Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys

Abstract

Human immunodeficiency virus type 1 (HIV-1)-specific monoclonal antibodies with extraordinary potency and breadth have recently been described. In humanized mice, combinations of monoclonal antibodies have been shown to suppress viraemia, but the therapeutic potential of these monoclonal antibodies has not yet been evaluated in primates with an intact immune system. Here we show that administration of a cocktail of HIV-1-specific monoclonal antibodies, as well as the single glycan-dependent monoclonal antibody PGT121, resulted in a rapid and precipitous decline of plasma viraemia to undetectable levels in rhesus monkeys chronically infected with the pathogenic simian-human immunodeficiency virus SHIV-SF162P3. A single monoclonal antibody infusion afforded up to a 3.1 log decline of plasma viral RNA in 7 days and also reduced proviral DNA in peripheral blood, gastrointestinal mucosa and lymph nodes without the development of viral resistance. Moreover, after monoclonal antibody administration, host Gag-specific T-lymphocyte responses showed improved functionality. Virus rebounded in most animals after a median of 56 days when serum monoclonal antibody titres had declined to undetectable levels, although, notably, a subset of animals maintained long-term virological control in the absence of further monoclonal antibody infusions. These data demonstrate a profound therapeutic effect of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys as well as an impact on host immune responses. Our findings strongly encourage the investigation of monoclonal antibody therapy for HIV-1 in humans.

Figure 1. Therapeutic efficacy of the triple PGT121/3BNC117/b12 mAb cocktail

Plasma viral RNA (log copies/ml) in rhesus monkeys chronically infected with SHIV-SF162P3 following infusions of PGT121, 3BCN117, and b12 on day 0 and day 7 (arrows) for 14 days (a) and 224 days (b). Plasma viral RNA in rhesus monkeys chronically infected with SHIV-SF162P3 following infusions with the control mAb DEN3 (87-09) or saline on day 0 and day 7 (arrows) for 14 days (c) and 224 days (d). e, Proviral DNA (copies/10⁶ PBMC) in the monkeys that received the therapeutic mAb cocktail or controls (inset). f, Log inhibition of viral replication in CD8+ T lymphocyte virus suppression assays following mAb infusion. One animal had no recoverable virus at week 2. PD-1+Ki67+ expression on Gag-specific CD8+ (g) and CD4+ (h) T lymphocytes following mAb infusion.

Figure 2. Therapeutic efficacy of the double PGT121/3BNC117 mAb cocktail

Plasma viral RNA (log copies/ml) in rhesus monkeys chronically infected with SHIV-SF162P3 following a single infusion (arrows) of PGT121, 3BCN117, and b12 (a); PGT121 and 3BNC117 (b); or the control mAb DEN3 (c). d, Plasma viral RNA in monkeys that received PGT121 and 3BNC117 following a second infusion on day 105. PD-1+Ki67+ expression on Gag-specific CD8+ (e) and CD4+ (f) T lymphocytes in the monkeys that received PGT121 and 3BNC117. Proviral DNA (copies/10⁶ cells) in lymph nodes (g) and gastrointestinal mucosa (h) before (day 105) and 14 days after (day 119) the second mAb infusion with PGT121 and 3BNC117 in the four animals with detectable viremia.

Figure 3. Therapeutic efficacy of the single mAbs PGT121 and 3BNC117

Plasma viral RNA (log copies/ml) in rhesus monkeys chronically infected with SHIV-SF162P3 following a single infusion (arrows) of PGT121 (a), 3BNC117 (b), or the control mAb DEN3 (c). Proviral DNA (copies/10⁶ cells) in PBMC (d), lymph nodes (e), and gastrointestinal mucosa (f) 14 days following the mAb infusion in the animals that received PGT121 or DEN3. Red bars indicate means. Assays for one of the DEN3 treated controls failed. PD-1+Ki67+ expression on Gag-specific CD8+ (g) and CD4+ (h) T lymphocytes in the monkeys that received PGT121.

Figure 4. Therapeutic efficacy of PGT121 or PGT121-containing mAb cocktails in chronically SHIV-infected rhesus monkeys

a, Summary of the therapeutic effect of PGT121 alone or PGT121-containing mAb cocktails in the 18 rhesus monkeys chronically infected with SHIV-SF162P3, as well as in the subgroups of animals with baseline viral loads of <3.5 log RNA copies/ml (N=3) (b), 3.5–5.3 log RNA copies/ml (N=13) (c), and >5.3 log RNA copies/ml (N=2) (d). Red lines indicates median log viral loads. e, Correlation of baseline viral loads with times to viral rebound. P value reflects two-sided Spearman rank-correlation test. f, Comparison of setpoint viral loads at baseline before mAb administration and following viral rebound. P value reflects two-sided Wilcoxon matched pairs signed-rank test. Red line indicates median log viral loads.

Extended Data Figure 1. Monoclonal Ab titers following administration of the triple PGT121/3BNC117/b12 mAb cocktail

PGT121, 3BNC117, and b12 titers in the monkeys described in Fig. 1 following infusion of the triple mAb cocktail (arrows).

Extended Data Figure 2. Neutralizing Ab titers following administration of the triple PGT121/3BNC117/b12 mAb cocktail

SHIV-SF162P3 and SHIV-SF162P4 serum NAb ID50 titers in the monkeys described in Fig. 1 following infusion of the triple mAb cocktail (left) or saline or DEN3 (right).

Extended Data Figure 3. Gag-specific T lymphocyte responses following administration of the triple PGT121/3BNC117/b12 mAb cocktail

Gag-specific IFN-γ+ CD8+ (left) and CD4+ (right) T lymphocyte responses in the monkeys described in Fig. 1 following infusion of the triple mAb cocktail.

Extended Data Figure 4. Monoclonal Ab titers following administration of the double PGT121/3BNC117 mAb cocktail

PGT121, 3BNC117, and b12 titers in the monkeys described in Fig. 2 that received PGT121, 3BCN117, and b12 (a); PGT121 and 3BNC117 (b); or the second infusion of PGT121 and 3BNC117 (c).

Extended Data Figure 5. Monkey anti-human antibody titers following mAb administration

ELISAs assessing anti-b12, anti-PGT121, anti-3BNC117, and anti-DEN3 antibodies at week 6 and week 10 following mAb infusion in the monkeys described in Fig. 2.

Extended Data Figure 6. Neutralization sensitivity of SHIV-SF162P3 pseudovirus and our SHIV-SF162P3 challenge stock

TZM-bl neutralization assays of PGT121, 3BNC117, and b12 against the SHIV-SF162P3 pseudovirus (top) and against the SHIV-SF162P3 challenge stock (middle, bottom). Note sensitivity of our SHIV-SF162P3 challenge stock to PGT121 but relative resistance to 3BNC117.

Extended Data Figure 7. Monoclonal Ab titers following administration of the single mAbs PGT121 and 3BNC117

PGT121 and 3BNC117 titers in the monkeys described in Fig. 3 following infusion of the single mAbs.

Extended Data Figure 8. Virus replicative capacity and following virus rebound

Numbers of GFP positive infected GHOST indicator cells per well after 3 and 6 days of culture with baseline or rebound SHIV-SF162P3 virus.

Extended Data Figure 9. Monoconal antibody sensitivity to N332A mutated SHIV-SF162P3

TZM-bl neutralization assays of PGT121, PGT124, PGT128, PGT130, and PGV04 against SHIV-SF162P3 containing the N332A mutation. Note 100-fold reduced sensitivity to PGT121 but more profound escape from PGT124 and PGT128.