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

Abstract The HIV-1 envelope glycoprotein gp120 binds to 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 shown to resist HIV-1 infection despite co-expressing CD4 and co-receptors. In this study, we found that TNF receptor type II (TNFR2) directly bound to gp120, with the binding site on gp120 in close 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, similar in structure to TNFR2 and sharing 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 warrant future investigation. SUMMARY This study reveals that TNFR2 directly binds to HIV-1 gp120, inhibiting its interaction with CD4 and reducing HIV-1 infection in CD4+ T cells. The findings highlight TNFR2’s potential role in protecting cells and offer insights for HIV-1 prevention or therapy.