Tumor Necrosis Factor Receptor 2 Inhibits HIV-1 Infection by Blocking the Binding of gp120 to CD4

The HIV-1 envelope glycoprotein gp120 binds to the CD4 molecule and then undergoes conformational changes to interact with the co-receptors CCR5 or CXCR4, resulting in cellular entrance. However, certain types of cells, such as macrophages and CD4⁺Foxp3⁺ regulatory T cells (Tregs), have been shown to resist HIV-1 infection despite co-expressing CD4 and co-receptors. In this study, we found that tumor necrosis factor receptor type II (TNFR2) directly binds to gp120, with the binding site on gp120 in proximity to that of CD4. Intriguingly, exogenous TNFR2 had the capacity to inhibit the binding of gp120 to CD4⁺ T cells. Furthermore, the infection of CD4⁺CCR5⁺ cells by pseudoviruses containing the HIV-1 envelope was inhibited by TNFR2 protein. In contrast, TNFR1, which is structurally similar to TNFR2 and shares the same ligand, failed to inhibit the infection of CD4⁺ T cells by HIV-1 pseudoviruses. This property of TNFR2 may be harnessed in the prevention or treatment of HIV-1 infection and thus warrants future investigation.