Role of Human CD4 D1D2 Domain in HIV-1 Infection

Abstract

Broadly neutralizing antibodies and appropriate immunogens are critical for preexposure prophylaxis and therapeutic HIV vaccines. In this study, we aimed to explore effective antibodies against the genetically diverse HIV-1 strains by investigating the roles of human CD4 D1D2 domain and nonvariable immugens. The human CD4 D1D2 domain and the chimeric protein of mouse D1 domain/human D2 domain were expressed in Sf9 insect cells and purified by gel-filtration chromatography. The human CD4 D1D2 domain potently inhibited the infection of 77.8% HIV-1 pseudoviruses, including the clades AE, B' and BC, with less than 20 μg/mL of IC(50). pcDNA3.1-mhD1D2m and pcDNA3.1-mhD2m plasmids were used for the production of mouse anti-human CD4 polyclonal antibodies. The neutralizing activities of the polyclonal antibodies were determined by using pseudotyped HIV-1 viruses. The antibodies induced by plasmids containing human CD4 D1D2 domain were able to potently inhibit all pseudotyped HIV-1 strains. The antibodies from mhD1D2m-immunized mice also showed strong binding capacity to CD4 expressed on the surface of TZM-bl cells. The potent and broad inhibitory activity of antibodies against the human CD4 D1D2 domain may be used to develop effective passive immunization agent to control the spread of HIV infection.

HIV-1 gp41-targeting fusion inhibitory peptides enhance the gp120-targeting protein-mediated inactivation of HIV-1 virions

“…8 D1D2, the first two domains of CD4, were subsequently investigated as an anti-HIV-1 drug candidate. The HIV-1 inhibitory activity of D1D2 is high, 9 but its stability is low, and it binds to CD4 + T cells and human B cells in the absence of HIV-1. 10 To overcome these disadvantages, we developed mD1.22, which comprises the first single domain of D1D2 and is stable in isolation and highly soluble.…”

Generation and characterization of humanization CD4 knock-in mice expressing chimeric mouse/human CD4 protein

“…Speci cally, the extracellular domains 1 (D1) and 2 (D2) of the CD4 glycoprotein hold a pivotal position in this process, as they interact with the β2 domain of MHC class II, thereby stabilizing the MHC-TCR complex interaction and nely regulating the activation of CD4 + T cells [9][10][11] . Moreover, these extracellular domains of the CD4 glycoprotein serve as critical targets in human immunode ciency virus (HIV) infection [12][13][14] . Therefore, understanding the intricate molecular interactions between these domains and MHC class II molecules bears signi cant importance in the eld of molecular immunology, as it holds the potential to inform the development of promising therapeutic strategies and elucidate the underlying pathological mechanisms of immunerelated diseases.…”

Anti-CD4: An Alternative Way to Inhibit HIV Infection

“…This saw there placement of the Mu5A8 CDR region with human IgG4, and mutations to amino acids in the FR region, which resulted in 95% humanization of ibalizumab and its a remarkably long half-life [9]. The epitope of ibalizumab sits mainly on the D2domain of CD4-residues P121, P122, and Q163-with contribution from residue E77 and probably S79 and L96 of the D1 domain [25]. This epitope does not interfere with gp120 binding to CD4.…”