title: Balance between activation and regulation of HIV-specific CD8+ T-cell response after modified vaccinia Ankara B therapeutic vaccination.
abstract: BACKGROUND
  The causes of HIV-vaccines failure are poorly understood. Therapeutic vaccination with modified vaccinia Ankara (MVA)-B in HIV-1-infected individuals did not control the virus upon analytical treatment interruption (ATI). We investigated whether the functional characteristics of HIV-specific CD8 T-cell responses stimulated by this vaccine, and the level of exhaustion of these cells might explain these results.
  
  
  METHODS
  Twenty-one HIV-1 chronically infected patients on combination antiretroviral therapy, included in the therapeutic vaccine trial RISVAC03, were studied: 13 immunized and eight controls. Functional characteristics, cytotoxic potential and exhaustion of HIV-specific CD8 T cells, were evaluated by polychromatic flow cytometry. Differences between groups were tested using nonparametric tests.
  
  
  RESULTS
  MVA-B vaccine induced an increase in HIV-specific CD8 T-cell response, but also increased their levels of exhaustion. At week 18 (following three immunizations) the level of response increased with respect to baseline (P = 0.02). A significant increase at weeks 18 and 24 (ATI) in granzyme B content was also observed. Interestingly, an increase in expression of exhaustion markers was found at weeks 18 (P = 0.006) and 24 (P = 0.01). However, there was no significant change in the functional profile of vaccine-induced CD8 cells. At week 36, in parallel to the rebound of plasma viremia after 12 weeks ATI, a significant increase in the level of CD8 response, in granzyme B content and in exhaustion markers expression, was observed in both groups.
  
  
  CONCLUSIONS
  We show that therapeutic vaccination with MVA-B tilts the balance between activation and regulation of the response of HIV-specific CD8 T cells towards regulation, which impacts on the viral rebound after ATI.
authors.affiliation: aIIS-Fundación Jiménez Díaz, UAM, Madrid bHospital Universitario Rey Juan Carlos, Móstoles cIrsicaixa/HIVACAT, Autonomous University of Barcelona, Hospital Germans Trias i Pujol, Badalona dHospital General Universitario Gregorio Marañon, Madrid eHospital Clinic, Barcelona fCentro Nacional de Investigaciones Cardiovasculares CNIC gCentro Nacional de Biotecnologia, Madrid hInstitució Catalana de Recerca i Estudis Avancats (ICREA), Barcelona iUniversity of Vic and Central Catalonia, Vic, Spain.
authors.forename: Norma
authors.initials: N
authors.lastname: Rallón
authors.forename: Beatriz
authors.initials: B
authors.lastname: Mothe
authors.forename: Juan C
authors.initials: JC
authors.lastname: Lopez Bernaldo de Quiros
authors.forename: Montserrat
authors.initials: M
authors.lastname: Plana
authors.forename: José M
authors.initials: JM
authors.lastname: Ligos
authors.forename: María
authors.initials: M
authors.lastname: Montoya
authors.forename: Maria A
authors.initials: MA
authors.lastname: Muñoz-Fernández
authors.forename: Mariano
authors.initials: M
authors.lastname: Esteban
authors.forename: Felipe
authors.initials: F
authors.lastname: Garcia
authors.forename: Christian
authors.initials: C
authors.lastname: Brander
authors.forename: José M
authors.initials: JM
authors.lastname: Benito
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004337:Drug Carriers; D005260:Female; D005434:Flow Cytometry; D005822:Genetic Vectors; D015658:HIV Infections / Q000628:therapy*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics
chemical_list: D016915:AIDS Vaccines; D004337:Drug Carriers; D014614:Vaccines, Synthetic