Early antibody therapy can induce long-lasting immunity to SHIV

Abstract

Highly potent and broadly neutralizing anti-HIV-1 antibodies (bNAbs) have been used to prevent and treat lentivirus infections in humanized mice, macaques, and humans. In immunotherapy experiments, administration of bNAbs to chronically infected animals transiently suppresses virus replication, which invariably returns to pre-treatment levels and results in progression to clinical disease. Here we show that early administration of bNAbs in a macaque simian/human immunodeficiency virus (SHIV) model is associated with very low levels of persistent viraemia, which leads to the establishment of T-cell immunity and resultant long-term infection control. Animals challenged with SHIVAD8-EO by mucosal or intravenous routes received a single 2-week course of two potent passively transferred bNAbs (3BNC117 and 10-1074 (refs 13, 14)). Viraemia remained undetectable for 56-177 days, depending on bNAb half-life in vivo. Moreover, in the 13 treated monkeys, plasma virus loads subsequently declined to undetectable levels in 6 controller macaques. Four additional animals maintained their counts of T cells carrying the CD4 antigen (CD4+) and very low levels of viraemia persisted for over 2 years. The frequency of cells carrying replication-competent virus was less than 1 per 106 circulating CD4+ T cells in the six controller macaques. Infusion of a T-cell-depleting anti-CD8β monoclonal antibody to the controller animals led to a specific decline in levels of CD8+ T cells and the rapid reappearance of plasma viraemia. In contrast, macaques treated for 15 weeks with combination anti-retroviral therapy, beginning on day 3 after infection, experienced sustained rebound plasma viraemia when treatment was interrupted. Our results show that passive immunotherapy during acute SHIV infection differs from combination anti-retroviral therapy in that it facilitates the emergence of potent CD8+ T-cell immunity able to durably suppress virus replication.

Conflict of interest statement

The authors declare no competing financial interests.

Figures

Extended Data Figure 1. Sustained suppression of virus replication by a 2-week course of combination bNAb treatment following IR SHIVAD8-EO challenge

Plasma viral RNA levels and 10-1074 or 3BNC117 mAb concentrations following bNAb therapy beginning on day 3 post IR challenge are shown (n = 6).

Extended Data Figure 2. Sustained suppression of virus replication by a 2-week course of combination bNAb treatment following intravenous SHIVAD8-EO challenge

Plasma viral RNA levels and 10-1074 or 3BNC117 mAb concentrations following bNAb therapy beginning on day 3 post intravenous challenge are shown (n = 7).

Extended Data Figure 3. Analyses of selected SHIVAD8 gp120 sequences known to confer resistance to 10-1074 or 3BNC117 monoclonal antibodies present in virus rebounding following immunotherapy

Nucleotide sequences present in amplicons, obtained from animals DELV (day 84 PI), DEWL (day 72 PI), DF06 (day 99 PI), or MAF (day 90 PI) during virus rebound (shown in Extended Data Fig 2d–g), were evaluated. SHIVAD8-EO gp120 sequences are shown at the top. Mutations conferring resistance to 10-1074 (vertical bars) and 3BNC117 (horizontal bars) are highlighted.

Extended Data Figure 4. CD8+ T cell responses and memory phenotype

a) Memory CD8+ T cell responses to SIVmac239 Gag measured by ICS as a sum of IFN-γ, IL-2, TNF, CD107a, MIP-1B, and IL-10. Supp = during bNAb mediated viral suppression, Peak = during peak of virus rebound, Base = following resolution of rebound, Late = during late stage of virus infection; colored bars = mean, whiskers = SEM. b) Polyfunctionality of the CD8+ T cell responses in macaques inoculated by the intravenous route. c) CD8+ T cell memory subsets in macaques inoculated by the intravenous route. N= naïve, CM = central memory, EM = effector memory, TEM = terminal effector memory.

Extended Data Figure 5. FACS analyses of CD8+ cells in controller animals following administration of depleting anti-CD8 mAbs

CD8+ lymphocytes were collected from controller monkeys MVJ, DEWL, and DEMR following infusion of the MT807R1anti-CD8α mAb (a,b) or the CD8b255R1 anti-CD8β mAb (c,d) and the CD3+CD8+ and CD3–CD8+ fractions determined.

Extended Data Figure 6. Administration of cART during the acute SHIVAD8-EO infection of macaques does not result in controller status

cART (Tenofovir, Emtricitabine, and Raltagravir) was administered daily to three animals for 15 weeks beginning on day 3 post IR challenge with 1000 TCID50 of SHIVAD8–EO.

Figure 1. Control of SHIVAD8-EO replication by a 2-week course of combination bNAb therapy

a, Six macaques were inoculated intrarectally with 1000 TCID50 of SHIVAD8-EO and were treated with 10-1074 plus 3BNC117 (10mg/kg of each) mAbs on days 3, 10, and 17 PI. Gray curves denote replication profiles of 6 similarly inoculated but untreated animals. Macaques inoculated intravenously with 1000 TCID50(b) or 100 TCID50(c) of SHIVAD8-EO were treated with 10-1074 plus 3BNC117 mAbs as in panel a. Gray curves in panel b indicate the replication kinetics of four untreated monkeys inoculated intravenously with 5000 or 500 TCID50 of SHIVAD8-EO. Plasma viral loads were measured by the standard RT-PCR assay (limit of detection 100 SHIV RNA copies/ml) at the indicated times.

Figure 2. Establishment of controller status in bNAb treated animals inoculated with SHIVAD8-EO by the intrarectal route

Plasma virus loads (black) and CD4+ T cell levels (red) are shown in 3 Controller (a–c) or 3 Non-Controller (d–f) macaques.

Figure 3. Establishment of controller status in bNAb treated animals inoculated with SHIVAD8-EO by the intravenous route

Plasma virus loads (black) and CD4+ T cell levels (red) are shown in 3 Controller (a–c) or 4 Non-Controller (d–g) macaques.

Figure 4. Depletion of CD8+ T cells in controller macaques results in the rapid induction of plasma viremia

Plasma SHIVAD8-EO levels prior to and following administration of anti-CD8 depleting mAbs to six controller monkeys. The black arrows in each panel indicate the time of infusion of the anti-CD8α depleting mAb MT807R1. The red arrows in panels a to c indicate infusion of the anti-CD8β depleting mAb CD8b255R1 to controller macaques MVJ, DEMR, and DEWL.