Therapeutic Vaccination With Dendritic Cells Loaded With Autologous HIV Type 1-Infected Apoptotic Cells

Abstract

Background: We report the results of a phase I/II, open-label, single-arm clinical trial to evaluate the safety and anti-human immunodeficiency virus type 1 (HIV-1) efficacy of an autologous dendritic cell (DC)-based HIV-1 vaccine loaded with autologous HIV-1-infected apoptotic cells.

Methods: Antiretroviral therapy (ART)-naive individuals were enrolled, and viremia was suppressed by ART prior to delivery of 4 doses of DC-based vaccine. Participants underwent treatment interruption 6 weeks after the third vaccine dose. The plasma HIV-1 RNA level 12 weeks after treatment interruption was compared to the pre-ART (ie, baseline) level.

Results: The vaccine was safe and well tolerated but did not prevent viral rebound during treatment interruption. Vaccination resulted in a modest but significant decrease in plasma viremia from the baseline level (from 4.53 log10 copies/mL to 4.27 log10 copies/mL;P= .05). Four of 10 participants had a >0.70 log10 increase in the HIV-1 RNA load in plasma following vaccination, despite continuous ART. Single-molecule sequencing of HIV-1 RNA in plasma before and after vaccination revealed increases in G>A hypermutants in gag and pol after vaccination, which suggests cytolysis of infected cells.

Conclusions: A therapeutic HIV-1 vaccine based on DCs loaded with apoptotic bodies was safe and induced T-cell activation and cytolysis, including HIV-1-infected cells, in a subset of study participants.

Clinical trials registration: NCT00510497.

Keywords: HIV-1; apoptotic cell; dendritic cell; residual viremia; therapeutic vaccine.

© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Figures

Figure 1.

Study design. Virus was obtained from antiretroviral (ART)–naive study participants prior to initiating ART consisting of a protease inhibitor–based regimen. Human immunodeficiency virus type 1 (HIV-1) RNA obtained prior to the viral isolation phase served as the pre-ART specimen (pre-ART). After viral suppression for at least 8 weeks, participants underwent leukapheresis to obtain monocytes and lymphocytes that were used for the ApB DC vaccine. Blood samples obtained at the date of leukapheresis served as the time point before vaccine receipt (pre-V). Four weeks after leukapheresis, participants received 3 vaccine doses (V1–V3) 2 weeks apart. Six weeks after the V3, blood samples were again obtained, after which participants underwent antiretroviral treatment interruption (ATI). A fourth vaccine dose was given 2 weeks after ATI (V4; ATI+2). The primary end point was 12 weeks from the start of ATI.

Figure 2.

Human immunodeficiency virus type 1 (HIV-1) RNA levels in the vaccinated subjects. The figure shows the changes in levels of HIV-1 RNA before antiretroviral therapy (Pre-ART) and at the primary end point, which was 12 weeks from the start of treatment interruption. We observed a modest decrease in the HIV-1 RNA load, from 4.53 log10 copies/mL to 4.27 log10 copies/mL (P = .049, by the Wilcoxon signed rank test).

Figure 3.

Changes of CD8+ T-cell polyfunctional response to Gag p55 peptide pool before vaccine receipt and after vaccine receipt (immediately before antiretroviral treatment interruption [ATI] and at the study end point). The pie charts show the proportion of CD8+ T cells that secreted >1 immune mediator (interleukin 2 [IL-2], interferon γ [IFN-γ], tumor necrosis factor α [TNF-α], macrophage inflammatory protein 1β [MIP-1β], and CD107α) in response to stimulation with Gag peptide. The portion of the pie chart in yellow indicates the proportion of CD8+ T cells that secreted only one immune mediator. CD107α was the most common immune mediator expressed by CD8+ T cells that secreted only 1 immune mediator following stimulation with Gag. Among those that secreted 2 immune mediators, the combination of CD107α and IL-2 was the most common. There were no significant differences in polyfunctional response following vaccinations. There appeared to be a modest increase in polyfunctional response in 4 of 10 participants (red squares) but a decrease in 2 of 10 participants (green squares). Polyfunctional responses did not correlate with viral control at end point.

Figure 4.

Effect of dendritic cell (DC)–based vaccination on T-cell activation. A, Changes in CD8+ T-cell activation before and after vaccine receipt. The frequency of CD8+ T cells coexpressing HLA-DR and CD38 significantly increased after the first vaccine dose (V1). This decreased to frequencies before vaccine receipt by the time immediately before antiretroviral treatment interruption (ATI; ie, 6 weeks after V3). Bar graphs show median values and interquartile ranges. P values were determined by the Wilcoxon signed rank test. B, Changes in CD4+ T-cell activation before and after vaccine receipt. Similar to CD8+ T-cell activation, the frequency of CD4+ T cells coexpressing HLA-DR and CD38 increased after V1 but returned to levels before vaccine receipt 6 weeks after V3. Bar graphs show median values and interquartile ranges. P values were determined by the Wilcoxon signed rank test.

Figure 5.

Changes in residual viremia after ApB dendritic cell (DC) vaccination during ART. Single-copy assay was performed on plasma samples obtained at 3 time points: before vaccine receipt, after vaccine receipt (V2+1) and immediately before antiretroviral treatment [ART] interruption [before ATI]). Despite receiving ART, there was a ≥0.7 log increase (median, 0.75 log) in residual plasma human immunodeficiency virus type 1 (HIV-1) RNA between before vaccine receipt/V2+1 and immediately before ATI time points in 4 of 10 participants.

Figure 6.

The ratio of interleukin 12 (IL-12) to interleukin 10 (IL-10) levels was evaluated to see whether the vaccine was more proinflammatory. The black bars show the individual ratios of IL-12 to IL-10 levels for the 4 of 10 participants who had an increase in residual viremia level (measured by a single-copy assay [SCA]), while the white bars show the ratios for the other 6 participants. The 4 participants with increasing residual viremia after vaccine receipt had significantly higher ratios than the other 6 (1.28 vs 0.041; P = .038).

Figure 7.

Neighbor-joining phylogenetic analyses of single-genome p6-Pro-Pol RNA or DNA sequences obtained from the virus isolated for vaccine production (vaccine prep), before antiretroviral therapy (pre-ART), after vaccine receipt (post-vaccine), and after antiretroviral treatment interruption (ATI) from study participant 9's plasma and peripheral blood mononuclear cells (PBMCs; A) and patient 10's plasma and PBMCs (B). Hypermutant RNA was observed in plasma after vaccination, suggesting that their presence resulted from cell death rather than from packaging into virions. Abbreviation: APD, average pairwise distance.