Protection of Humanized Mice From Repeated Intravaginal HIV Challenge by Passive Immunization: A Model for Studying the Efficacy of Neutralizing Antibodies In Vivo

Abstract

Humanized mice reconstituted with a human immune system can be mucosally infected with human immunodeficiency virus (HIV), opening up the possibility of studying HIV transmission in a small-animal model. Here we report that passive immunization with the broadly neutralizing antibody b12 protected humanized mice against repetitive intravaginal infection in a dose-dependent manner. In addition, treatment with the antibody PGT126, which is more potent in vitro, was more efficacious in vivo and provided sterilizing protection. Our results demonstrate that humanized mice can be used as a small-animal model to study the efficacy and mechanism of broadly neutralizing antibody protection against HIV acquisition.

Keywords: HIV transmission; humanized mice; mucosal infection; neutralizing antibodies.

Figure 1.

Passive immunization with b12 or PGT126 protects bone marrow–liver–thymus (BLT) mice against low-dose repeated human immunodeficiency virus (HIV) intravaginal challenge. Groups of BLT mice (n = 4–8) received antibody treatment intraperitoneally 2 days before each intravaginal challenge with 2–3 × 10⁴ tissue culture infective dose HIV-1 strain JRCSF (HIV_JRCSF) weekly. Results were pooled from 2 experiments (batch 164, closed circles; batch 192, open circles). Plasma viremia (A) and peripheral blood CD4⁺ T-cell percentage (B) were assessed 1 day before challenge. A total of 8 HIV challenges were performed. A, Viral loads measured by HIV RNA copies/mL of plasma using a quantitative reverse-transcription polymerase chain reaction assay. Viral loads are plotted against the number of HIV challenges required to achieve the indicated level of plasma viremia. Mice that had to be sacrificed before receiving 8 challenges are indicated (†). RNA samples with ≤3 copies/µL of RNA were considered negative and normalized to 1. B, CD4⁺ T-cell percentages among the human CD3⁺ T-cell gate in peripheral blood analyzed by flow cytometry. C, Kaplan–Meier curves displaying the number of challenges to the proportion of uninfected mice. Apart from the curve corresponding to the group treated with 2-mg/kg b12 (P = .92), the curves corresponding to 10-mg/kg b12 (P = .01), 50-mg/kg b12 (P < .001), 10-mg/kg PGT126 (P = .003), and 50-mg/kg PGT126 (P < .001) treatment are significantly different from that for the control-treated group, as shown by a log-rank test. The dashed line marks the median infection rate. D, Mean plasma levels (left panel) and mean dilution (middle panel) and mean neutralization titers (right panel) producing 50% neutralization HIV_JRCSF in vitro for each mouse in the different groups over the course of the experiment or until infection. In A, B, and C each circle represents 1 mouse. Results are presented as means with standard deviations, and significance was calculated using a Kruskal–Wallis test .*P ≤ .05; ^†P ≤ .01. Abbreviation: IC₅₀, median inhibitory concentration.