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CD4 immunoadhesin is a recombinant fusion protein consisting of a combination of CD4 and the fragment crystallizable region, similarly known as immunoglobulin. It belongs to the antibody (Ig) gene family. CD4 is a surface receptor for human immunodeficiency virus (HIV). The CD4 immunoadhesin molecular fusion allow the protein to possess key functions from each independent subunit. The CD4 specific properties include the gp120-binding and HIV-blocking capabilities. Properties specific to immunoglobulin are the long plasma half-life and Fc receptor binding. The properties of the protein means that it has potential to be used in AIDS therapy as of 2017. Specifically, CD4 immunoadhesin plays a role in antibody-dependent cell-mediated cytotoxicity (ADCC) towards HIV-infected cells. While natural anti-gp120 antibodies exhibit a response towards uninfected CD4-expressing cells that have a soluble gp120 bound to the CD4 on the cell surface, CD4 immunoadhesin will not exhibit a response. One of the most relevant of these possibilities is its ability to cross the placenta.

History and significance

CD4 immunoadhesin was first developed in the mid-1990s as a potential therapeutic agent for HIV/AIDS. The protein is a fusion of the extracellular domain of the CD4 receptor and the Fc domain of human immunoglobulin G (IgG), which is the most abundant antibody isotype in the human body. The Fc domain of IgG confers several important properties to the fusion protein, including increased half-life in the bloodstream, enhanced binding to Fc receptors on immune cells, and the ability to activate complement.

The development of CD4 immunoadhesin was based on the observation that the CD4 receptor plays a critical role in the entry of HIV into human cells. HIV uses the CD4 receptor as a primary receptor to attach to the surface of target cells, and then uses a co-receptor, either CCR5 or CXCR4, to facilitate entry into the cell. By blocking the interaction between the CD4 receptor and HIV, CD4 immunoadhesin was hoped to prevent the virus from entering and infecting human cells.

CD4 immunoadhesin has been extensively studied in preclinical and clinical trials as a potential treatment for HIV/AIDS. In addition to its antiviral activity, CD4 immunoadhesin has also been investigated for its potential immunomodulatory effects. For example, the fusion protein has been shown to induce the production of cytokines, such as interleukin-2 (IL-2) and interferon-gamma (IFN-γ), which are important for the activation and proliferation of immune cells.

Despite its potential as a therapeutic agent, the development of CD4 immunoadhesin has faced several challenges. One major obstacle is the emergence of drug-resistant strains of HIV, which can limit the effectiveness of CD4 immunoadhesin in certain patients. Additionally, the need for frequent dosing and the potential for immune responses against the fusion protein have also limited the clinical application of CD4 immunoadhesin.

Nevertheless, CD4 immunoadhesin remains an important tool for understanding the biology of HIV and the mechanisms of viral entry. The protein has also inspired the development of other immunoadhesin molecules, such as CD4-IgG2 and CD4-mimetic compounds, which are being investigated as potential therapies for HIV/AIDS.

Structure and function

CD4 immunoadhesin is a bifunctional protein that has the ability to block HIV infection, inhibit autoreactive T-cell activation, and potentially modulate immune responses. Its structure, which consists of the extracellular domain of CD4 and the Fc region of IgG1, allows for soluble circulation throughout the body.

The extracellular domain of CD4 contains four immunoglobulin-like domains (D1-D4), which are responsible for binding to the major histocompatibility complex (MHC) class II molecules on antigen-presenting cells. The Fc region of IgG1 is responsible for mediating effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC) and complement activation.

CD4-Ig works by mimicking the binding of CD4 to HIV, thereby preventing the virus from infecting T-helper cells. HIV infects T-helper cells by binding to the CD4 receptor and the co-receptor CCR5 or CXCR4. CD4-Ig binds to the viral envelope glycoprotein gp120, which is responsible for HIV binding to CD4. By binding to gp120, CD4-Ig prevents the virus from binding to the CD4 receptor on T-helper cells, thus preventing infection.

CD4-Ig has also been investigated as a potential treatment for other diseases that involve immune dysregulation, such as multiple sclerosis and rheumatoid arthritis. In these diseases, CD4-Ig may work by inhibiting the activation of autoreactive T-cells. CD4-Ig binds to MHC class II molecules on antigen-presenting cells, thereby preventing the activation of T-helper cells that are specific for self-antigens.

