Vaccination of HIV-1+ Patients with Dendritic Cells Loaded with HIV-1 Lipopeptides Elicits Broad T Cell Immunity Associated to a Reduced Peak of HIV-1 Viral Load following HAART Interruption
Yves Levy*1,2,3, R Thiebaut4,5, M Montes6,7, C Lacabaratz1,2,3, L Sloan6, C Harrod6, L Richert4,5, G Chêne4,5, J Banchereau6,7, K Palucka6,7, for the ANRS Vaccine Network/Vaccine Res Inst
1INSERM U955, Créteil, France; 2Univ Paris-Est Créteil Faculté de Med, France; 3Groupe Henri-Mondor Albert-Chenevier, Immunologie Clin, Créteil, France; 4INSERM U897, Bordeaux, France; 5Univ Bordeaux Segalen, France; 6Baylor Inst for Immunology Res, Ctr for Human Vaccines, Dallas, TX, US; and 7INSERM U899, Dallas, TX, US
Background: The limitations of HAART have revitalized consideration of the prospect of a functional cure. The DALIA trial tested the hypothesis that immunization with HIV peptide-loaded dendritic cells (DC) may improve HIV immune responses and help to contain viral replication.
Methods: Nineteen patients with CD4 >500 cells/m3 and HIV RNA <50 copies/mL under HAART received at week 0, 4, 8, and 12 ex vivo generated interferon alpha (IFN-α) DC loaded with HIV-1 lipopeptides. Analytical treatment interruption (ATI) was conducted from week 24. CD4 counts and viral load were evaluated weekly until week 28 and every month thereafter. HAART resumption regardless of the reason and CD4 <350 cells/mm3 were considered as safety endpoints. HIV-specific immunity was evaluated at weeks –4, 16, and 48 using ex vivo IFN-γ ELISpot; intracellular cytokine staining (ICS); cytokine multiplex analysis for interleukin-2 (IL-2), IL-5, IL-10, IL-13, IL-17, IL-21, IFN-γ, TNF-α, and IP10. Peripheral blood mononuclear cells (PBMC) were stimulated with HIV peptide pools (15-mers). Student t test and Wilcoxon rank-sum tests were used for statistical analyses with estimation of the false discovery rates (FDR) for controlling test multiplicity.
Results: Vaccine regimen was well tolerated. Median (IQR) CD4 counts were 670 (553 to 832), 668 (530 to 739), and 412 (368 to 527) cells/mm3 at entry, week 24, and week 48, respectively. Following ATI, all patients experienced a viral rebound in 14 days in median (8 to 31). Median highest observed viral load (peak) was 5 (4.22 to 5.23) log10 copies/mL. Eight patients resumed HAART for CD4 <350 cells/mm3. Median (IQR) SFU/106 PBMC rose from 192 (140 to 1150) at week –4 to 875 (580 to 1165) and 1878 (1102 to 4443) at weeks 16 and 48, respectively. At the same time points the breadth of the response (nb of peptide pools) increased from 1 (1 to 3) to 4 (2 to 5) (p = 0.009) and 6 (3 to 7) (p = 0.003). Percent of polyfunctional CD4+ (>2 cytokines among IFN-γ, TNF-α, IL-2) increased from 0.026% (week –4) to 0.32% (week 16) (p = 0.002). Respective % of CD8+ were 0.26% and 0.35% (p = 0.005). Production (MFI or concentrations) of IL-2, IFN-γ, IL-21, IL-13 (FDR <0.05) increased significantly at week 16. An inverse correlation between % of polyfunctionnal CD4+ (r = –0.6, p = 0.01, FDR=.02), production of IL-2 (r=-0.63, P = .009, FDR=.02); IFN-γ (r=0.56, P = .02, FDR=.03) and IL-13 (r = –0.71, p = 0.002, FDR = 0.01) and the peak of viral load was found.
Conclusions: DC vaccination elicited polyfunctional HIV-specific responses associated with a reduced peak of viral load following ATI. Next trials will be designed to improve immunogenicity of the vaccine strategy and its impact on viral reservoir.