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

Abstract

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-γ, 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-ß 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-γ production and DTH. At baseline, responders had higher CD8(+) T cell degranulation (p=0.05) and CD4(+) INF-γ production (p=0.01), whereas non-responders had higher production of proinflammatory TNF-α, IL-1α and IL-1ß (p<0.045) and regulatory IL-10 (p=0.07). Notably, IL-10 and TGF-ß 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.

• Authors: Andreas Lind, Kristin Brekke, Maja Sommerfelt, Jens O Holmberg, Hans Christian D Aass, Ingebjørg Baksaas, Birger Sørensen, Anne Ma Dyrhol-Riise, Dag Kvale
• Journal: Vaccine (Vaccine) Vol. 31 Issue 41 Pg. 4611-8 (Sep 23 2013) ISSN: 1873-2518 [Electronic] Netherlands
• PMID: 23906886 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Chemical References

• AIDS Vaccines
• Cytokines
• Vacc-4x
• Granzymes

Topics

• AIDS Vaccines (administration & dosage, immunology)
• CD8-Positive T-Lymphocytes (immunology)
• Cell Proliferation
• Cytokines (metabolism)
• Female
• Granzymes (metabolism)
• HIV-1 (immunology)
• Humans
• Hypersensitivity, Delayed
• Immunization, Secondary (methods)
• Immunosuppression Therapy
• Male
• Middle Aged