In addition to its role in blocking HIV infection and inhibiting autoreactive T-cell activation, CD4-Ig may also have immunomodulatory effects. CD4 is known to be involved in the regulation of immune responses, and CD4-Ig may therefore have the ability to modulate immune responses in a way that is beneficial for the treatment of various diseases.

CD4 immunoadhesin functions by blocking the interaction between the HIV envelope glycoprotein (gp120) and the CD4 receptor on the surface of CD4-positive cells. By binding to gp120, CD4 immunoadhesin prevents the virus from attaching to and entering host cells, thus inhibiting the spread of HIV infection. CD4 immunoadhesin has been shown to be effective in vitro and in animal models of HIV infection, and has been used in clinical trials as a potential treatment for HIV/AIDS.

Clinical applications

CD4 immunoadhesin has been studied extensively in preclinical and clinical trials as a potential treatment for HIV/AIDS. In a phase I/II clinical trial, CD4 immunoadhesin was found to be safe and well-tolerated in HIV-positive patients, and was able to reduce viral load in some patients. However, the development of CD4 immunoadhesin as a therapeutic agent for HIV/AIDS has been hampered by several factors, including the emergence of drug-resistant strains of HIV, the need for frequent dosing, and the potential for immune responses against the fusion protein.

In a phase I/II clinical trial conducted by the National Institute of Allergy and Infectious Diseases (NIAID), 25 HIV-positive patients received intravenous infusions of CD4 immunoadhesin over a period of 12 weeks. The trial found that CD4 immunoadhesin was safe and well-tolerated in all patients, with no serious adverse events reported. Additionally, some patients showed a reduction in viral load, although the effect was not sustained after the end of the treatment period.

Despite these promising results, the development of CD4 immunoadhesin as a therapeutic agent for HIV/AIDS has faced several challenges. One major obstacle is the emergence of drug-resistant strains of HIV, which can limit the effectiveness of CD4 immunoadhesin in certain patients. Additionally, the need for frequent dosing and the potential for immune responses against the fusion protein have also limited the clinical application of CD4 immunoadhesin.

To address these challenges, researchers have explored various strategies to improve the efficacy and safety of CD4 immunoadhesin. For example, some studies have investigated the use of CD4 immunoadhesin in combination with other antiretroviral therapies to enhance the antiviral effect and reduce the risk of drug resistance. Other studies have focused on engineering CD4 immunoadhesin variants with improved pharmacokinetic properties and reduced immunogenicity.

Classification

CD4 immunoadhesin is a recombinant protein designed to mimic the extracellular portion of the CD4 receptor. The CD4 receptor belongs to the immunoglobulin superfamily and is composed of four extracellular domains (D1-D4), a transmembrane domain, and a cytoplasmic tail. The extracellular domains of CD4 are responsible for binding to the major histocompatibility complex (MHC) class II molecules on antigen-presenting cells, which is essential for the activation of T helper cells.

CD4 immunoadhesin is classified as a fusion protein, which is a type of recombinant protein that combines two or more proteins into a single molecule. In the case of CD4 immunoadhesin, the protein consists of the extracellular domains of the CD4 receptor fused to the constant region of the human immunoglobulin G (IgG) antibody. This fusion allows CD4 immunoadhesin to bind to the HIV envelope glycoprotein and block viral entry into host cells.

The use of immunoadhesins as therapeutic agents is a relatively new field, and several other immunoadhesins have been developed for various clinical applications. For example, a fusion protein consisting of the extracellular domain of the human epidermal growth factor receptor (HER2) and the Fc portion of human IgG has been approved for the treatment of breast cancer. Another fusion protein, consisting of the extracellular domain of the interleukin-4 receptor alpha subunit (IL-4Rα) and the Fc portion of human IgG, has shown promise as a potential treatment for asthma.

CD4 immunoadhesin is unique in its ability to bind to the HIV envelope glycoprotein and block viral entry, making it an important tool for understanding the biology of HIV and developing new treatments for the virus. However, the clinical application of CD4 immunoadhesin has faced several challenges, including its short half-life in vivo and the development of resistance by the virus.