A broad range of mutations in HIV-1 neutralizing human monoclonal antibodies specific for V2, V3, and the CD4 binding site

Abstract

The HIV vaccine-induced neutralizing antibodies (Abs) display low rates of mutation in their variable regions. To determine the range of neutralization mediated by similar human monoclonal Abs (mAbs) but derived from unselected chronically HIV-1 infected subjects, we tested a panel of 66 mAbs specific to V3, CD4 binding site (CD4bs) and V2 regions. The mAbs were tested against 41 pseudoviruses, including 15 tier 1 and 26 tier 2, 3 viruses, showing that the neutralization potency and breadth of anti-V3 mAbs were significantly higher than those of the anti-CD4bs and anti-V2 mAbs, and only anti-V3 mAbs were able to neutralize some tier 2, 3 viruses. The percentage of mutations in the variable regions of the heavy (VH) and light (VL) chains varied broadly in a range from 2% to 18% and correlated moderately with the neutralization breadth of tier 2, 3 viruses. There was no correlation with neutralization of tier 1 viruses as some mAbs with low and high percentages of mutations neutralized the same number of viruses. The electrostatic interactions between anti-V3 mAbs and the charged V3 region may contribute to their neutralization because the isoelectric points of the VH CDR3 of 48 anti-V3 mAbs were inversely correlated with the neutralization breadth of tier 2, 3 viruses. The results demonstrate that infection-induced antibodies to CD4bs, V3 and V2 regions can mediate cross-clade neutralization despite low levels of mutations which can be achieved by HIV-1 vaccine-induced antibodies.

Functional and Structural Characterization of Human V3-Specific Monoclonal Antibody 2424 with Neutralizing Activity against HIV-1 JRFL

“…2424 neutralized six viruses (BX08.16, BaL26, SS1196.1, REJO4541, JRCSF, and JRFL.JB), and three of these viruses (JRFL, JRCSF, and REJO4541) are relatively resistant to other V3 MAbs (26,50). This neutralization pattern paralleled the 2424 binding to V3 peptides of the corresponding viruses.…”

“…The IC 50 s of other V3 MAbs against JRFL were also shown previously to range from 11 to Ͼ50 g/ml (26). More recently, when a panel of 48 V3 MAbs was tested, 2424 was also found to be the most potent against JRFL (50). The greater potency of 2424 was further shown by its ability to achieve a neutralization plateau of 100%, a level unattainable by 447-52D and the other V3 MAbs tested ( Fig.…”

“…Moreover, while the majority of V3 MAbs use light chains, 2424 uses a light chain. Only 17 out of 70 human V3 MAbs with known VH and VL genes use light chains (23,38,50,52). Together, these data suggest that 2424 is a unique MAb targeting an epitope in the V3 loop that may be more accessible or occluded differently compared to the other V3 epitopes.…”

“…This MAb has VH and VL gene pairing not used by the other V3 MAbs (50). The 2424 VH and VL genes are somatically mutated 14.4% and 5.1% from the germ line IGHV3-53 and IGLV2-28 genes, respectively.…”

HIV Envelope gp120 Alters T Cell Receptor Mobilization in the Immunological Synapse of Uninfected CD4 T Cells and Augments T Cell Activation

“…SLBs containing OKT3, ICAM-1, and gp120 were treated with 10 g/ml MAb for 30 min prior to introduction of the cells and washed three times with the assay buffer to remove excess MAb. MAbs 654, 2158, and 2558 have potent neutralizing activities against HIV-1 SF162, from which the gp120 protein used in this study was derived (50% inhibitory concentrations of Ͻ1, 6, and Ͻ1 g/ml, respectively [43]). Control MAb 1418 is specific for parvovirus and does not neutralize HIV.…”