title: Therapeutic immunization with HIV-1 Tat reduces immune activation and loss of regulatory T-cells and improves immune function in subjects on HAART.
abstract: Although HAART suppresses HIV replication, it is often unable to restore immune homeostasis. Consequently, non-AIDS-defining diseases are increasingly seen in treated individuals. This is attributed to persistent virus expression in reservoirs and to cell activation. Of note, in CD4(+) T cells and monocyte-macrophages of virologically-suppressed individuals, there is continued expression of multi-spliced transcripts encoding HIV regulatory proteins. Among them, Tat is essential for virus gene expression and replication, either in primary infection or for virus reactivation during HAART, when Tat is expressed, released extracellularly and exerts, on both the virus and the immune system, effects that contribute to disease maintenance. Here we report results of an ad hoc exploratory interim analysis (up to 48 weeks) on 87 virologically-suppressed HAART-treated individuals enrolled in a phase II randomized open-label multicentric clinical trial of therapeutic immunization with Tat (ISS T-002). Eighty-eight virologically-suppressed HAART-treated individuals, enrolled in a parallel prospective observational study at the same sites (ISS OBS T-002), served for intergroup comparison. Immunization with Tat was safe, induced durable immune responses, and modified the pattern of CD4(+) and CD8(+) cellular activation (CD38 and HLA-DR) together with reduction of biochemical activation markers and persistent increases of regulatory T cells. This was accompanied by a progressive increment of CD4(+) T cells and B cells with reduction of CD8(+) T cells and NK cells, which were independent from the type of antiretroviral regimen. Increase in central and effector memory and reduction in terminally-differentiated effector memory CD4(+) and CD8(+) T cells were accompanied by increases of CD4(+) and CD8(+) T cell responses against Env and recall antigens. Of note, more immune-compromised individuals experienced greater therapeutic effects. In contrast, these changes were opposite, absent or partial in the OBS population. These findings support the use of Tat immunization to intensify HAART efficacy and to restore immune homeostasis.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00751595.
authors.affiliation: National AIDS Center, Istituto Superiore di Sanità, Rome, Italy. barbara.ensoli@iss.it
authors.forename: Barbara
authors.initials: B
authors.lastname: Ensoli
authors.forename: Stefania
authors.initials: S
authors.lastname: Bellino
authors.forename: Antonella
authors.initials: A
authors.lastname: Tripiciano
authors.forename: Olimpia
authors.initials: O
authors.lastname: Longo
authors.forename: Vittorio
authors.initials: V
authors.lastname: Francavilla
authors.forename: Simone
authors.initials: S
authors.lastname: Marcotullio
authors.forename: Aurelio
authors.initials: A
authors.lastname: Cafaro
authors.forename: Orietta
authors.initials: O
authors.lastname: Picconi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Paniccia
authors.forename: Arianna
authors.initials: A
authors.lastname: Scoglio
authors.forename: Angela
authors.initials: A
authors.lastname: Arancio
authors.forename: Cristina
authors.initials: C
authors.lastname: Ariola
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Ruiz Alvarez
authors.forename: Massimo
authors.initials: M
authors.lastname: Campagna
authors.forename: Donato
authors.initials: D
authors.lastname: Scaramuzzi
authors.forename: Cristina
authors.initials: C
authors.lastname: Iori
authors.forename: Roberto
authors.initials: R
authors.lastname: Esposito
authors.forename: Cristina
authors.initials: C
authors.lastname: Mussini
authors.forename: Florio
authors.initials: F
authors.lastname: Ghinelli
authors.forename: Laura
authors.initials: L
authors.lastname: Sighinolfi
authors.forename: Guido
authors.initials: G
authors.lastname: Palamara
authors.forename: Alessandra
authors.initials: A
authors.lastname: Latini
authors.forename: Gioacchino
authors.initials: G
authors.lastname: Angarano
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Ladisa
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Soscia
authors.forename: Vito S
authors.initials: VS
authors.lastname: Mercurio
authors.forename: Adriano
authors.initials: A
authors.lastname: Lazzarin
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Tambussi
authors.forename: Raffaele
authors.initials: R
authors.lastname: Visintini
authors.forename: Francesco
authors.initials: F
authors.lastname: Mazzotta
authors.forename: Massimo
authors.initials: M
authors.lastname: Di Pietro
authors.forename: Massimo
authors.initials: M
authors.lastname: Galli
authors.forename: Stefano
authors.initials: S
authors.lastname: Rusconi
authors.forename: Giampiero
authors.initials: G
authors.lastname: Carosi
authors.forename: Carlo
authors.initials: C
authors.lastname: Torti
authors.forename: Giovanni
authors.initials: G
authors.lastname: Di Perri
authors.forename: Stefano
authors.initials: S
authors.lastname: Bonora
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Ensoli
authors.forename: Enrico
authors.initials: E
authors.lastname: Garaci
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology; D000328:Adult; D000368:Aged; D023241:Antiretroviral Therapy, Highly Active; D001247:Asthenia / Q000209:etiology; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003131:Combined Modality Therapy; D005260:Female; D015658:HIV Infections / Q000276:immunology* / Q000628:therapy / Q000821:virology; D015497:HIV-1 / Q000276:immunology* / Q000378:metabolism; D006706:Homeostasis / Q000276:immunology; D006801:Humans; D007114:Immunization / Q000009:adverse effects / Q000379:methods; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000209:etiology; D011446:Prospective Studies; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D016896:Treatment Outcome; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; C421254:human immunodeficiency virus type 1 Tat vaccine; D054322:tat Gene Products, Human Immunodeficiency Virus