Protection of Macaques against pathogenic simian/human immunodeficiency virus 89.6PD by passive transfer of neutralizing antibodies

Abstract

The role of antibody in protection against human immunodeficiency virus (HIV-1) has been difficult to study in animal models because most primary HIV-1 strains do not infect nonhuman primates. Using a chimeric simian/human immunodeficiency virus (SHIV) based on the envelope of a primary isolate (HIV-89.6), we performed passive-transfer experiments in rhesus macaques to study the role of anti-envelope antibodies in protection. Based on prior in vitro data showing neutralization synergy by antibody combinations, we evaluated HIV immune globulin (HIVIG), and human monoclonal antibodies (MAbs) 2F5 and 2G12 given alone, compared with the double combination 2F5/2G12 and the triple combination HIVIG/2F5/2G12. Antibodies were administered 24 h prior to intravenous challenge with the pathogenic SHIV-89.6PD. Six control monkeys displayed high plasma viremia, rapid CD4(+)-cell decline, and clinical AIDS within 14 weeks. Of six animals given HIVIG/2F5/2G12, three were completely protected; the remaining three animals became SHIV infected but displayed reduced plasma viremia and near normal CD4(+)-cell counts. One of three monkeys given 2F5/2G12 exhibited only transient evidence of infection; the other two had marked reductions in viral load. All monkeys that received HIVIG, 2F5, or 2G12 alone became infected and developed high-level plasma viremia. However, compared to controls, monkeys that received HIVIG or MAb 2G12 displayed a less profound drop in CD4(+) T cells and a more benign clinical course. These data indicate a general correlation between in vitro neutralization and protection and suggest that a vaccine that elicits neutralizing antibody should have a protective effect against HIV-1 infection or disease.

FIG. 1

Neutralization curves for individual antibodies and combinations. Dose-response data were generated by serial dilutions of antibody starting at 200 μg/ml for MAbs 2F5 and 2G12 and 20,000 μg/ml for HIVIG. Double- and triple-antibody combinations were diluted in a fixed ratio (e.g., the initial dilution of HIVIG/2F5/2G12 contained a final concentration of 20,000 μg of HIVIG per ml and 200 μg of each MAb per ml). Note that the x axis is labeled to display the MAb concentration; for HIVIG, the corresponding concentration was 100-fold greater than the MAb concentration.

FIG. 2

Viral load in plasma (RNA copies per milliliter) and peripheral CD4⁺-T-cell values (% CD4) for three control (IVIG) and three treated (HIVIG/2F5/2G12) animals in the initial passive-transfer experiment.

FIG. 3

ISH on inguinal lymph nodes removed 2 weeks after virus challenge. (A) Multiple RNA-positive cells and follicular involution in a control animal. (B and C) Rare or no infected cells in treated animals that were partially (B) or completely (C) protected against infection.

FIG. 4

Viral load in plasma (A) and percentage of CD4⁺ T cells (B) in 18 monkeys after SHIV challenge. The passively administered antibody is noted at the top of each graph.

FIG. 5

Pharmacokinetics of infused antibody. (A) Three monkeys infused with the double combination 2F5/2G12. Open symbols represent the concentration of 2F5, and solid symbols represent the concentration of 2G12. Note the substantially longer half-life of MAb 2G12. (B) Comparison of MAb 2F5 concentration in monkeys that received 2F5/2G12 (open symbols) and those that received HIVIG/2F5/2G12 (solid symbols). Note the longer half-life of 2F5 in monkeys that received the double-antibody combination.

FIG. 6

SHIV-89.6PD neutralization by undiluted monkey plasma obtained on the day of virus challenge. Results are shown for representative plasma samples from monkeys infused with IVIG, HIVIG, 2F5, or 2G12 (A), three monkeys that received 2F5/2G12 (B), and six monkeys that received HIVIG/2F5/2G12.