Broadly Neutralizing Human Anti-HIV Antibody 2G12 Is Effective in Protection against Mucosal SHIV Challenge Even at Low Serum Neutralizing Titers

Abstract

Developing an immunogen that elicits broadly neutralizing antibodies (bNAbs) is an elusive but important goal of HIV vaccine research, especially after the recent failure of the leading T cell based HIV vaccine in human efficacy trials. Even if such an immunogen can be developed, most animal model studies indicate that high serum neutralizing concentrations of bNAbs are required to provide significant benefit in typical protection experiments. One possible exception is provided by the anti-glycan bNAb 2G12, which has been reported to protect macaques against CXCR4-using SHIV challenge at relatively low serum neutralizing titers. Here, we investigated the ability of 2G12 administered intravenously (i.v.) to protect against vaginal challenge of rhesus macaques with the CCR5-using SHIVSF162P3. The results show that, at 2G12 serum neutralizing titers of the order of 1∶1 (IC90), 3/5 antibody-treated animals were protected with sterilizing immunity, i.e. no detectable virus replication following challenge; one animal showed a delayed and lowered primary viremia and the other animal showed a course of infection similar to 4 control animals. This result contrasts strongly with the typically high titers observed for protection by other neutralizing antibodies, including the bNAb b12. We compared b12 and 2G12 for characteristics that might explain the differences in protective ability relative to neutralizing activity. We found no evidence to suggest that 2G12 transudation to the vaginal surface was significantly superior to b12. We also observed that the ability of 2G12 to inhibit virus replication in target cells through antibody-mediated effector cell activity in vitro was equivalent or inferior to b12. The results raise the possibility that some epitopes on HIV may be better vaccine targets than others and support targeting the glycan shield of the envelope.

Vaccination with peptide mimetics of the gp41 prehairpin fusion intermediate yields neutralizing antisera against HIV-1 isolates

“…This view has been reinforced by recent studies showing that HIV-1 infection can be limited or even prevented in animals with a wide range of functional antibody titers as measured by in vitro neutralization assays when these antibodies are continuously present, as would be the case for vaccine-induced immunity (31,37,38).…”

“…The higher neutralizing IC 50 titers obtained with HXB2-V570A in purified IgG from sera of animals immunized with either (CCIZN36) 3 or (CCIPN36) 3 suggested that neutralization responses should be detectable in unfractionated serum. To gain preliminary insight on the breadth of the neutralization response, we tested individual guinea pig serum samples from these groups against a small panel of HIV-1 isolates as well as simian HIV (SHIV) SF162p3, which has previously been tested in multiple monkey challenge studies (29)(30)(31). The HIV-1 viruses used for this panel are representative of tier 1 isolates, defined as being sensitive to antibody-mediated neutralization and mainly comprising T celladapted viruses (32).…”

Kinetic mechanism for HIV-1 neutralization by antibody 2G12 entails reversible glycan binding that slows cell entry

“…2 L and M), slow neutralization mechanisms leave a window of opportunity for virus escape. Whereas previous studies using passively transferred NMAbs suggest that 2G12 may be more inhibitory than MPER NMAbs in vivo (32,40), both b12 and 2G12 are highly protective (31,40,41). Further studies will be needed to learn whether information concerning NAb neutralization mechanisms and kinetics can be used to advance the HIV-1 vaccine effort.…”

“…On the basis of this evidence, we tested the possibility that NAbs might function by slowing HIV-1 entry. We initially used NMAb 2G12, which binds to N-glycans with α (1, 2)-linked mannose termini at positions N295, N332, and N392 near the V3 loop in the "glycan shield" region of gp120 (1,29,30), because 2G12 strongly inhibits HIV-1 and SHIV in vivo (1,31,32). We report that 2G12 functions by this kinetic mechanism.…”

Enhanced HIV-1 neutralization by antibody heteroligation

“…Several broadly neutralizing antibodies (bNAbs) to HIV-1 gp160 have been isolated, including a group that binds to gp120 (10)(11)(12)(13)(14)(15)(16)(17)(18) and a group that is specific for gp41 (19)(20)(21). Importantly, passive transfer of bNAbs to monkeys effectively protects them against simian-human immunodeficiency virus infection (22)(23)(24)(25)(26)(27)(28)(29)(30)(31), and it has therefore been proposed that vaccines that elicit such antibodies may be protective against infection in humans (1,2,(32)(33)(34).…”