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. 2001 Sep;75(17):8340-7.
doi: 10.1128/jvi.75.17.8340-8347.2001.

Antibody protects macaques against vaginal challenge with a pathogenic R5 simian/human immunodeficiency virus at serum levels giving complete neutralization in vitro

P W Parren  1 , P A Marx, A J Hessell, A Luckay, J Harouse, C Cheng-Mayer, J P Moore, D R Burton
Affiliations

Antibody protects macaques against vaginal challenge with a pathogenic R5 simian/human immunodeficiency virus at serum levels giving complete neutralization in vitro

P W Parren et al. J Virol. 2001 Sep.

Abstract

A major unknown in human immunodeficiency virus (HIV-1) vaccine design is the efficacy of antibodies in preventing mucosal transmission of R5 viruses. These viruses, which use CCR5 as a coreceptor, appear to have a selective advantage in transmission of HIV-1 in humans. Hence R5 viruses predominate during primary infection and persist throughout the course of disease in most infected people. Vaginal challenge of macaques with chimeric simian/human immunodeficiency viruses (SHIV) is perhaps one of the best available animal models for human HIV-1 infection. Passive transfer studies are widely used to establish the conditions for antibody protection against viral challenge. Here we show that passive intravenous transfer of the human neutralizing monoclonal antibody b12 provides dose-dependent protection to macaques vaginally challenged with the R5 virus SHIV(162P4). Four of four monkeys given 25 mg of b12 per kg of body weight 6 h prior to challenge showed no evidence of viral infection (sterile protection). Two of four monkeys given 5 mg of b12/kg were similarly protected, whereas the other two showed significantly reduced and delayed plasma viremia compared to control animals. In contrast, all four monkeys treated with a dose of 1 mg/kg became infected with viremia levels close to those for control animals. Antibody b12 serum concentrations at the time of virus challenge corresponded to approximately 400 (25 mg/kg), 80 (5 mg/kg), and 16 (1 mg/kg) times the in vitro (90%) neutralization titers. Therefore, complete protection against mucosal challenge with an R5 SHIV required essentially complete neutralization of the infecting virus. This suggests that a vaccine based on antibody alone would need to sustain serum neutralizing antibody titers (90%) of the order of 1:400 to achieve sterile protection but that lower titers, around 1:100, could provide a significant benefit. The significance of such substerilizing neutralizing antibody titers in the context of a potent cellular immune response is an important area for further study.

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Figures

FIG. 1
FIG. 1
Temporal analysis of SHIV162P4 plasma viremia in macaques pretreated with different doses of antibody b12. Plasma viral loads are shown for animals treated with 25 mg of control antibody/kg (A), 25 mg of b12/kg (B), 5 mg of b12/kg (C), and 1 mg of b12/kg (D) following vaginal challenge with SHIV162P4. Each curve depicts an individual animal. The curves for R360, L426, AV86, and P311 are coincident. The curves for R084 and N833 are coincident. Neut, neutralizing.
FIG. 2
FIG. 2
Comparison of averaged plasma viral loads for macaques in different treatment groups. The mean viral loads were calculated for all the animals in each of the groups described in the legend to Fig. 1. In addition, we calculated the mean viral load of the nine untreated animals from the challenge virus titration experiment. Although the viral challenge dose in this experiment varied, calculating the mean was warranted since the onset as well as the peak viremias fell into a relatively narrow range (Table 1). The 5-mg/kg group was split into two subgroups corresponding to the two completely protected monkeys (curve is coincident with the 25-mg/kg curve) and the two monkeys in which viremia was delayed.
FIG. 3
FIG. 3
The concentration of b12 resulting in half-maximal protection (Protect50) in animals as a function of the concentration resulting in half-maximal neutralization (Neut50) in vitro. The concentrations of b12 required to neutralize 50% of the challenge virus in vitro and completely protect 50% of animals against infection with the same virus were derived from this study and previous studies using hu-PBL-SCID mice (10, 29). The data points shown (left to right) correspond to HIV-1LAI (hu-PBL-SCID), HIV-1SF2 (hu-PBL-SCID), HIV-1JR-CSF (hu-PBL-SCID), SHIV162P4 (macaques), and HIV-1AD6 (hu-PBL-SCID). For experiments in which half-maximal protection was not determined exactly, an error bar is shown with a range indicating the lower and upper limits of the antibody concentration required.
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