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T-cell surface glycoprotein CD4 (CD4) is a critical co-receptor predominantly expressed on helper T cells, regulatory T cells, and monocytes, where it facilitates antigen recognition and immune signaling. It functions by binding to the non-polymorphic region of Major Histocompatibility Complex (MHC) class II molecules on antigen-presenting cells, which stabilizes the interaction with the T-cell receptor (TCR) and recruits the tyrosine kinase Lck to initiate intracellular signaling cascades [1][2]. Beyond its physiological role in the adaptive immune response, CD4 is well-known as the primary entry receptor for Human Immunodeficiency Virus type 1 (HIV-1) and type 2 (HIV-2), as well as Human Herpesvirus 6 (HHV-6) [3][6]. The interaction between the viral gp120 protein and CD4 is the initial step in the viral infection cycle, making it a major focus of antiviral research. Therapeutic agents targeting CD4, such as the monoclonal antibody Ibalizumab, have been approved for treating multi-drug resistant HIV by blocking viral entry without causing significant immunosuppression [4]. Additionally, anti-CD4 antibodies like Zanolimumab have been investigated for the treatment of cutaneous T-cell lymphomas and autoimmune disorders like rheumatoid arthritis [5][9]. CD4+ T-cell counts remain the gold-standard biomarker for monitoring disease progression and immune status in HIV-infected individuals [8].
CD4-directed post-attachment HIV-1 inhibition, viral entry blockade, MHC class II binding inhibition, T-cell signaling modulation, and antibody-dependent cellular cytotoxicity (ADCC) in T-cell lymphomas.
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