Mucosal AIDS virus transmission is enhanced by antiviral IgG isolated early in infection

Abstract

Objective: Antibody-dependent enhancement (ADE) affects host-virus dynamics in fundamentally different ways: i) enhancement of initial virus acquisition, and/or ii) increased disease progression/severity. Here we address the question whether anti-HIV-1 antibodies can enhance initial infection. While cell-culture experiments hinted at this possibility, in-vivo proof remained elusive.

Design: We used passive immunization in nonhuman primates challenged with simian-human immunodeficiency virus (SHIV), a chimera expressing HIV-1 envelope. We purified IgG from rhesus monkeys with early-stage SHIV infection - before cross-neutralizing anti-HIV-1 antibodies had developed - and screened for maximal complement-mediated antibody-dependent enhancement (C'-ADE) of viral replication with a SHIV strain phylogenetically distinct from that harbored by IgG donor macaques. IgG fractions with maximal C'-ADE but lacking neutralization were combined to yield enhancing anti-SHIV IgG (enSHIVIG).

Results: We serially enrolled naive macaques (Group 1) to determine the minimal and 50% animal infectious doses required to establish persistent infection after intrarectal SHIV challenge. The first animal was inoculated with a 1 : 10 virus-stock dilution; after this animal's viral RNA load was >104copies/ml, the next macaque was challenged with 10x less virus, a process repeated until viremia no longer ensued. Group 2 was pretreated intravenously with enSHIVIG 24 h before SHIV challenge. Overall, Group 2 macaques required 3.4-fold less virus compared to controls (P = 0.002). This finding is consistent with enhanced susceptibility of the passively immunized animals to mucosal SHIV challenge.

Conclusion: These passive immunization data give proof of IgG-mediated enhanced virus acquisition after mucosal exposure - a potential concern for antibody-based AIDS vaccine development.

Fig. 1

Anti-SHIV IgG responses in donor monkeys RKu-12 and RPm-12 at the weeks post SHIV-2873Nip challenge indicated.

Fig. 2

Characterization of pooled early-stage enhancing IgG, termed enSHIVIG.

Fig. 3

C’-ADE of enSHIVIG pool depleted of anti-gp120 antibodies.

Fig. 4

Animal study timeline.

Fig. 5

Plasma viral RNA (vRNA) loads after intrarectal SHIV-1157ipd3N4 challenge.