Adenovirus 5‐ and 35‐based immunotherapy enhances the strength but not breadth or quality of immunity during chronic SIV infection

Abstract

Heterologous adenovirus-based vectors hold promise as preventative HIV vaccines but their capacity to induce effective T-cell immunity in established infection has not been explored. We vaccinated rhesus macaques chronically infected with SIVmac251 and undergoing antiretroviral therapy (ART) with human adenovirus serotype 5-based vectors expressing SIV Gag, Env, and Nef with and without IL-15 and evaluated vaccine immunogenicity. Vaccination increased Ag-specific T cells 20-fold but did not expand the breadth of epitopes recognized or the quality of response, as the majority of CD8 1 and CD4 1 T cells produced only one cytokine irrespective of vaccination. Immunization transiently restored blood CD4 1 central memory T cells (Tcm) and boosted CD4 1 and CD81 Tcm and effector cell responses but did not prevent virus rebound upon cessation of ART. Boosting with human adenovirus serotype 35-based vectors during a second ART cycle increased Ag-specific T cells to 50-fold above pre-vaccination levels and boosted CD4 1 Tcm numbers but did not expand the breadth or quality of immunity or control virus levels following drug discontinuation. The number of blood CD4 1 Tcm correlated positively with complexity of T-cell responses and negatively with virus load, suggesting that more complete restoration of this subset through vaccination would be beneficial.Key words: Cellular immunology . HIV . Vaccination . Virology IntroductionAdenovirus (Ad)-based vectors have arisen as leading vaccine candidates for the prevention of HIV infection [1][2][3] based on studies in rhesus macaques demonstrating robust immunogenicity and control of infection with SIV/HIV hybrid viruses and the pathogenic SIVmac251 strain [4][5][6]. However, the recent failure of the Merck Phase IIB STEP trial of a replication-defective human adenovirus serotype 5 (Ad5)-based vaccine against HIV in humans has raised concerns over the nature of the immune response induced by these vectors [7][8][9] and has placed renewed emphasis on nonhuman primate models to address this issue Eur. J. Immunol. 2009. 39: 2437-2449 DOI 10.1002 Immunity to infection 2437 [10]. Mounting evidence suggests that the quality of the T-cell response may be as important as the magnitude of this response in containing infection [11], with durable control of HIV associated with Ag-specific CD4 1 and CD8 1 T cells producing multiple cytokines and chemokines [12][13][14][15]. Immunogenicity studies indicate that Ad5-based vectors promote restricted cellular immunity consisting of CD8 1 T-cell-dominated responses devoid of IL-2 production [16][17][18]. In contrast, combining Ad5 with rare heterologous Ad-based vectors increases the magnitude, breadth, and quality of vaccine-induced T-cell response and significantly controls SIV infection in monkeys [6,17]. These and other studies in mice [19,20] suggest that prime-boost vaccine strategies that combine Ad5 with other viral vectors may be effective at generating superior T-cell responses against HIV. While emphasis has been placed on evaluating...

Early Myeloid Dendritic Cell Dysregulation is Predictive of Disease Progression in Simian Immunodeficiency Virus Infection

“…Immunotherapy consisted of priming with Ad serotype 5 (Ad5)-based vectors expressing SIV Gag, Env and Nef with or without IL-15 at weeks 16 and 22 followed by boosting with Ad35-based vectors expressing the same transgenes at weeks 36 and 42. Control-treated animals were given the same regimen of Ad5-ψ5 and Ad35-ψ5 vectors that lacked transgenes [20]. Ad-based immunotherapy boosted T cell responses to SIV but had no effect on virus load, progression to disease or survival [20](and data not shown).…”

“…Control-treated animals were given the same regimen of Ad5-ψ5 and Ad35-ψ5 vectors that lacked transgenes [20]. Ad-based immunotherapy boosted T cell responses to SIV but had no effect on virus load, progression to disease or survival [20](and data not shown). However, when analyzed independent of immunotherapy, animals in the cohort could be readily separated into two groups based on disease progression, with one group remaining healthy until elective sacrifice at a mean of 60 weeks post infection (n = 11, ‘stable’ group), and the other succumbing to AIDS with a mean survival time of 32 weeks (n = 10, ‘progressor’ group, Table 1).…”

“…Animals in this study were enrolled in an immunotherapy protocol using Ad-based vectors the majority of which has been previously described [20]. Animals were infected with the pathogenic isolate SIVmac251 by intravenous inoculation and received ART consisting of a combination of two reverse transcriptase inhibitors, 9-[2-(phosphonyl-methoxy)propyl]adenine (PMPA) and 2′-deoxy-5-fluoro-3′-thia-cytidine (FTC), from weeks 12 to 24 and weeks 32 to 44, depending on survival.…”

“…Blood mDC were identified in peripheral blood mononuclear cells (PBMC) as CD45 + lineage − HLA-DR + CD11c + cells (Figure 2A) and were enumerated based on the ratio of mDC to CD4 + T cells [20], [24]. Staining of blood cells with antibody to CD11c was inconsistent in animals R487 (stable group) and M5406 (progressor group) making it difficult to delineate mDC at all time points (data not shown), and as a result these animals were not studied further.…”

Comparable Genital Tract Infection, Pathology, and Immunity in Rhesus Macaques Inoculated with Wild-Type or Plasmid-Deficient Chlamydia trachomatis Serovar D

“…Central memory T cells (T CM ) are CD28 ϩ CD95 ϩ , and effector memory T cells (T EM ) are CD28 Ϫ CD95 ϩ (see Fig. S5 in the supplemental material) (27,28). The frequency of Chlamydia-specific CD4 ϩ T EM was significantly increased in the peripheral blood of controllers at week 2 (Fig.…”