Adenovirus 5- and 35-based immunotherapy enhances the strength but not breadth or quality of immunity during chronic SIV infection.
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(+) and CD4(+) T cells produced only one cytokine irrespective of vaccination. Immunization transiently restored blood CD4(+) central memory T cells (Tcm) and boosted CD4(+) and CD8(+) 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(+) Tcm numbers but did not expand the breadth or quality of immunity or control virus levels following drug discontinuation. The number of blood CD4(+) 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.
Soloff
Adam C
AC
Department of Infectious Diseases, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
Liu
Xiangdong
X
Gao
Wentao
W
Day
Richard D
RD
Gambotto
Andrea
A
Barratt-Boyes
Simon M
SM
D000260:Adenoviruses, Human; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D002908:Chronic Disease; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D015686:Gene Products, env / Q000235:genetics / Q000276:immunology; D015683:Gene Products, gag / Q000235:genetics / Q000276:immunology; D005822:Genetic Vectors; D006801:Humans; D016233:Immunotherapy, Active / Q000379:methods*; D019409:Interleukin-15 / Q000276:immunology* / Q000378:metabolism; D008253:Macaca mulatta; D018449:SAIDS Vaccines / Q000235:genetics / Q000627:therapeutic use*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000628:therapy*; D015302:Simian Immunodeficiency Virus / Q000276:immunology; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics / Q000276:immunology
D016207:Cytokines; D015686:Gene Products, env; D015683:Gene Products, gag; D019409:Interleukin-15; C429284:NEF protein, SIV; D018449:SAIDS Vaccines; D054334:Viral Regulatory and Accessory Proteins