User:Amabotsi/P24 capsid protein

Introduction
P24 is the most abundant HIV protein with each virus containing approximately 1,500 to 3,000 p24 molecules. 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. Detection of p24 protein is used in various diagnostic assays, including antigen tests, to identify the presence of HIV in a person's blood. These tests are designed to detect viral antigens, such as p24, only in the acute phase of HIV infection. After approximately 50 days of infection, the p24 antigen is often cleared from the bloodstream entirely.

Structure


P24 has a molecular weight of 24kDa and is encoded by the gag gene. The structure of HIV capsid was formed by X-ray crystallography and cryo-electron microscopy. 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. The C-terminal domain (CTD) has 4 α-helices, and an 11-residue unstructured region. . The N-terminal domain (NTD) facilitates contacts within the hexamer, while the C-terminal domain (CTD) forms dimers that bind to adjacent Hexamers. 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, either opening or closing it. Stabilizing the hexamer, an IP6 molecule binds to the pore's center. Additionally, the C-terminal domain includes a Major Homology Region (MHR) spanning amino acids 153 to 172 with 20 highly conserved amino acids. Moreover, the N-terminal domain features a loop (amino acids 85–93) that interacts with cyclophilin A or 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. The role of p24 capsid protein can be identified in the different stages of the HIV replication process.


 * Fusion: HIV replication cycle begins when HIV fuses with the surface of the host cell. The capsid containing the virus’s genome and proteins then enters the cells.


 * Reverse transcription: The capsid ensures the secure transport of the viral genome and reverse-transcription machinery from the cytoplasm's periphery to transcriptionally active sites in the nucleus. It achieves this by shielding the viral genome from detection by restriction factors, while still allowing the necessary molecules to diffuse through the core, facilitating the process of reverse transcription.


 * Assembly: It is involved in the assembly of new virus particles, facilitating the proper organization of viral components.


 * Budding: P24 contributes to the viral budding process, ensuring the proper packaging and release of mature and infectious virus particles.

P24 HIV capsid as a therapeutic target

 * New Antiretroviral therapy

The HIV-1 p24 capsid protein plays crucial roles throughout the viral 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 operates 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. 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.


 * Vaccine design

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

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 (as well as 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 patient blood as early as 2 weeks after HIV infection, further reducing the window period necessary to accurately detect the HIV status of the patient.