Non-neutralizing antibodies targeting the immunogenic regions of HIV-1 envelope reduce mucosal infection and virus burden in humanized mice—Hioe 2022

Vaccines produce antibodies to fight microbes. In the Thai RV144 HIV-1 vaccine trial, vaccination effectiveness was 31% and the only primary correlate of reduced risk was robust antibody response targeting the V1V2 region of HIV-1 envelope. Subsets of vaccinees had lower infection risk with V3 antibodies. However, antibodies identifying these areas do not neutralize. Thus, we passively administered human mAbs to humanized mice engrafted with CD34+ hematopoietic stem cells and then challenged them with an HIV-1 infectious molecular clone expressing the envelope of a tier 2 resistant HIV-1 strain. V3 mAb 2219 reduced virus burden better than V1V2 mAb 2158, but neither prevented infection. V3 mAb 2219 was better than V1V2 mAb 2158 at binding virus- and cell-associated HIV-1 envelope and mediating ADCP and C1q complement binding. 2219 Fc region mutations reduced effector activity in vitro and viral control in humanized animals. These findings show that antibodies without significant neutralizing activity need Fc activities other than ADCC.

Hioe, C. E., Li, G., Liu, X., Tsahouridis, O., He, X., Funaki, M., Klingler, J., Tang, A. F., Feyznezhad, R., Heindel, D. W., Wang, X. H., Spencer, D. A., Hu, G., Satija, N., Prévost, J., Finzi, A., Hessell, A. J., Wang, S., Lu, S., Chen, B. K., … Su, L. (2022). Non-neutralizing antibodies targeting the immunogenic regions of HIV-1 envelope reduce mucosal infection and virus burden in humanized mice. PLoS pathogens, 18(1), e1010183. https://doi.org/10.1371/journal.ppat.1010183