Reactivation of Neutralized HIV-1 by Dendritic Cells Is Dependent on the Epitope Bound by the Antibody

Abstract

Ab-neutralized HIV-1 can be captured by dendritic cells (DCs), which subsequently transfer infectious HIV-1 to susceptible CD4(+) T cells. In this study, we examined the capacity of early Abs, as well as recently identified broadly neutralizing Abs (bNAbs) targeting different envelope glycoprotein (Env) epitopes, to block HIV-1 transmission by immature and mature DCs to HIV-1-sensitive cells. Three bNAbs directed against the gp41 membrane proximal region of Env (2F5, 4E10, and 10E8) and three gp120 bNAbs targeting the CD4 binding site (b12, VRC01, and NIH45-46) were examined. In addition, eight glycan-dependent bNAbs targeting the V1V2 apex (PG9, PG16, and PGT145), the V3 loop (2G12, PGT121, and PGT128), and the gp120-gp41 interface of Env (PGT151 and 35O22) were tested. bNAbs that bound specific glycans showed, depending on the immature or mature state of the DC, diverse efficiencies in HIV-1 trans-infection. All bNAbs that bound the CD4 binding site blocked trans-infection, whereas all bNAbs directed against the membrane proximal region lost neutralizing activity after DC-mediated HIV-1 transmission. To understand how preneutralized HIV-1 can be transferred as infectious virus by DCs, we followed the processing of 2F5-treated HIV-1 by DCs with confocal microscopy. Inhibition of DC-internalization pathways could not reverse the dissociation of 2F5 from HIV-1, suggesting that Ab dissociation occurs directly at the plasma membrane. Collectively, these findings imply that the location of the epitope and the neutralization capacity of these Abs determine the efficiency of DC-mediated HIV-1 transfer.