P24 capsid protein

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The HIV capsid consists of roughly 2000 copies of the p24 protein. The p24 structure is shown in two representations: cartoon (top) and isosurface (bottom) P24 HIV-capsid.png
The HIV capsid consists of roughly 2000 copies of the p24 protein. The p24 structure is shown in two representations: cartoon (top) and isosurface (bottom)

The p24 capsid protein (CA) is the most abundant HIV protein with each virus containing approximately 1,500 to 3,000 p24 molecules. [1] It is the major structural protein within the capsid, and it is involved in maintaining the structural integrity of the virus and facilitating various stages of the viral life cycle, including viral entry into host cells and the release of new virus particles. [2] Detection of p24 protein's antigen can be used to identify the presence of HIV in a person's blood and diagnose HIV/AIDS, however, more modern tests have taken their place. [3] After approximately 50 days of infection, the p24 antigen is often cleared from the bloodstream entirely. [4]

Contents

Structure

Structure-of-HIV-1-capsid-A-The-structure-of-the-CA-monomer-showing-the-N and C-terminal domain Structure-of-HIV-1-capsid-A-The-structure-of-the-CA-monomer-showing-the-N-terminal (1).png
Structure-of-HIV-1-capsid-A-The-structure-of-the-CA-monomer-showing-the-N and C-terminal domain

P24 has a molecular weight of 24 kDa and is encoded by the gag gene. The structure of HIV capsid was determined by X-ray crystallography and cryo-electron microscopy. [5] The p24 capsid protein consists of two domains: the N-terminal domain and the C-terminal domain connected by flexible inter-domain linkers. The N-terminal domain (NTD) is made up of 7 α-helices (H) and β-hairpin. [6] [7] The C-terminal domain (CTD) has 4 α-helices and an 11-residue unstructured region. [8] [9] The N-terminal domain (NTD) facilitates contacts within the hexamer, while the C-terminal domain (CTD) forms dimers that bind to adjacent hexamers. [10] Each hexamer contains a size-selective pore surrounded by six positively charged arginine residues, and the pore is covered by a β-hairpin that can undergo conformational changes, which has both open and closed conformations. [11] At the center of the hexamers lies an IP6 molecule which stabilizes the tertiary structure of the molecule. Additionally, the C-terminal domain includes a major homology region (MHR) spanning amino acids 153 to 172 with 20 highly conserved amino acids. [11] Moreover, the N-terminal domain features a loop (amino acids 85–93) that interacts with the protein cyclophilin A (Cyp A).

Function

P24 is a structural protein that plays a crucial role in the formation and stability of the viral capsid, which protects the viral RNA. p24 capsid protein's roles in the HIV replicative process are summarized as follows:[ citation needed ]

p24 HIV capsid as a therapeutic target

New antiretroviral therapy

Cyclosporine, an immunosuppressant drug designed to prevent organ transplant rejection, has been shown to inhibit infection in HIV-1 positive people. [12] Cyclosporine acts as a competitive inhibitor to the capsid protein’s association with CypA, a cellular protein. CypA has been shown to be important for HIV’s infectivity.

The HIV-1 p24 capsid protein plays crucial roles throughout the replication cycle, making it an attractive therapeutic target. Unlike the viral enzymes (protease, reverse transcriptase and integrase) that are currently targeted by small-molecule antiretroviral drugs, p24 capsid proteins operate through protein-protein interactions. Capsid inhibitors, such as Lenacapavir and GS-6207, interfere with the activities of the HIV capsid protein and underwent evaluation in phase-1 clinical trials as monotherapies. [13] [14] They demonstrated anti-viral activity against all subtypes with no cross-resistance with current antiretroviral drugs. [13] [14] These findings support therapies aimed at disrupting the functions of the HIV capsid protein. [15]

Vaccine design

P24 can induce cellular immune responses and has been included in some vaccine strategies. [3]

Diagnosis

Fourth generation-HIV test

P24 is a target for the immune system, and antibodies against p24 are used in diagnostic tests to detect the presence of HIV antibodies. Fourth-generation HIV immunoassays detect viral p24 protein in the blood and patient antibodies against the virus. Previous generation tests relied on detecting patient antibodies alone; it takes about 3–4 weeks for the earliest antibodies to be detected. The p24 protein can be detected in a patient's blood as early as 2 weeks after infection, further reducing the window period necessary to accurately detect the HIV status of the patient. [16]

In other retroviruses

Retrovirus capsid, N-terminal
Identifiers
Symbol?
InterPro IPR008919
Retrovirus capsid, C-terminal
Identifiers
Symbol?
InterPro IPR008916

All retroviruses have an orthologous capsid protein denoted by the two-letter symbol CA. [17]

