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Abstract
BackgroundA key goal for HIV-1 envelope immunogen design is the induction of cross-reactive neutralizing antibodies (nAbs). As AIDS vaccine recipients will not be exposed to strains exactly matching any immunogens due to multiple HIV-1 quasispecies circulating in the human population worldwide, heterologous SHIV challenges are essential for realistic vaccine efficacy testing in primates. We assessed whether polyclonal IgG, isolated from rhesus monkeys (RMs) with high-titer nAbs (termed SHIVIG), could protect RMs against the R5-tropic tier-2 SHIV-2873Nip, which was heterologous to the viruses or HIV-1 envelopes that had elicited SHIVIG.ResultsSHIVIG demonstrated binding to HIV Gag, Tat, and Env of different clades and competed with the broadly neutralizing antibodies b12, VRC01, 4E10, and 17b. SHIVIG neutralized tier 1 and tier 2 viruses, including SHIV-2873Nip. NK-cell depletion decreased the neutralizing activity of SHIVIG 20-fold in PBMC assays. Although SHIVIG neutralized SHIV-2873Nip in vitro, this polyclonal IgG preparation failed to prevent acquisition after repeated intrarectal low-dose virus challenges, but at a dose of 400 mg/kg, it significantly lowered peak viremia (P = 0.001). Unexpectedly, single-genome analysis revealed a higher number of transmitted variants at the low dose of 25 mg/kg, implying increased acquisition at low SHIVIG levels. In vitro, SHIVIG demonstrated complement-mediated Ab-dependent enhancement of infection (C’-ADE) at concentrations similar to those observed in plasmas of RMs treated with 25 mg/kg of SHIVIG.ConclusionOur primate model data suggest a dual role for polyclonal anti-HIV-1 Abs depending on plasma levels upon virus encounter.
Highlights
A key goal for HIV-1 envelope immunogen design is the induction of cross-reactive neutralizing antibodies
Attempts to use primates to elucidate the role of Abs were conducted with polyclonal IgG isolated from HIV-1-infected subjects and showed either no or complete protection against laboratoryadapted, neutralization-sensitive viruses in chimpanzees depending on challenge virus doses [3,4,5]
When HIVIG alone or combined with broadly neutralizing monoclonal antibody (bnmAb) was tested against SHIV89.6PD [7,8], only the combination of HIVIG with bnmAbs resulted in moderate prevention of virus acquisition
Summary
A key goal for HIV-1 envelope immunogen design is the induction of cross-reactive neutralizing antibodies (nAbs). The RV144 vaccine trial showed moderate efficacy (31.2%) and raised the possibility that nonneutralizing Abs may be associated with protection against HIV-1 acquisition [1] In this regard, a biologically relevant non-human primate model, in which macaques are passively immunized with Abs against simian-human immunodeficiency virus (SHIV) followed by repeated mucosal challenges with a heterologous R5 SHIV at low doses, may mimic key aspects of HIV-1 transmission among humans and play an important role in dissecting the mechanism(s) of Ab action in HIV-1 transmission and its prevention [2]. Two out of 10 macaques remained aviremic, one treated with highdose IgG and the other one challenged with a low dose of virus [9]
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