HIV-1 Tat immunization restores immune homeostasis and attacks the HAART-resistant blood HIV DNA: results of a randomized phase II exploratory clinical trial.
BACKGROUND
The phase II multicenter, randomized, open label, therapeutic trial (ISS T-002, Clinicaltrials.gov NCT00751595) was aimed at evaluating the immunogenicity and the safety of the biologically active HIV-1 Tat protein administered at 7.5 or 30 μg, given 3 or 5 times monthly, and at exploring immunological and virological disease biomarkers. The study duration was 48 weeks, however, vaccinees were followed until the last enrolled subject reached the 48 weeks. Reported are final data up to 144 weeks of follow-up. The ISS T-002 trial was conducted in 11 clinical centers in Italy on 168 HIV positive subjects under Highly Active Antiretroviral Therapy (HAART), anti-Tat Antibody (Ab) negative at baseline, with plasma viremia <50 copies/mL in the last 6 months prior to enrollment, and CD4(+) T-cell number ≥200 cells/μL. Subjects from a parallel observational study (ISS OBS T-002, Clinicaltrials.gov NCT0102455) enrolled at the same clinical sites with the same criteria constituted an external reference group to explore biomarkers of disease.


RESULTS
The vaccine was safe and well tolerated and induced anti-Tat Abs in most patients (79%), with the highest frequency and durability in the Tat 30 μg groups (89%) particularly when given 3 times (92%). Vaccination promoted a durable and significant restoration of T, B, natural killer (NK) cells, and CD4(+) and CD8(+) central memory subsets. Moreover, a significant reduction of blood proviral DNA was seen after week 72, particularly under PI-based regimens and with Tat 30 μg given 3 times (30 μg, 3x), reaching a predicted 70% decay after 3 years from vaccination with a half-life of 88 weeks. This decay was significantly associated with anti-Tat IgM and IgG Abs and neutralization of Tat-mediated entry of oligomeric Env in dendritic cells, which predicted HIV-1 DNA decay. Finally, the 30 μg, 3x group was the only one showing significant increases of NK cells and CD38(+)HLA-DR(+)/CD8(+) T cells, a phenotype associated with increased killing activity in elite controllers.


CONCLUSIONS
Anti-Tat immune responses are needed to restore immune homeostasis and effective anti-viral responses capable of attacking the virus reservoir. Thus, Tat immunization represents a promising pathogenesis-driven intervention to intensify HAART efficacy.
Pathology and Microbiology, San Gallicano Institute, Istituti Fisioterapici Ospitalieri, Rome, Italy. ensoli@ifo.it.
Fabrizio
F
Ensoli
National AIDS Center, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome, 00161, Italy. aurelio.cafaro@iss.it.
Aurelio
A
Cafaro
Department of Biomolecular Science, University of Urbino, Urbino, Italy. anna.casabianca@uniurb.it.
Anna
A
Casabianca
Pathology and Microbiology, San Gallicano Institute, Istituti Fisioterapici Ospitalieri, Rome, Italy. tripiciano@ifo.it.|National AIDS Center, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome, 00161, Italy. tripiciano@ifo.it.
Antonella
A
Tripiciano
National AIDS Center, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome, 00161, Italy. stefania.bellino@iss.it.
Stefania
S
Bellino
National AIDS Center, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome, 00161, Italy. olimpia.longo@iss.it.
Olimpia
O
Longo
Pathology and Microbiology, San Gallicano Institute, Istituti Fisioterapici Ospitalieri, Rome, Italy. francavilla@ifo.it.|National AIDS Center, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome, 00161, Italy. francavilla@ifo.it.
Vittorio
V
Francavilla
National AIDS Center, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome, 00161, Italy. orietta.picconi@iss.it.
Orietta
O
Picconi
National AIDS Center, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome, 00161, Italy. cecilia.sgadari@iss.it.
Cecilia
C
Sgadari
National AIDS Center, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome, 00161, Italy. sonia.moretti@iss.it.
