Therapeutic immunization with human immunodeficiency virus type 1 (HIV-1) peptide-loaded dendritic cells is safe and induces immunogenicity in HIV-1-infected individuals

Abstract

Treatments for human immunodeficiency virus type 1 (HIV-1)-positive individuals that augment HIV-1 suppression and have potential for achieving long-term control of HIV-1 viremia in the absence of antiretroviral therapy (ART) are urgently needed. We therefore conducted a phase I, clinical safety trial of a dendritic cell (DC)-based vaccination strategy as immunotherapy for HIV-1-positive individuals on ART. We studied 18 HIV-1-positive subjects on ART who underwent leukapheresis to obtain peripheral blood mononuclear cells for DC generation from monocytes cultured with cytokines. Mature DC were pulsed with three HIV-1 HLA*A0201 Gag, Env, and Pol peptides and one influenza A virus matrix protein peptide. The vaccine was administered to donors randomized to receive two vaccinations, either intravenously or subcutaneously. The primary end points were safety and tolerability of two doses of peptide-DC vaccine (3 million versus 10 million). Secondary end points included gamma interferon (IFN-gamma) enzyme-linked immunospot assay responses and clinical correlates of an immune response to vaccination. Autologous DC-peptide vaccine was safe, well tolerated, and feasible for use in all participants. Adverse events were rare. Although the trial was not powered to assess an immunologic response, a significantly increased frequency of HIV-1 peptide-specific IFN-gamma-positive cells was observed 2 weeks following the second vaccine, with three individuals responding to all four peptides. DC vaccination was safe, was feasible, and showed promise of immunogenicity in ART-treated, HIV-1-positive individuals. Additional studies of DC immunization strategies for HIV-1 infection are warranted.

FIG. 1.

ELISPOT responses to vaccine peptides over time for three individuals (subjects 2, 5, and 11) who had significant responses to all vaccine peptides. Although the responses were variable, the best responses were observed at week 6, 2 weeks following the second vaccination. FLU, influenza A virus matrix protein.

FIG. 2.

Actual mean ELISPOT responses per 10⁵ PBMC of all 18 participants. From baseline to week 6, on average, an increase in the frequency of the HIV-1-specific lymphocytes was observed. Responses were highest for the FLU, influenza A virus matrix protein (FLU) peptide, probably as a result of multiple, previous influenza virus vaccinations, but were statistically significant for the Pol and Gag peptides, and there was a trend toward significance for the Env peptide. P values represent a statistically significant increase in spot-forming cells (SFC)/10⁵ PBMC above the prevaccination values. Error bars indicate standard deviations.

FIG. 3.

CD8⁺ T-cell responses to Gag and Env peptides observed from week 0 through week 12 after low- and high-dose vaccination (P = 0.07 for Gag and 0.04 for Env by Wilcoxon rank sum test). SFC, spot-forming cells. Error bars indicate standard deviations.

FIG. 4.

Box plots for each peptide, showing the medians of the groups as a whole. The results demonstrate that within each group there was considerable variability of response as indicated by the frequency of peptide-specific T cells in the peripheral circulation. FLU, influenza A virus matrix protein. SFC, spot-forming cells. Error bars indicate 95% confidence intervals.

FIG. 5.

Actual spot counts (spots/10⁵ cells on the y axis) for responses to Pol (bottom panels) and Env (top panels) by individual subjects (x axis). Hatch patterns represent weeks 0, 4, 6, 8, and 12, respectively. Overall, subjects with higher nadir CD4 cell counts (>150 cells/mm³) (right panels) appeared to respond better to vaccination than subjects with lower nadir CD4 cell counts (≤150 cells/mm³) (left panels).