Sequential Vacc-4x and romidepsin during combination antiretroviral therapy (cART): Immune responses to Vacc-4x regions on p24 and changes in HIV reservoirs

• DOI: 10.1016/j.jinf.2017.09.004
• Publication Date: 2017-09-14T09:33:22Z
• Authors: G. Tapia; J.F. Højen; M. Ökvist; R. Olesen; S. Leth; S.K. Nissen; D.J. VanBelzen; U. O'Doherty; A. Mørk; K. Krogsgaard; O.S. Søgaard; L. Østergaard; M. Tolstrup; G. Pantaleo; M.A. Sommerfelt
• Keywords: Adult; Male; Denmark; CD8-Positive T-Lymphocytes; Romidepsin; 03 medical and health sciences; Depsipeptides; HIV Seropositivity; Journal Article; Humans; AIDS Vaccines; Immunity, Cellular; 0303 health sciences; HDACi; Latency reversal; HIV; Viral Load; Therapeutic vaccine; 16. Peace & justice; Vacc-4x; Virus Latency; 3. Good health; Anti-Retroviral Agents; HIV-1; Cytokines; Drug Therapy, Combination; Female; Immunotherapy

The REDUC clinical study Part B investigated Vacc-4x/rhuGM-CSF therapeutic vaccination prior to HIV latency reversal using romidepsin. The main finding was a statistically significant reduction from baseline in viral reservoir measurements. Here we evaluated HIV-specific functional T-cell responses following Vacc-4x/rhuGM-CSF immunotherapy in relation to virological outcomes on the HIV reservoir.This study, conducted in Aarhus, Denmark, enrolled participants (n = 20) with CD4>500 cells/mm3 on cART. Six Vacc-4x (1.2 mg) intradermal immunizations using rhuGM-CSF (60 μg) as adjuvant were followed by 3 weekly intravenous infusions of romidepsin (5 mg/m2). Immune responses were determined by IFN-γ ELISpot, T-cell proliferation to p24 15-mer peptides covering the Vacc-4x region, intracellular cytokine staining (ICS) to the entire HIVGag and viral inhibition.The frequency of participants with CD8+ T-cell proliferation assay positivity was 8/16 (50%) at baseline, 11/15 (73%) post-vaccination, 6/14 (43%) during romidepsin, and 9/15 (60%)post-romidepsin. Participants with CD8+ T-cell proliferation assay positivity post-vaccination showed reductions in total HIV DNA post-vaccination (p = 0.006; q = 0.183), post-latency reversal (p = 0.005; q = 0.183), and CA-RNA reductions post-vaccination (p = 0.015; q = 0.254). Participants (40%) were defined as proliferation 'Responders' having ≥2-fold increase in assay positivity post-baseline. Robust ELISpot baseline responses were found in 87.5% participants. No significant changes were observed in the proportion of polyfunctional CD8+ T-cells to HIVGag by ICS. There was a trend towards increased viral inhibition from baseline to post-vaccination (p = 0.08).In this 'shock and kill' approach supported by therapeutic vaccination, CD8+ T-cell proliferation represents a valuable means to monitor functional immune responses as part of the path towards functional HIV cure.