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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...

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Autores principales: Ensoli, Barbara, Nchabeleng, Maphoshane, Ensoli, Fabrizio, Tripiciano, Antonella, Bellino, Stefania, Picconi, Orietta, Sgadari, Cecilia, Longo, Olimpia, Tavoschi, Lara, Joffe, Daniel, Cafaro, Aurelio, Francavilla, Vittorio, Moretti, Sonia, Pavone Cossut, Maria Rosaria, Collacchi, Barbara, Arancio, Angela, Paniccia, Giovanni, Casabianca, Anna, Magnani, Mauro, Buttò, Stefano, Levendal, Elise, Ndimande, John Velaphi, Asia, Bennett, Pillay, Yogan, Garaci, Enrico, Monini, Paolo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899930/
https://www.ncbi.nlm.nih.gov/pubmed/27277839
http://dx.doi.org/10.1186/s12977-016-0261-1
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author Ensoli, Barbara
Nchabeleng, Maphoshane
Ensoli, Fabrizio
Tripiciano, Antonella
Bellino, Stefania
Picconi, Orietta
Sgadari, Cecilia
Longo, Olimpia
Tavoschi, Lara
Joffe, Daniel
Cafaro, Aurelio
Francavilla, Vittorio
Moretti, Sonia
Pavone Cossut, Maria Rosaria
Collacchi, Barbara
Arancio, Angela
Paniccia, Giovanni
Casabianca, Anna
Magnani, Mauro
Buttò, Stefano
Levendal, Elise
Ndimande, John Velaphi
Asia, Bennett
Pillay, Yogan
Garaci, Enrico
Monini, Paolo
author_facet Ensoli, Barbara
Nchabeleng, Maphoshane
Ensoli, Fabrizio
Tripiciano, Antonella
Bellino, Stefania
Picconi, Orietta
Sgadari, Cecilia
Longo, Olimpia
Tavoschi, Lara
Joffe, Daniel
Cafaro, Aurelio
Francavilla, Vittorio
Moretti, Sonia
Pavone Cossut, Maria Rosaria
Collacchi, Barbara
Arancio, Angela
Paniccia, Giovanni
Casabianca, Anna
Magnani, Mauro
Buttò, Stefano
Levendal, Elise
Ndimande, John Velaphi
Asia, Bennett
Pillay, Yogan
Garaci, Enrico
Monini, Paolo
author_sort Ensoli, Barbara
collection PubMed
description 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 ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12977-016-0261-1) contains supplementary material, which is available to authorized users.
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spelling pubmed-48999302016-06-10 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 Ensoli, Barbara Nchabeleng, Maphoshane Ensoli, Fabrizio Tripiciano, Antonella Bellino, Stefania Picconi, Orietta Sgadari, Cecilia Longo, Olimpia Tavoschi, Lara Joffe, Daniel Cafaro, Aurelio Francavilla, Vittorio Moretti, Sonia Pavone Cossut, Maria Rosaria Collacchi, Barbara Arancio, Angela Paniccia, Giovanni Casabianca, Anna Magnani, Mauro Buttò, Stefano Levendal, Elise Ndimande, John Velaphi Asia, Bennett Pillay, Yogan Garaci, Enrico Monini, Paolo Retrovirology Research 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 ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12977-016-0261-1) contains supplementary material, which is available to authorized users. BioMed Central 2016-06-09 /pmc/articles/PMC4899930/ /pubmed/27277839 http://dx.doi.org/10.1186/s12977-016-0261-1 Text en © Ensoli et al. 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Ensoli, Barbara
Nchabeleng, Maphoshane
Ensoli, Fabrizio
Tripiciano, Antonella
Bellino, Stefania
Picconi, Orietta
Sgadari, Cecilia
Longo, Olimpia
Tavoschi, Lara
Joffe, Daniel
Cafaro, Aurelio
Francavilla, Vittorio
Moretti, Sonia
Pavone Cossut, Maria Rosaria
Collacchi, Barbara
Arancio, Angela
Paniccia, Giovanni
Casabianca, Anna
Magnani, Mauro
Buttò, Stefano
Levendal, Elise
Ndimande, John Velaphi
Asia, Bennett
Pillay, Yogan
Garaci, Enrico
Monini, Paolo
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899930/
https://www.ncbi.nlm.nih.gov/pubmed/27277839
http://dx.doi.org/10.1186/s12977-016-0261-1
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