HIV-Tat immunization induces cross-clade neutralizing antibodies and CD4(+) T cell increases in antiretroviral-treated South African volunteers: a randomized phase II clinical trial.
BACKGROUND
Although combined antiretroviral therapy (cART) has saved millions of lives, it is incapable of full immune reconstitution and virus eradication. The transactivator of transcription (Tat) protein is a key human immunodeficiency virus (HIV) virulence factor required for virus replication and transmission. Tat is expressed and released extracellularly by infected cells also under cART and in this form induces immune dysregulation, and promotes virus reactivation, entry and spreading. Of note, anti-Tat antibodies are rare in natural infection and, when present, correlate with asymptomatic state and reduced disease progression. This suggested that induction of anti-Tat antibodies represents a pathogenesis-driven intervention to block progression and to intensify cART. Indeed Tat-based vaccination was safe, immunogenic and capable of immune restoration in an open-label, randomized phase II clinical trial conducted in 168 cART-treated volunteers in Italy. To assess whether B-clade Tat immunization would be effective also in patients with different genetic background and infecting virus, a phase II trial was conducted in South Africa.


METHODS
The ISS T-003 was a 48-week randomised, double-blinded, placebo-controlled trial to evaluate immunogenicity (primary endpoint) and safety (secondary endpoint) of B-clade Tat (30 μg) given intradermally, three times at 4-week intervals, in 200 HIV-infected adults on effective cART (randomised 1:1) with CD4(+) T-cell counts ≥200 cells/µL. Study outcomes also included cross-clade anti-Tat antibodies, neutralization, CD4(+) T-cell counts and therapy compliance.


RESULTS
Immunization was safe and well-tolerated and induced durable, high titers anti-Tat B-clade antibodies in 97 % vaccinees. Anti-Tat antibodies were cross-clade (all vaccinees tested) and neutralized Tat-mediated entry of oligomeric B-clade and C-clade envelope in dendritic cells (24 participants tested). Anti-Tat antibody titers correlated positively with neutralization. Tat vaccination increased CD4(+) T-cell numbers (all participants tested), particularly when baseline levels were still low after years of therapy, and this had a positive correlation with HIV neutralization. Finally, in cART non-compliant patients (24 participants), vaccination contained viral load rebound and maintained CD4(+) T-cell numbers over study entry levels as compared to placebo.


CONCLUSIONS
The data indicate that Tat vaccination can restore the immune system and induces cross-clade neutralizing anti-Tat antibodies in patients with different genetic backgrounds and infecting viruses, supporting the conduct of phase III studies in South Africa. Trial registration ClinicalTrials.gov NCT01513135, 01/23/2012.
National AIDS Center, Istituto Superiore di Sanità, Rome, Italy. barbara.ensoli@iss.it.
Barbara
B
Ensoli
MeCRU, Sefako Makgatho Health Sciences University (SMU), Ga-Rankuwa, South Africa.
Maphoshane
M
Nchabeleng
Laboratory of Clinical Pathology and Microbiology, San Gallicano Institute, Istituti Fisioterapici Ospitalieri, Rome, Italy.
Fabrizio
F
Ensoli
National AIDS Center, Istituto Superiore di Sanità, Rome, Italy.|Laboratory of Clinical Pathology and Microbiology, San Gallicano Institute, Istituti Fisioterapici Ospitalieri, Rome, Italy.
Antonella
A
Tripiciano
National AIDS Center, Istituto Superiore di Sanità, Rome, Italy.|National Center for Epidemiology, Surveillance and Health Promotion, Istituto Superiore di Sanità, Rome, Italy.
Stefania
S
Bellino
National AIDS Center, Istituto Superiore di Sanità, Rome, Italy.
Orietta
O
Picconi
National AIDS Center, Istituto Superiore di Sanità, Rome, Italy.
Cecilia
C
Sgadari
National AIDS Center, Istituto Superiore di Sanità, Rome, Italy.|Italian Medicines Agency, Rome, Italy.
Olimpia
O
Longo
Head Office, National AIDS Center, Istituto Superiore di Sanità, Cape Town, South Africa.|European Center for Disease Prevention and Control, Stockholm, Sweden.
Lara
L
Tavoschi
Head Office, National AIDS Center, Istituto Superiore di Sanità, Cape Town, South Africa.
Daniel
D
Joffe
National AIDS Center, Istituto Superiore di Sanità, Rome, Italy.
Aurelio
A
Cafaro
National AIDS Center, Istituto Superiore di Sanità, Rome, Italy.|Laboratory of Clinical Pathology and Microbiology, San Gallicano Institute, Istituti Fisioterapici Ospitalieri, Rome, Italy.
Vittorio
V
Francavilla
National AIDS Center, Istituto Superiore di Sanità, Rome, Italy.
Sonia
S
Moretti
National AIDS Center, Istituto Superiore di Sanità, Rome, Italy.
Maria Rosaria
MR
Pavone Cossut
National AIDS Center, Istituto Superiore di Sanità, Rome, Italy.
Barbara
B
Collacchi
National AIDS Center, Istituto Superiore di Sanità, Rome, Italy.|Laboratory of Clinical Pathology and Microbiology, San Gallicano Institute, Istituti Fisioterapici Ospitalieri, Rome, Italy.
Angela
A
Arancio
National AIDS Center, Istituto Superiore di Sanità, Rome, Italy.|Laboratory of Clinical Pathology and Microbiology, San Gallicano Institute, Istituti Fisioterapici Ospitalieri, Rome, Italy.
Giovanni
G
Paniccia
Department of Biomolecular Science, University of Urbino, Urbino, Italy.
Anna
A
Casabianca
Department of Biomolecular Science, University of Urbino, Urbino, Italy.
Mauro
M
Magnani
National AIDS Center, Istituto Superiore di Sanità, Rome, Italy.
Stefano
S
Buttò
South African Medical Research Council, Cape Town, South Africa.|Health Systems Trust, Cape Town, South Africa.
Elise
E
Levendal
Department of Health, Marshall Town, Gauteng Province, South Africa.
John Velaphi
JV
Ndimande
National Department of Health, Pretoria, South Africa.
Bennett
B
Asia
National Department of Health, Pretoria, South Africa.
Yogan
Y
Pillay
Istituto Superiore di Sanità, Rome, Italy.|University of Tor Vergata, Rome, Italy.
Enrico
E
Garaci
Head Office, National AIDS Center, Istituto Superiore di Sanità, Cape Town, South Africa.
Paolo
P
Monini
D016915:AIDS Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology*; D000293:Adolescent; D000328:Adult; D057134:Antibodies, Neutralizing / Q000097:blood*; D023241:Antiretroviral Therapy, Highly Active; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003429:Cross Reactions; D005260:Female; D015483:HIV Antibodies / Q000097:blood*; D015658:HIV Infections / Q000276:immunology* / Q000628:therapy* / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007115:Immunization Schedule; D000071497:Immunogenicity, Vaccine; D008297:Male; D008875:Middle Aged; D013019:South Africa; D014611:Vaccination; D019562:Viral Load; D055815:Young Adult; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D054322:tat Gene Products, Human Immunodeficiency Virus
AIDS; CD4+ T cells; Clinical trials; Cross-clade antibodies; HIV; Neutralization; Tat; Therapy intensification; Vaccine; cART