Background
Therapeutic vaccines offer a promising strategy to boost immune responses, reduce the HIV reservoir and potentially achieve ART-free remission. In this study, we characterized HIV-specific T-cell responses and assessed their correlation with the intact HIV reservoir in the RV534 trial.
Methods
25 youths (M/F=13/12; median age=15 years) with perinatal HIV, on ART since 6 mo of age, VL<200 copies/mL (adjusted for 1×106 CD4+ T cells), received HIVIS DNA and MVA-CMDR vaccines alone (Arm1, n=10), together with HPV vaccine Cervarix (Arm2, n=10), or Cervarix alone (Arm3, n=5). AS04 adjuvant in Cervarix is a TLR4 agonist. HIV-specific T cell responses were longitudinally assessed using Activation-Induced Marker (AIM)/ICS flow cytometry by stimulating PBMCs with Gag or Env peptide pools (Pt.Ps). MIMOSA (Mixture Models for Single-cell Assays) was used to evaluate HIV-specific T-cells expressing ≥1 cytokine or AIM following Pt.Ps stimulation. Responses were classified as positive if FDR<0.05. Genomic DNA was extracted from 3×106 enriched CD4+ T cells to quantify intact and defective HIV proviruses with a subtype C-specific, triplex (gag, pol, env) Intact Proviral DNA Assay at wk0 and 72.
Results
Immunological data were analyzed blinded. MIMOSA detected consistently higher HIV-specific T-cell responses in the HIVIS-DNA/MVA-CMDR vaccine Arms (1,2) compared with the control Arm (3), at wk60. Significant differences were observed both in Arm1 vs. Arm3 (odds ratio [OR] = 2.11, p<0.001) and Arm2 vs. Arm3 (OR=1.86, p<0.001). Arm2 exhibited the largest longitudinal increase, with a 1.11-fold change in responder frequency by wk 60 relative to baseline. In Arm2, a longitudinal analysis revealed a significant change over time for CD8+ T-cell frequency co-expressing CD107a and TNF-α after Gag stimulation (p=0.0152), from baseline to wk60. Change in this cell population (wk60-wk-6) was associated with the change in the viral reservoir (wk72-wk0), only in Arm2, where higher increases of CD8+CD107a+TNF-α+ T-cells were associated with reductions in intact HIV copies/1×106cells (Env: rho=-0.77, p=0.009; Gag: rho=-0.745, p=0.013).
Conclusions
Data indicate that the combined HIV vaccines adjuvanted with Cervarix can elicit durable HIV-specific T-cell responses, which appear to correlate with a concomitant reduction in the viral reservoir. However, additional studies, particularly TCR sequencing analyses, are required to comprehensively characterize the breadth and specificity of these HIV-specific T-cell responses.
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