title: 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.affiliation: Department of Infectious Diseases, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway. Electronic address: andreas.lind@medisin.uio.no.
authors.forename: Andreas
authors.initials: A
authors.lastname: Lind
authors.forename: Kristin
authors.initials: K
authors.lastname: Brekke
authors.forename: Maja
authors.initials: M
authors.lastname: Sommerfelt
authors.forename: Jens O
authors.initials: JO
authors.lastname: Holmberg
authors.forename: Hans Christian D
authors.initials: HC
authors.lastname: Aass
authors.forename: Ingebjørg
authors.initials: I
authors.lastname: Baksaas
authors.forename: Birger
authors.initials: B
authors.lastname: Sørensen
authors.forename: Anne Ma
authors.initials: AM
authors.lastname: Dyrhol-Riise
authors.forename: Dag
authors.initials: D
authors.lastname: Kvale
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D005260:Female; D053804:Granzymes / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D006968:Hypersensitivity, Delayed; D007117:Immunization, Secondary / Q000379:methods*; D007165:Immunosuppression Therapy; D008297:Male; D008875:Middle Aged
chemical_list: D016915:AIDS Vaccines; D016207:Cytokines; C494182:Vacc-4x; D053804:Granzymes
keywords: HIV-1; Immune regulation; Immune therapy; Immunization; T cells