Enhanced clearance of HIV-1-infected cells by broadly neutralizing antibodies against HIV-1 in vivo

Abstract

Antiretroviral drugs and antibodies limit HIV-1 infection by interfering with the viral life cycle. In addition, antibodies also have the potential to guide host immune effector cells to kill HIV-1-infected cells. Examination of the kinetics of HIV-1 suppression in infected individuals by passively administered 3BNC117, a broadly neutralizing antibody, suggested that the effects of the antibody are not limited to free viral clearance and blocking new infection but also include acceleration of infected cell clearance. Consistent with these observations, we find that broadly neutralizing antibodies can target CD4(+) T cells infected with patient viruses and can decrease their in vivo half-lives by a mechanism that requires Fcγ receptor engagement in a humanized mouse model. The results indicate that passive immunotherapy can accelerate elimination of HIV-1-infected cells.

Figure 1. Comparison of viral load measurements (filled circles, solid black lines) with best-fit model predictions (solid colored lines)

Each green line shows the predicted viral load over time, normalized by its initial amount, V_P(t)/V_P(0), in a model whereby antibody can only neutralize free virus particles. Each purple line shows a modified model whereby antibody can also lead to clearance of infected cells. Only those patients with a day 1 viral load lower than baseline are shown. Open circles and dashed black lines represent data points that were not used for parameter estimation. Within each subfigure, we note the quantity Δlog₁₀V_P(t_min) = log₁₀(V_P,min/V_P(0)), i.e. the viral load at the nadir and the time in days at which this occurs for the data (black letters), and the predictions for a model with free virus clearance only (green) and a model that also includes infected cell clearance (purple). This predicted minimum for each patient and model is denoted with a star.

Figure 2. bNAbs accelerate clearance of HIV-1-infected cells in vivo

(A) Scatter plot showing the percentage of Gag⁺ cells among CD3⁺CD8⁻ cells in 3BNC117 (600 μg) or isotype control treated mice 5 hours after HIV_YU2-infected cell transfer. (B) Percentage of Gag⁺ cells among CD3⁺CD8⁻ cells in bNAbs (3BNC117 + 10–1074, 300 μg each) or isotype control treated mice 5 hours after HIV_YU2-infected cell transfer (left panel). Cell-associated HIV-1 RNA was measured in enriched human cells extracted from the spleen of mice 5 hours after transfer, plotted as the ratio of HIV-1 RNA to the number of CD3⁺CD8⁻ cells for each mouse (right panel). (C) Graphs represent transfer experiments with cells infected by HIV_2C1, HIV_2C5, HIV_2D3, or HIV_2E5. Each dot represents one mouse. Lines represent median values. Data represent 2–4 independent experiments with a total of 6–13 mice per condition. *P<0.05; **P<0.005; ***P<0.001, two-tailed Mann–Whitney U test.

Figure 3. FcγR engagement is required to facilitate clearance of HIV-1-infected cells

(A) Percentage of Gag⁺ cells among CD3⁺CD8⁻ cells in bNAbs, GRLR-bNAbs, or isotype control treated mice. (B) NRG mice were injected with mouse FcγRII/III/IV blocking antibodies or isotype control 6 hours before injection of bNAbs. Graphs show the percentage of Gag⁺ cells among CD3⁺CD8⁻ cells. (C) Percentage of Gag⁺ cells among CD3⁺CD8⁻ cells in mice receiving FcγRIV blocking antibody, or isotype control. (D) Infected cell clearance in chronically HIV-1_YU2-infected hu-mice. Scatter plot shows the ratio of the percentage of Gag⁺ cells among CD3⁺CD8⁻ cells before and 5 hours after 3BNC117, GRLR-3BNC117, or isotype control injection. Each dot represents one mouse. Lines represent median values. Data represent 2–4 independent experiments for each condition with a total of 7–12 mice per condition. *P<0.05; **P<0.005; ***P<0.001, two-tailed Mann–Whitney U test.