Abstract
The core of HIV-1 viruses bearing the capsid change N74D (HIV-1-N74D) do not bind the human protein CPSF6. In primary human CD4+ T cells, HIV-1-N74D viruses exhibit an infectivity defect when compared to wild-type. We first investigated whether loss of CPSF6 binding accounts for the loss of infectivity. Depletion of CPSF6 in human CD4+ T cells did not affect the early stages of wild-type HIV-1 replication, suggesting that defective infectivity in the case of HIV-1-N74D viruses is not due to the loss of CPSF6 binding. Based on our previous result that cyclophilin A (Cyp A) protected HIV-1 from human tripartite motif-containing protein 5α (TRIM5αhu ) restriction in CD4+ T cells, we found that depletion of TRIM5αhu in CD4+ T cells rescued the infectivity of HIV-1-N74D, suggesting that HIV-1-N74D cores interacted with TRIM5αhu . Accordingly, TRIM5αhu binding to HIV-1-N74D cores was increased compared with that of wild-type cores, and consistently, HIV-1-N74D cores lost their ability to bind Cyp A. In agreement with the notion that N74D capsids are defective in their ability to bind Cyp A, we found that HIV-1-N74D viruses were 20-fold less sensitive to TRIMCyp restriction when compared to wild-type viruses in OMK cells. Structural analysis revealed that N74D hexameric capsid protein in complex with PF74 is different from wild-type hexameric capsid protein in complex with PF74, which explains the defect of N74D capsids to interact with Cyp A. In conclusion, we showed that the decreased infectivity of HIV-1-N74D in CD4+ T cells is due to a loss of Cyp A protection from TRIM5αhu restriction activity.
Original language | English (US) |
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Article number | 363 |
Journal | Viruses |
Volume | 14 |
Issue number | 2 |
DOIs | |
State | Published - Feb 2022 |
Funding
Funding: This research was funded by NIH grants AI087390, AI120860, AI150472, GM124169-01, GM138396, GM082250, AI117943, AI165236 and AI150998. This research was also funded by the NCI grant ACB-12002. Acknowledgments: We thank Anna T. Gres for her important leadership role in the early stages of the N74D structural work. Recombinant Cyp A was kindly provided by Owen Pornillos (Univ. of Virginia). We are grateful of the NIH AIDS repository for reagents. We also acknowledge funding from the Nahmias-Schinazi Distinguished Chair in Research. X-ray diffraction data were collected at beamline 4.2.2 of the Advanced Light Source, a U.S. DOE Office of Science User Facility under Contract No. DE-AC02-05CH11231, which is supported in part by the ALS-ENABLE program funded by the National Institutes of Health. X-ray diffraction data were also collected at GM/CA@APS beamline 23-ID-D, which has been funded by the National Cancer Institute. The Advanced Photon Source (APS), a U.S. Department of Energy (DOE) Office of Science User Facility is operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357.
Keywords
- CPSF6
- Capsid
- Core
- HIV-1
- N74D
- Restriction
- TRIM5α
ASJC Scopus subject areas
- Infectious Diseases
- Virology
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Dive into the research topics of 'TRIM5α Restriction of HIV-1-N74D Viruses in Lymphocytes Is Caused by a Loss of Cyclophilin A Protection'. Together they form a unique fingerprint.Datasets
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N74D mutant of the HIV-1 capsid protein in complex with PF-3450074 (PF74)
Selyutina, A. (Contributor), Simons, L. M. (Contributor), Kirby, K. A. (Contributor), Bulnes-Ramos, A. (Contributor), Hu, P. (Contributor), Sarafianos, S. G. (Contributor), Hultquist, J. F. (Contributor) & Diaz-Griffero, F. (Contributor), Protein Data Bank (PDB), May 4 2022
DOI: 10.2210/pdb7MKC/pdb, https://www.wwpdb.org/pdb?id=pdb_00007mkc
Dataset
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N74D mutant of the HIV-1 capsid protein
Selyutina, A. (Contributor), Simons, L. M. (Contributor), Kirby, K. A. (Contributor), Bulnes-Ramos, A. (Contributor), Hu, P. (Contributor), Sarafianos, S. G. (Contributor), Hultquist, J. F. (Contributor) & Diaz-Griffero, F. (Contributor), Protein Data Bank (PDB), May 4 2022
DOI: 10.2210/pdb7MN0/pdb, https://www.wwpdb.org/pdb?id=pdb_00007mn0
Dataset