HIV-1 Vpu restricts Fc-mediated effector functions in vivo—Prevost 2022

In the RV144 vaccine experiment, nnAbs were found to protect against HIV-1 infection via antibody-dependent cellular cytotoxicity (ADCC). Using a vpu-defective virus, nnAb Fc-mediated effector activities altered HIV-1 infection in vivo. We wondered if the lack of Vpu expression was linked to the observed nnAbs activity as Vpu downregulates cell-surface CD4, which causes conformational changes in the viral envelope glycoprotein (Env). Restoring Vpu expression lowers nnAb recognition of infected cells, making them ADCC-resistant. In humanized mice infected with a vpu-defective virus, nnAbs lower viral loads, but not wild-type viruses. CD4-mimetics "open" Env and reveal nnAb epitopes, making wild-type viruses vulnerable to Fc-effector activities. This study emphasizes Vpu-mediated humoral response avoidance.

Prévost, J., Anand, S. P., Rajashekar, J. K., Zhu, L., Richard, J., Goyette, G., Medjahed, H., Gendron-Lepage, G., Chen, H. C., Chen, Y., Horwitz, J. A., Grunst, M. W., Zolla-Pazner, S., Haynes, B. F., Burton, D. R., Flavell, R. A., Kirchhoff, F., Hahn, B. H., Smith, A. B., 3rd, Pazgier, M., … Finzi, A. (2022). HIV-1 Vpu restricts Fc-mediated effector functions in vivo. Cell reports, 41(6), 111624. https://doi.org/10.1016/j.celrep.2022.111624