Background
T cell immunity may explain sustained viral control off ART after bNAbs in non-human primates, but evidence from human trials is limited. Proof of a bNAb-induced ‘vaccinal effect’ requires evidence of both enhanced HIV-specific immunity and associated viral control. The RIO trial facilitated analysis of participants receiving two LS-bNAbs (10-1074 & 3BNC117) followed by analytical treatment interruption (ATI).
Methods
68 participants (on ART within 3/12 of primary HIV) were randomised 1:1 to receive two LS-bNAbs (Arm A) or placebo (Arm B) and ATI. T cell immunity was measured by gamma-interferon ELISPOT with HIV full genome 15-mer overlapping peptides, proliferation (Cell Trace Violet) and Activation Induced Marker (AIM) assays (CD25, OX40, 41BB, CD69), the latter two using pooled peptides (Gag, Pol, Env, Nef). 32 Arm A participants were assayed at pre-bNAb baseline and then, if VL suppressed <200 RNA copies/ml, at 12 (n=25), 20-24 (n=18) and 36 (n=6) weeks after bNAb dosing. Assay data were compared using Wilcoxon matched-pairs signed rank analyses. Survival analyses split assay data at medians (log-rank test).
Results
BNAbs resulted in viral control for at least 20 weeks in 65% of participants in Arm A. After bNAb dosing and ATI, proliferation of HIV Gag specific CD4+ and CD8+ T cells increased between Weeks 0 and 12 (2.4 vs 4.1%; P=0.006 and 8.5 vs 13.1%; P=0.008, respectively)), sustained to Week 36 (P=0.03 for both). HIV Gag-specific AIM+ CD4+ T cells significantly increased between Weeks 0 and 12 (0.13 vs 0.21%; P=0.05). Gag ELISpot responses significantly increased from baseline (134 sfu/106 PBMCs) through Week 12 (210 sfu/106 PBMCs; P=0.006) to Week 24 (235 sfu/106 PBMCs; p=0.024). Gag responses were dominant, with only weak evidence for shifts in responses to other major HIV proteins (Pol, Nef, Env). 12 weeks after dosing, there was enrichment for CD8+ effector memory cells, and inflation of Th1 cells (P=0.01) with associated increases in expression of both Th1 HLA DR/CD38 (P=0.04) and memory CD4+ and CD8+ T betHi/EomesLo (P=0.04 and P=0.008, respectively). At time of submission, there was evidence for an association between baseline CD8+ T cell proliferation to Gag and viral control (HR 1.92; P=0.097), most marked in participants who remained suppressed >15 weeks after bNAb dosing (HR 3.72; P=0.004).
Conclusions
In RIO, after dosing with two LS-bNAbs and an ATI, there was increased Gag-specific T cell immunity in aviraemic participants which was associated with viral control.