases
Toccafondi, E. (2022) · doi:10.70675/2facab6ezc20az472dz8350z9fb6e718e1d4 · Cited by 1 · see citing works
Retroviral_integration_sites_distribution_across_gene_length.R
Singh, P. (2023) · Harvard Dataverse · doi:10.7910/dvn/au3kyv
Self-citationJang, S., Radhakrishnan, R., Greenwood, J., Singh, P. K., Bedwell, G. J., Robles‐Sikisaka, R., Routh, A. L., & Engelman, A. (2026) · mBio · doi:10.1128/mbio.02276-26
Self-citation
- Authors
- Li, W., Singh, P. K., Sowd, G. A., Bedwell, G. J., Jang, S., Achuthan, V., Oleru, A. V., Wong, D., Fadel, H. J., Lee, K., KewalRamani, V. N., Poeschla, E. M., Herschhorn, A., & Engelman, A. N.
- Affiliations
- Harvard University (US)
- Dana-Farber Cancer Institute (US)
- Mayo Clinic (US)
- Frederick National Laboratory for Cancer Research (US)
- University of Colorado Anschutz (US)
- Corresponding author
- Engelman, Alan N.
- ORCID
- Venue
- mBio
- Publisher
- American Society for Microbiology
- Published
- 2020-10-27
- Volume
- 11
- Issue
- 5
- ISSN
- 2150-7511 (ISSN-L)
- 2161-2129
- PMC
- PMC7527728
- OpenAlex
- W3090834913
- Cited by
- 64
- References
- 90
- Citations by year
- 2026: 6 · 2025: 13 · 2024: 11 · 2023: 7 · 2022: 13 · 2021: 13 · 2020: 1
- FWCI
- 4.61
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- mBio (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- HHS | NIH | National Institute of Allergy and Infectious Diseases (AI039394, AI052014, AI007386, AI060354)
- 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
- retroviral integration, CPSF6, LEDGF/p75, HIV-1, integration site mapping, host factors, HIV cure, chromatin targeting
- MeSH terms
- Animals, Cats, Cattle, Cell Line, Horses, Humans, Macaca mulatta, Primates, Virus Replication, Lentivirus, Virus Integration, Evolution, Molecular, Jurkat Cells, Intercellular Signaling Peptides and Proteins, mRNA Cleavage and Polyadenylation Factors, Mice, HEK293 Cells
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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