Abstract
HIV-1-specific CD4+ and CD8+ T lymphocytes are important for HIV-1 replication control. F4/AS01 consists of F4 recombinant fusion protein (containing clade B Gag/p24, Pol/RT, Nef and Gag/p17) formulated in AS01 Adjuvant System, and was shown to induce F4-specific polyfunctional CD4+ T-cell responses in humans. While replication-incompetent recombinant HIV-1/SIV antigen-expressing human adenoviral vectors can elicit high-frequency antigen-specific CD8+ T-cell responses, their use is hampered by widespread pre-existing immunity to human serotypes. Non-human adenovirus serotypes associated with lower prevalence may offer an alternative strategy. We evaluated the immunogenicity of AdC7-GRN (‘A’), a recombinant chimpanzee adenovirus type 7 vector expressing clade B Gag, RT and Nef, and F4/AS01 (‘P’), when delivered intramuscularly in homologous (PP or AA) and heterologous (AAPP or PPAA) prime-boost regimens, in macaques and mice. Vaccine-induced HIV-1-antigen-specific T cells in peripheral blood (macaques), liver, spleen, and intestinal and genital mucosa (mice) were characterized by intracellular cytokine staining. Vaccine-specific IgG antibodies (macaques) were detected using ELISA. In macaques, only the heterologous prime-boost regimens induced polyfunctional, persistent and balanced CD4+ and CD8+ T-cell responses specific to each HIV-1 vaccine antigen. AdC7-GRN priming increased the polyfunctionality of F4/AS01-induced CD4+ T cells. Approximately 50% of AdC7-GRN-induced memory CD8+ T cells exhibited an effector-memory phenotype. HIV-1-specific antibodies were detected with each regimen. In mice, antigen-specific CD4+ and CD8+ T-cell responses were detected in the mucosal and systemic anatomical compartments assessed. When administered in heterologous prime-boost regimens, AdC7-GRN and F4/AS01 candidate vaccines acted complementarily in inducing potent and persistent peripheral blood HIV-1-specific CD4+ and CD8+ T-cell responses and antibodies in macaques. Besides, adenoviral vector priming modulated the cytokine-expression profile of the protein-induced CD4+ T cells. Each regimen induced HIV-1-specific T-cell responses in systemic/local tissues in mice. This suggests that prime-boost regimens combining adjuvanted protein and low-seroprevalent chimpanzee adenoviral vectors represent an attractive vaccination strategy for clinical evaluation.
Highlights
Evidence suggests that CD4+ and CD8+ T lymphocytes play a critical role in controlling human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) replication
HIV-1-specific CD4+ and CD8+ T-cell responses were detected by flow cytometry
CD4+ T-cell responses following homologous prime-boost regimens peaked two weeks after the second immunization at Weeks 6 or 14, with HIV-1-specific CD4+ T-cell responses that were significantly higher for F4/AS01 than for AdC7-GRN (p
Summary
Evidence suggests that CD4+ and CD8+ T lymphocytes play a critical role in controlling human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) replication. The appearance of virus-specific CD8+ T cells is closely associated with the initial drop in viremia occurring during primary HIV-1 infection [1,2,3], and vaccine-induced effector memory T-cell responses were shown to control pathogenic SIVmac239 replication in rhesus macaques, with some evidence of viral clearance [4,5]. There appears to be an inverse relationship between HIV-1-specific CD4+ T-cell functions and viral load [6]. Studies in long-term non-progressors and HIV controllers revealed that the presence of specific, polyfunctional CD4+ and CD8+ T cells in HIV-infected patients is associated with longterm non-progressing disease and low viral load [9,10,11,12,13]. While the ultimate objective of vaccine development efforts is the generation of a preventive HIV-1 vaccine inducing sterilizing immunity based on protective antibodies, a vaccine that is able to induce potent and polyfunctional T cell-mediated immune responses may be beneficial in controlling viral replication in the early stages of infection (reviewed in [14,15])
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