See also

References

  1. Summers MF, Henderson LE, Chance MR, Bess JW, South TL, Blake PR, et al. (May 1992). "Nucleocapsid zinc fingers detected in retroviruses: EXAFS studies of intact viruses and the solution-state structure of the nucleocapsid protein from HIV-1". Protein Science. 1 (5): 563–574. doi:10.1002/pro.5560010502. PMC   2142235 . PMID   1304355.
  2. Rossi E, Meuser ME, Cunanan CJ, Cocklin S (January 2021). "Structure, Function, and Interactions of the HIV-1 Capsid Protein". Life. 11 (2): 100. Bibcode:2021Life...11..100R. doi: 10.3390/life11020100 . PMC   7910843 . PMID   33572761.
  3. 1 2 Larijani MS, Sadat SM, Bolhassani A, Pouriayevali MH, Bahramali G, Ramezani A (2019). "In Silico Design and Immunologic Evaluation of HIV-1 p24-Nef Fusion Protein to Approach a Therapeutic Vaccine Candidate". Current HIV Research. 16 (5): 322–337. doi:10.2174/1570162x17666190102151717. PMC   6446525 . PMID   30605062.
  4. Hurt CB, Nelson JA, Hightow-Weidman LB, Miller WC (December 2017). "Selecting an HIV Test: A Narrative Review for Clinicians and Researchers". Sexually Transmitted Diseases. 44 (12): 739–746. doi:10.1097/OLQ.0000000000000719. PMC   5718364 . PMID   29140890.
  5. Zhao G, Perilla JR, Yufenyuy EL, Meng X, Chen B, Ning J, et al. (May 2013). "Mature HIV-1 capsid structure by cryo-electron microscopy and all-atom molecular dynamics". Nature. 497 (7451): 643–646. Bibcode:2013Natur.497..643Z. doi:10.1038/nature12162. PMC   3729984 . PMID   23719463.
  6. Gitti RK, Lee BM, Walker J, Summers MF, Yoo S, Sundquist WI (July 1996). "Structure of the amino-terminal core domain of the HIV-1 capsid protein". Science. 273 (5272): 231–235. Bibcode:1996Sci...273..231G. doi:10.1126/science.273.5272.231. PMID   8662505. S2CID   5960953.
  7. Momany C, Kovari LC, Prongay AJ, Keller W, Gitti RK, Lee BM, et al. (September 1996). "Crystal structure of dimeric HIV-1 capsid protein". Nature Structural Biology. 3 (9): 763–770. doi:10.1038/nsb0996-763. PMID   8784350. S2CID   33672057.
  8. Du S, Betts L, Yang R, Shi H, Concel J, Ahn J, et al. (February 2011). "Structure of the HIV-1 full-length capsid protein in a conformationally trapped unassembled state induced by small-molecule binding". Journal of Molecular Biology. 406 (3): 371–386. doi:10.1016/j.jmb.2010.11.027. PMC   3194004 . PMID   21146540.
  9. Gamble TR, Yoo S, Vajdos FF, von Schwedler UK, Worthylake DK, Wang H, et al. (October 1997). "Structure of the carboxyl-terminal dimerization domain of the HIV-1 capsid protein". Science. 278 (5339): 849–853. Bibcode:1997Sci...278..849G. doi:10.1126/science.278.5339.849. PMID   9346481.
  10. Tan A, Pak AJ, Morado DR, Voth GA, Briggs JA (January 2021). "Immature HIV-1 assembles from Gag dimers leaving partial hexamers at lattice edges as potential substrates for proteolytic maturation". Proceedings of the National Academy of Sciences of the United States of America. 118 (3). Bibcode:2021PNAS..11820054T. doi: 10.1073/pnas.2020054118 . PMC   7826355 . PMID   33397805.
  11. 1 2 Obr M, Kräusslich HG (July 2018). "The secrets of the stability of the HIV-1 capsid". eLife. 7: e38895. doi: 10.7554/eLife.38895 . PMC   6067877 . PMID   30063007.
  12. Sokolskaja, Elena; Olivari, Silvia; Zufferey, Madeleine; Strambio-De-Castillia, Caterina; Pizzato, Massimo; Luban, Jeremy (May 2010). "Cyclosporine Blocks Incorporation of HIV-1 Envelope Glycoprotein into Virions". Journal of Virology. 84 (9): 4851–4855. doi:10.1128/JVI.01699-09. ISSN   0022-538X. PMC   2863729 . PMID   20181694.
  13. 1 2 Link JO, Rhee MS, Tse WC, Zheng J, Somoza JR, Rowe W, et al. (August 2020). "Clinical targeting of HIV capsid protein with a long-acting small molecule". Nature. 584 (7822): 614–618. Bibcode:2020Natur.584..614L. doi:10.1038/s41586-020-2443-1. PMC   8188729 . PMID   32612233.
  14. 1 2 Dvory-Sobol H, Shaik N, Callebaut C, Rhee MS (January 2022). "Lenacapavir: a first-in-class HIV-1 capsid inhibitor". Current Opinion in HIV and AIDS. 17 (1): 15–21. doi: 10.1097/COH.0000000000000713 . PMID   34871187. S2CID   244940471.
  15. Lang, Stuart (2025-06-18). "Understanding the HIV-CA protein and the ligands that bind at the N-terminal domain (NTD) - C-terminal domain (CTD) interface". RSC Medicinal Chemistry. 16 (6): 2373–2387. doi:10.1039/D5MD00111K. ISSN   2632-8682. PMC   12018806 . PMID   40291137.
  16. Constantine N (February 1998). "HIV Antibody Assays". HIV InSite Knowledge Base. Archived from the original on 2001-06-25 via hivinsite.ucsf.edu.
  17. Perilla, JR; Gronenborn, AM (May 2016). "Molecular Architecture of the Retroviral Capsid". Trends in biochemical sciences. 41 (5): 410–420. doi:10.1016/j.tibs.2016.02.009. PMC   4879823 . PMID   27039020.

Further reading