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A Nonneutralizing Anti-HIV-1 Antibody Turns into a Neutralizing Antibody When Expressed on the Surface of HIV-1-Susceptible Cells: A New Way to Fight HIV¹

Seung-Jae Lee^*, Laura Garza^*, Jun Yao^*, Abner L. Notkins and Paul Zhou^2,*

^* Department of Virology and Immunology, Southwest Foundation for Biomedical Research, San Antonio, TX 78245; and Experimental Medicine Section, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892

During HIV-1 infection or vaccination, HIV-1 envelope spikes elicit Ab responses. Neutralizing Abs block viral entry by recognizing epitopes on spikes critical for their interaction with receptor, coreceptors or fusion. In contrast, nonneutralizing Abs fail to do so because they recognize epitopes either buried or exposed but not critical for viral entry. Previously, we produced a high-affinity human mAb against the cluster II determinant of gp41. This Ab or its recombinant Fab and single-chain Fv have been repeatedly shown to bind to HIV-1 gp160 or gp41, but fail to block viral entry. We report that, surprisingly, expression of this nonneutralizing anti-HIV-1 gp41 single-chain Fv on the surface of human CD4 T cells markedly inhibits HIV-1 replication and cell-cell fusion. The inhibition targets the HIV-1 envelope at the level of viral entry, regardless of HIV-1 tropism. Although this bona fide nonneutralizing Ab does not neutralize HIV-1 entry when produced as a soluble protein, it acts as a neutralizing Ab when expressed on the cell surface. Expressing Abs on the surface of HIV-1-susceptible cells can be a new way to fight HIV-1.