Boosters of a therapeutic HIV-1 vaccine induce divergent T cell responses related to regulatory mechanisms

摘要

Therapeutic human immunodeficiency virus (HIV) vaccines aim to reduce disease progression by inducing HIV-specific T cells. Vacc-4x are peptides derived from conserved domains within HIV-1 p24 Gag. Previously, Vacc-4x induced T cell responses in 90% of patients which were associated with reduced viral loads. Here we evaluate the effects of Vacc-4x boosters on T cell immunity and immune regulation seven years after primary immunization. Twenty-five patients on effective antiretroviral therapy received two Vacc-4x doses four weeks apart and were followed for 16 weeks. Vacc-4x T cell responses were measured by proliferation (CFSE), INF-gamma, CD107a, Granzyme B, Delayed-Type Hypersensitivity test (DTH) and cytokines and chemokines (Luminex). Functional regulation of Vacc-4x-specific T cell proliferation was estimated in vitro using anti-IL-10 and anti-TGF-beta monoclonal antibodies. Vacc-4x-specific CD8(+) T cell proliferation increased in 80% after either the first (64%) or second (16%) booster. Only 40% remained responders after two boosters with permanently increased Vacc-4x-specific proliferative responses (p = 0.005) and improved CD8(+) T cell degranulation, IFN-gamma production and DTH. At baseline, responders had higher CD8(+) T cell degranulation (p = 0.05) and CD4(+) INF-gamma production (p = 0.01), whereas non-responders had higher production of proinflammatory TNF-alpha, IL-1 alpha and IL-1 beta (p < 0.045) and regulatory IL-10 (p = 0.07). Notably, IL-10 and TGF-beta mediated downregulation of Vacc-4x-specific CD8(+) T cell proliferation increased only in non-responders (p < 0.001). Downregulation during the study correlated to higher PD-1 expression on Vacc-4x-specific CD8+ T cells (r = 0.44, p = 0.037), but was inversely correlated to changes in Vacc4x-specific CD8(+) T cell proliferation (r = -0.52, p = 0.012). These findings show that Vacc-4x boosters can improve T cell responses in selected patients, but also induce vaccine-specific downregulation of T cell responses in others. Broad surveillance of T cell functions during immunization may help to individualize boosting, where assessment of vaccine-related immune regulation should be further explored as a potential new parameter. (C) 2013 The Authors. Published by Elsevier Ltd. All rights reserved.