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Updated: Jul 16, 2026
Stem-cell Based Engineered Immunity Against HIV Infection in the Humanized Mouse Model
Published on: July 2, 2016
A human mutant CD4 molecule resistant to HIV-1 binding restores helper T-lymphocyte functions in murine CD4-deficient
Dong-Ku Kim1, Satoko Tahara-Hanaoka, Tahara-Hanaoka Satoko
1Cell and Gene Therapy Research Institute, College of Medicine, Pochon CHA University, CHA General Hospital, Seoul 135-081, Korea. dokukim@cha.ac.kr
Insights
Engineered CD4 (muthCD4) resistant to HIV-1 binding can still support T cell development and function in mice. This finding offers potential for new HIV treatment strategies.
Area of Science:
- Immunology
- Virology
- Molecular Biology
Background:
- CD4 glycoprotein is crucial for T cell receptor signaling and serves as the primary receptor for HIV-1 entry via gp120 binding.
- Previous studies showed mutations in CD4 abolish HIV-1 gp120 binding, preventing viral entry.
- The impact of these mutations on CD4's natural function, specifically its binding to MHC molecules and overall T cell activity, remained unclear.
Purpose of the Study:
- To investigate whether mutations rendering CD4 resistant to HIV-1 binding affect its interaction with MHC molecules and its essential functions in T cell development and signaling.
- To assess the in vivo functionality of a mutant human CD4 (muthCD4) in a mouse model lacking endogenous CD4.
Main Methods:
- Generated transgenic mouse lines expressing a mutant human CD4 (muthCD4) gene.
- Utilized CD4-enhancer/promoter for tissue-specific expression.
- Crossed transgenic mice with CD4-knockout mice (muthCD4TG/KO) to eliminate endogenous murine CD4 influence.
- Analyzed T lymphocyte development, maturation, and function in the thymus, spleen, and lymph nodes.
Main Results:
- Transgenic mice expressing muthCD4 (muthCD4TG/KO) exhibited normal T lymphocyte expansion and maturation in the thymus.
- Mature T lymphocytes expressing muthCD4 were detected in peripheral lymphoid organs (spleen and lymph nodes).
- These T cells demonstrated functional capacity, including B cell activation and antibody response to a T-dependent antigen.
Conclusions:
- A human CD4 variant modified for HIV-1 resistance (muthCD4) can effectively restore T cell development and helper T cell functions in vivo.
- This suggests that CD4's role in T cell signaling is largely preserved despite modifications aimed at blocking HIV-1 binding.
- Further research into muthCD4 molecules could pave the way for novel therapeutic approaches to HIV infection.
Abstract:
CD4 is a cell surface glycoprotein that acts as a co-receptor for the T cell antigen receptor by binding to a non-polymorphic portion of MHC molecules. CD4 also functions as a receptor for human immunodeficiency virus type-I (HIV-1) because the viral envelope glycoprotein gp120 binds to CD4 with a high affinity. We have previously demonstrated that introduction of mutations into CD4 abolished the binding of gp120 and prevented HIV-1 from entering cells and spreading. However, whether introduction of such mutations into CD4 causes decreased binding to MHC and loss of function is yet to be determined. We generated transgenic mouse lines by injecting a mutant human CD4 (muthCD4) gene under a murine CD4 enhancer/promoter to ensure tissue and stage specific expression. To exclude the influence of endogenous murine CD4, transgenic mice were crossed with murine CD4-targeted mice to produce muthCD4 transgenic mice lacking endogenous CD4 (muthCD4TG/KO mice). In these mice, T lymphocytes expressing muthCD4 expanded and matured in the thymus and were present in the spleen and lymph nodes. They also activated B cells to mount an antibody response to a T-dependent antigen. The results from this study suggest that a human variant of CD4 modified to be resistant to HIV-1 binding can rescue the signaling for T cell development in the thymus in vivo, having helper T cell functions. Thus, further characterization of muthCD4 molecules should open the way to new HIV treatment modalities.
