P24 capsid protein explained

The P24 capsid protein 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, 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]

Structure

P24 has a molecular weight of 24kDa 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. 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:

P24 HIV capsid as a therapeutic target

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. These findings support therapies aimed at disrupting the functions of the HIV capsid protein.

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

See also

HIV vaccine

Diagnosis

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.[15]

Further reading

Notes and References

  1. Summers MF, Henderson LE, Chance MR, Bess JW, South TL, Blake PR, Sagi I, Perez-Alvarado G, Sowder RC, Hare DR . 6 . 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 . May 1992 . 1304355 . 2142235 . 10.1002/pro.5560010502 .
  2. Rossi E, Meuser ME, Cunanan CJ, Cocklin S . Structure, Function, and Interactions of the HIV-1 Capsid Protein . Life . 11 . 2 . 100 . January 2021 . 33572761 . 7910843 . 10.3390/life11020100 . free . 2021Life...11..100R .
  3. Larijani MS, Sadat SM, Bolhassani A, Pouriayevali MH, Bahramali G, Ramezani A . 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 . 2019 . 30605062 . 6446525 . 10.2174/1570162x17666190102151717 .
  4. Hurt CB, Nelson JA, Hightow-Weidman LB, Miller WC . Selecting an HIV Test: A Narrative Review for Clinicians and Researchers . en-US . Sexually Transmitted Diseases . 44 . 12 . 739–746 . December 2017 . 29140890 . 5718364 . 10.1097/OLQ.0000000000000719 .
  5. Zhao G, Perilla JR, Yufenyuy EL, Meng X, Chen B, Ning J, Ahn J, Gronenborn AM, Schulten K, Aiken C, Zhang P . 6 . Mature HIV-1 capsid structure by cryo-electron microscopy and all-atom molecular dynamics . Nature . 497 . 7451 . 643–646 . May 2013 . 23719463 . 3729984 . 10.1038/nature12162 . 2013Natur.497..643Z .
  6. Gitti RK, Lee BM, Walker J, Summers MF, Yoo S, Sundquist WI . Structure of the amino-terminal core domain of the HIV-1 capsid protein . Science . 273 . 5272 . 231–235 . July 1996 . 8662505 . 10.1126/science.273.5272.231 . 5960953 . 1996Sci...273..231G .
  7. Momany C, Kovari LC, Prongay AJ, Keller W, Gitti RK, Lee BM, Gorbalenya AE, Tong L, McClure J, Ehrlich LS, Summers MF, Carter C, Rossmann MG . 6 . Crystal structure of dimeric HIV-1 capsid protein . Nature Structural Biology . 3 . 9 . 763–770 . September 1996 . 8784350 . 10.1038/nsb0996-763 . 33672057 .
  8. Du S, Betts L, Yang R, Shi H, Concel J, Ahn J, Aiken C, Zhang P, Yeh JI . 6 . 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 . February 2011 . 21146540 . 3194004 . 10.1016/j.jmb.2010.11.027 .
  9. Gamble TR, Yoo S, Vajdos FF, von Schwedler UK, Worthylake DK, Wang H, McCutcheon JP, Sundquist WI, Hill CP . 6 . Structure of the carboxyl-terminal dimerization domain of the HIV-1 capsid protein . Science . 278 . 5339 . 849–853 . October 1997 . 9346481 . 10.1126/science.278.5339.849 . 1997Sci...278..849G .
  10. Tan A, Pak AJ, Morado DR, Voth GA, Briggs JA . 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 . January 2021 . 33397805 . 7826355 . 10.1073/pnas.2020054118 . 2021PNAS..11820054T . free .
  11. Obr M, Kräusslich HG . The secrets of the stability of the HIV-1 capsid . eLife . 7 . e38895 . July 2018 . 30063007 . 6067877 . 10.7554/eLife.38895 . free .
  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 . en . 84 . 9 . 4851–4855 . 10.1128/JVI.01699-09 . 0022-538X . 2863729 . 20181694.
  13. Link JO, Rhee MS, Tse WC, Zheng J, Somoza JR, Rowe W, Begley R, Chiu A, Mulato A, Hansen D, Singer E, Tsai LK, Bam RA, Chou CH, Canales E, Brizgys G, Zhang JR, Li J, Graupe M, Morganelli P, Liu Q, Wu Q, Halcomb RL, Saito RD, Schroeder SD, Lazerwith SE, Bondy S, Jin D, Hung M, Novikov N, Liu X, Villaseñor AG, Cannizzaro CE, Hu EY, Anderson RL, Appleby TC, Lu B, Mwangi J, Liclican A, Niedziela-Majka A, Papalia GA, Wong MH, Leavitt SA, Xu Y, Koditek D, Stepan GJ, Yu H, Pagratis N, Clancy S, Ahmadyar S, Cai TZ, Sellers S, Wolckenhauer SA, Ling J, Callebaut C, Margot N, Ram RR, Liu YP, Hyland R, Sinclair GI, Ruane PJ, Crofoot GE, McDonald CK, Brainard DM, Lad L, Swaminathan S, Sundquist WI, Sakowicz R, Chester AE, Lee WE, Daar ES, Yant SR, Cihlar T . 6 . Clinical targeting of HIV capsid protein with a long-acting small molecule . Nature . 584 . 7822 . 614–618 . August 2020 . 32612233 . 8188729 . 10.1038/s41586-020-2443-1 . 2020Natur.584..614L .
  14. Dvory-Sobol H, Shaik N, Callebaut C, Rhee MS . Lenacapavir: a first-in-class HIV-1 capsid inhibitor . Current Opinion in HIV and AIDS . 17 . 1 . 15–21 . January 2022 . 34871187 . 10.1097/COH.0000000000000713 . 244940471 . free .
  15. Web site: February 1998 . HIV Antibody Assays . dead . https://web.archive.org/web/20010625032219/http://hivinsite.ucsf.edu/InSite.jsp?page=kb-02-02-01 . 2001-06-25 . HIV InSite Knowledge Base . hivinsite.ucsf.edu . Constantine N.

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