Highly potent HIV-specific antibody neutralization in vitro translates into effective protection against mucosal SHIV challenge in vivo

Abstract

Most animal studies using passive administration of HIV broadly neutralizing monoclonal antibodies (bnMAbs) have associated protection against high-dose mucosal viral challenge with relatively high serum concentrations of antibody. We recently identified several bnMAbs remarkable for their in vitro potency against HIV. Of these bnMAbs, PGT121 is one of the most broad and potent antibodies isolated to date and shows 10- to 100-fold higher neutralizing activity than previously characterized bnMAbs. To evaluate the protective potency of PGT121 in vivo, we performed a protection study in rhesus macaques. Animals were i.v. administered 5 mg/kg, 1 mg/kg, or 0.2 mg/kg PGT121 24 h before being vaginally challenged with a single high dose of chimeric simian-human immunodeficiency virus (SHIV)(SF162P3). Sterilizing immunity was achieved in all animals administered 5 mg/kg and 1 mg/kg and three of five animals administered 0.2 mg/kg PGT121, with corresponding average antibody serum concentrations of 95 µg/mL, 15 µg/mL, and 1.8 µg/mL, respectively. The results suggest that a protective serum concentration for PGT121 is in the single-digit µg/mL for SHIV(SF162P3), showing that PGT121 can mediate sterilizing immunity at serum concentrations that are significantly lower than those observed in previous studies and that may be achievable through vaccination with the development of a suitable immunogen.

Fig. 1.

Neutralization of SHIV_SF162P3 by bnMAb PGT121. Neutralization was measured by two assays: SHIV_SF162P3 pseudovirus using TZM-bl cells (A) and replication competent SHIV_SF162P3 using rhesus macaque PBMCs (B). Both assays show potent neutralization of SHIV_SF162P3 by PGT121 compared with other bnMAbs. In the TZM-bl cell-based assay the following IC₅₀s were obtained, 0.005 µg/mL PGT121, 0.04 µg/mL b12, 8.8 µg/mL 2G12, and 0.10 µg/mL VRC01 and in the rhesus macaque PBMC-based assay 0.002 µg/mL PGT121 and 0.36 µg/mL b12. Values are means and SDs of five wells. The assays were performed three times with similar results.

Fig. 2.

Plasma viremia in macaques pretreated with different doses of the bnMAbs PGT121 and challenged with SHIV_SF162P3. Plasma viral loads are shown for animals administered 5 mg/kg PGT121 (A), 1 mg/kg PGT121 (B), 0.2 mg/kg PGT121 (C), and 5 mg/kg DEN3 (D). Sterilizing immunity was observed for all animals given 5 mg/kg and 1 mg/kg PGT121, and in three of five animals given 0.2 mg/kg. One animal (r95090) administered 5 mg/kg PGT121 was euthanized 3 wk after challenge because of unrelated illness. Necropsy showed no sign of viral infection. All animals treated with the control antibody DEN3 became infected. The assay sensitivity limit was 150 RNA copies per mL.

Fig. 3.

Serum concentration of PGT121 in antibody-treated animals. PGT121 concentrations were determined throughout the study. The results show average serum concentrations of 95 µg/mL, 15 µg/mL, and 1.8 µg/mL at the time of challenge in the 5 mg/kg group, 1 mg/kg group, and 0.2 mg/kg group, respectively. A serum half-life for the elimination phase was calculated to be 5.8 d. Values are means and SDs.