Sonia
S
Moretti
National AIDS Center, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome, 00161, Italy. mariarosaria.pavonecossut@iss.it.
Maria R Pavone
MR
Cossut
Pathology and Microbiology, San Gallicano Institute, Istituti Fisioterapici Ospitalieri, Rome, Italy. arancio@ifo.it.|National AIDS Center, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome, 00161, Italy. arancio@ifo.it.
Angela
A
Arancio
Department of Biomolecular Science, University of Urbino, Urbino, Italy. chiara.orlandi@uniurb.it.
Chiara
C
Orlandi
National AIDS Center, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome, 00161, Italy. leonardo.sernicola@iss.it.
Leonardo
L
Sernicola
National AIDS Center, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome, 00161, Italy. mariateresa.maggiorella@iss.it.
Maria T
MT
Maggiorella
Pathology and Microbiology, San Gallicano Institute, Istituti Fisioterapici Ospitalieri, Rome, Italy. paniccia@ifo.it.|National AIDS Center, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome, 00161, Italy. paniccia@ifo.it.
Giovanni
G
Paniccia
Division of Infectious Diseases, University Policlinic of Modena, Modena, Italy. crimuss@unimore.it.
Cristina
C
Mussini
Division of Infectious Diseases, S. Raffaele Hospital, Milan, Italy. lazzarin.adriano@hsr.it.
Adriano
A
Lazzarin
Unit of Infectious Diseases, University Hospital of Ferrara, Ferrara, Italy. l.sighinolfi@ospfe.it.
Laura
L
Sighinolfi
Department of Infectious Dermatology, San Gallicano Hospital, Rome, Italy. palamara@ifo.it.
Guido
G
Palamara
Division of Infectious Diseases, San Gerardo Hospital, Monza, Italy. andrea.gori@unimib.it.
Andrea
A
Gori
Division of Infectious Diseases, University of Bari, Policlinic Hospital, Bari, Italy. gioacchino.angarano@uniba.it.
Gioacchino
G
Angarano
Unit of Infectious Diseases, S.M. Annunziata Hospital, Florence, Italy. massimo.dipietro@asf.toscana.it.
Massimo
M
Di Pietro
Institute of Tropical and Infectious Diseases, L. Sacco Hospital, University of Milan, Milan, Italy. massimo.galli@unimi.it.
Massimo
M
Galli
Department of Infectious Diseases, S. Maria Goretti Hospital, Latina, Italy. vitomercury@gmail.com.
Vito S
VS
Mercurio
Division of Tropical and Infectious Diseases, Spedali Civili, Brescia, Italy. francesco.castelli@unibs.it.
Francesco
F
Castelli
Clinic of Infectious Diseases, Amedeo di Savoia Hospital, Turin, Italy. giovanni.diperri@unito.it.
Giovanni
G
Di Perri
National AIDS Center, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome, 00161, Italy. paolo.monini@iss.it.
Paolo
P
Monini
Department of Biomolecular Science, University of Urbino, Urbino, Italy. mauro.magnani@uniurb.it.
Mauro
M
Magnani
Istituto Superiore di Sanità, Rome, Italy, present address University of Tor Vergata, Rome, 00173, Italy. garaci@med.uniroma2.it.
Enrico
E
Garaci
National AIDS Center, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome, 00161, Italy. barbara.ensoli@iss.it.
Barbara
B
Ensoli
D016915:AIDS Vaccines / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology*; D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000628:therapy*; D000328:Adult; D057134:Antibodies, Neutralizing / Q000097:blood; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D018791:CD4 Lymphocyte Count; D005260:Female; D005500:Follow-Up Studies; D015483:HIV Antibodies / Q000097:blood*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D007558:Italy; D007962:Leukocytes / Q000276:immunology; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D019562:Viral Load; D055815:Young Adult; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D054322:tat Gene Products, Human Immunodeficiency Virus