title: HIV-1 Reservoir Dynamics after Vaccination and Antiretroviral Therapy Interruption Are Associated with Dendritic Cell Vaccine-Induced T Cell Responses.
abstract: HIV-1-specific immune responses induced by a dendritic cell (DC)-based therapeutic vaccine might have some effect on the viral reservoir. Patients on combination antiretroviral therapy (cART) were randomized to receive DCs pulsed with autologous HIV-1 (n = 24) (DC-HIV-1) or nonpulsed DCs (n = 12) (DC-control). We measured the levels of total and integrated HIV-1 DNA in CD4 T cells isolated from these patients at 6 time points: before any cART; before the first cART interruption, which was at 56 weeks before the first immunization to isolate virus for pulsing DCs; before and after vaccinations (VAC1 and VAC2); and at weeks 12 and 48 after the second cART interruption. The vaccinations did not influence HIV-1 DNA levels in vaccinated subjects. After the cART interruption at week 12 postvaccination, while total HIV-1 DNA increased significantly in both arms, integrated HIV-1 DNA did not change in vaccinees (mean of 1.8 log10 to 1.9 copies/10(6) CD4 T cells, P = 0.22) and did increase in controls (mean of 1.8 log10 to 2.1 copies/10(6) CD4 T cells, P = 0.02) (P = 0.03 for the difference between groups). However, this lack of increase of integrated HIV-1 DNA observed in the DC-HIV-1 group was transient, and at week 48 after cART interruption, no differences were observed between the groups. The HIV-1-specific T cell responses at the VAC2 time point were inversely correlated with the total and integrated HIV-1 DNA levels after cART interruption in vaccinees (r [Pearson's correlation coefficient] = -0.69, P = 0.002, and r = -0.82, P < 0.0001, respectively). No correlations were found in controls. HIV-1-specific T cell immune responses elicited by DC therapeutic vaccines drive changes in HIV-1 DNA after vaccination and cART interruption. (This study has been registered at ClinicalTrials.gov under registration no. NCT00402142.)
  
  
  OBJECTIVE
  There is an intense interest in developing strategies to target HIV-1 reservoirs as they create barriers to curing the disease. The development of therapeutic vaccines aimed at enhancing immune-mediated clearance of virus-producing cells is of high priority. Few therapeutic vaccine clinical trials have investigated the role of therapeutic vaccines as a strategy to safely eliminate or control viral reservoirs. We recently reported that a dendritic cell-based therapeutic vaccine was able to significantly decrease the viral set point in vaccinated patients, with a concomitant increase in HIV-1-specific T cell responses. The HIV-1-specific T cell immune responses elicited by this therapeutic dendritic cell vaccine drove changes in the viral reservoir after vaccinations and significantly delayed the replenishment of integrated HIV-1 DNA after cART interruption. These data help in understanding how an immunization could shift the virus-host balance and are instrumental for better design of strategies to reach a functional cure of HIV-1 infection.
authors.affiliation: AIDS Research Group, IDIBAPS-HIVACAT, Hospital Clínic, University of Barcelona, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Andrés
authors.affiliation: AIDS Research Group, IDIBAPS-HIVACAT, Hospital Clínic, University of Barcelona, Barcelona, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Plana
authors.affiliation: AIDS Research Group, IDIBAPS-HIVACAT, Hospital Clínic, University of Barcelona, Barcelona, Spain.
authors.forename: Alberto C
authors.initials: AC
authors.lastname: Guardo
authors.affiliation: AIDS Research Group, IDIBAPS-HIVACAT, Hospital Clínic, University of Barcelona, Barcelona, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Alvarez-Fernández
authors.affiliation: AIDS Research Group, IDIBAPS-HIVACAT, Hospital Clínic, University of Barcelona, Barcelona, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Climent
authors.affiliation: AIDS Research Group, IDIBAPS-HIVACAT, Hospital Clínic, University of Barcelona, Barcelona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Gallart
authors.affiliation: AIDS Research Group, IDIBAPS-HIVACAT, Hospital Clínic, University of Barcelona, Barcelona, Spain.
authors.forename: Agathe
authors.initials: A
authors.lastname: León
authors.affiliation: Hospital Germans Trias i Pujol, IRSICAIXA-HIVACAT, Badalona, Spain.
authors.forename: Bonaventura
authors.initials: B
authors.lastname: Clotet
authors.affiliation: INSERM UMR-S 945, Université Paris VI Pierre et Marie Curie, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Autran
authors.affiliation: Vaccine and Gene Therapy Institute Florida, Port St. Lucie, Florida, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chomont
authors.affiliation: AIDS Research Group, IDIBAPS-HIVACAT, Hospital Clínic, University of Barcelona, Barcelona, Spain.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Gatell
authors.affiliation: AIDS Research Group, IDIBAPS-HIVACAT, Hospital Clínic, University of Barcelona, Barcelona, Spain.
authors.forename: Sonsoles
authors.initials: S
authors.lastname: Sánchez-Palomino
authors.affiliation: AIDS Research Group, IDIBAPS-HIVACAT, Hospital Clínic, University of Barcelona, Barcelona, Spain fgarcia@clinic.ub.es.
authors.forename: Felipe
authors.initials: F
authors.lastname: García
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D000328:Adult; D044966:Anti-Retroviral Agents / Q000008:administration & dosage*; D064592:Autografts; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation; D005260:Female; D015658:HIV Infections / Q000276:immunology / Q000628:therapy*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D014611:Vaccination; D019444:Vaccines, DNA / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology
chemical_list: D016915:AIDS Vaccines; D044966:Anti-Retroviral Agents; D019444:Vaccines, DNA