Continued Decay of HIV Proviral DNA Upon Vaccination With HIV-1 Tat of Subjects on Long-Term ART: An 8-Year Follow-Up Study

Cecilia Sgadari, Paolo Monini, Antonella Tripiciano, Orietta Picconi, Anna Casabianca, Chiara Orlandi, Sonia Moretti, Vittorio Francavilla, Angela Arancio, Giovanni Paniccia, Massimo Campagna, Stefania Bellino, Marianna Meschiari, Silvia Nozza, Laura Sighinolfi, Alessandra Latini, Antonio Muscatello, Annalisa Saracino, Massimo Di Pietro, Massimo GalliAurelio Cafaro, Mauro Magnani, Fabrizio Ensoli, Barbara Ensoli

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Abstract

Introduction: Tat, a key HIV virulence protein, has been targeted for the development of a therapeutic vaccine aimed at cART intensification. Results from phase II clinical trials in Italy (ISS T-002) and South Africa (ISS T-003) indicated that Tat vaccination promotes increases of CD4+ T-cells and return to immune homeostasis while reducing the virus reservoir in chronically cART-treated patients. Here we present data of 92 vaccinees (59% of total vaccinees) enrolled in the ISS T-002 8-year extended follow-up study (ISS T-002 EF-UP, ClinicalTrials.gov NCT02118168). Results: Anti-Tat antibodies (Abs) induced upon vaccination persisted for the entire follow-up in 34/92 (37%) vaccinees, particularly when all 3 Ab classes (A/G/M) were present (66% of vaccinees), as most frequently observed with Tat 30 μg regimens. CD4+ T cells increased above study-entry levels reaching a stable plateau at year 5 post-vaccination, with the highest increase (165 cells/μL) in the Tat 30 μg, 3 × regimen. CD4+ T-cell increase occurred even in subjects with CD4+ nadir ≤ 250 cells/uL and in poor immunological responders and was associated with a concomitant increase of the CD4+/CD8+ T-cell ratio, a prognostic marker of morbidity/mortality inversely related to HIV reservoir size. Proviral DNA load decreased over time, with a half-life of 2 years and an estimated 90% reduction at year 8 in the Tat 30 μg, 3 × group. In multivariate analysis the kinetic and amplitude of both CD4+ T-cell increase and proviral DNA reduction were fastest and highest in subjects with all 3 anti-Tat Ab classes and in the 30 μg, 3 × group, irrespective of drug regimens (NNRTI/NRTI vs. PI). HIV proviral DNA changes from baseline were inversely related to CD4+/CD8+ T-cell ratio and CD4+ T-cell changes, and directly related to the changes of CD8+ T cells. Further, HIV DNA decay kinetics were inversely related to the frequency and levels of intermittent viremia. Finally, Tat vaccination was similarly effective irrespective of the individual immunological status or HIV reservoir size at study entry. Conclusions: Tat immunization induces progressive immune restoration and reduction of virus reservoirs above levels reached with long-term cART, and may represent an optimal vaccine candidate for cART intensification toward HIV reservoirs depletion, functional cure, and eradication strategies.

Original languageEnglish
Number of pages1
JournalFrontiers in Immunology
Volume10
DOIs
Publication statusPublished - Jan 1 2019

Fingerprint

HIV-1
Vaccination
HIV
T-Lymphocytes
DNA
Vaccines
Viruses
Human Immunodeficiency Virus Proteins
Phase II Clinical Trials
Viremia
South Africa
Italy
Half-Life
Virulence
Anti-Idiotypic Antibodies
Immunization
Homeostasis
Multivariate Analysis
Morbidity
Mortality

Keywords

  • anti-Tat antibodies
  • cART
  • CD4+ T cells
  • CD4+/CD8+ T-cell ratio
  • HIV reservoirs
  • HIV therapeutic vaccine
  • proviral DNA
  • Tat

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

@article{88c3558d48104ab4ac4ce43c12b2bb75,
title = "Continued Decay of HIV Proviral DNA Upon Vaccination With HIV-1 Tat of Subjects on Long-Term ART: An 8-Year Follow-Up Study",
abstract = "Introduction: Tat, a key HIV virulence protein, has been targeted for the development of a therapeutic vaccine aimed at cART intensification. Results from phase II clinical trials in Italy (ISS T-002) and South Africa (ISS T-003) indicated that Tat vaccination promotes increases of CD4+ T-cells and return to immune homeostasis while reducing the virus reservoir in chronically cART-treated patients. Here we present data of 92 vaccinees (59{\%} of total vaccinees) enrolled in the ISS T-002 8-year extended follow-up study (ISS T-002 EF-UP, ClinicalTrials.gov NCT02118168). Results: Anti-Tat antibodies (Abs) induced upon vaccination persisted for the entire follow-up in 34/92 (37{\%}) vaccinees, particularly when all 3 Ab classes (A/G/M) were present (66{\%} of vaccinees), as most frequently observed with Tat 30 μg regimens. CD4+ T cells increased above study-entry levels reaching a stable plateau at year 5 post-vaccination, with the highest increase (165 cells/μL) in the Tat 30 μg, 3 × regimen. CD4+ T-cell increase occurred even in subjects with CD4+ nadir ≤ 250 cells/uL and in poor immunological responders and was associated with a concomitant increase of the CD4+/CD8+ T-cell ratio, a prognostic marker of morbidity/mortality inversely related to HIV reservoir size. Proviral DNA load decreased over time, with a half-life of 2 years and an estimated 90{\%} reduction at year 8 in the Tat 30 μg, 3 × group. In multivariate analysis the kinetic and amplitude of both CD4+ T-cell increase and proviral DNA reduction were fastest and highest in subjects with all 3 anti-Tat Ab classes and in the 30 μg, 3 × group, irrespective of drug regimens (NNRTI/NRTI vs. PI). HIV proviral DNA changes from baseline were inversely related to CD4+/CD8+ T-cell ratio and CD4+ T-cell changes, and directly related to the changes of CD8+ T cells. Further, HIV DNA decay kinetics were inversely related to the frequency and levels of intermittent viremia. Finally, Tat vaccination was similarly effective irrespective of the individual immunological status or HIV reservoir size at study entry. Conclusions: Tat immunization induces progressive immune restoration and reduction of virus reservoirs above levels reached with long-term cART, and may represent an optimal vaccine candidate for cART intensification toward HIV reservoirs depletion, functional cure, and eradication strategies.",
keywords = "anti-Tat antibodies, cART, CD4+ T cells, CD4+/CD8+ T-cell ratio, HIV reservoirs, HIV therapeutic vaccine, proviral DNA, Tat",
author = "Cecilia Sgadari and Paolo Monini and Antonella Tripiciano and Orietta Picconi and Anna Casabianca and Chiara Orlandi and Sonia Moretti and Vittorio Francavilla and Angela Arancio and Giovanni Paniccia and Massimo Campagna and Stefania Bellino and Marianna Meschiari and Silvia Nozza and Laura Sighinolfi and Alessandra Latini and Antonio Muscatello and Annalisa Saracino and {Di Pietro}, Massimo and Massimo Galli and Aurelio Cafaro and Mauro Magnani and Fabrizio Ensoli and Barbara Ensoli",
year = "2019",
month = "1",
day = "1",
doi = "10.3389/fimmu.2019.00233",
language = "English",
volume = "10",
journal = "Frontiers in Immunology",
issn = "1664-3224",
publisher = "Frontiers Media S.A.",

}

TY - JOUR

T1 - Continued Decay of HIV Proviral DNA Upon Vaccination With HIV-1 Tat of Subjects on Long-Term ART

T2 - An 8-Year Follow-Up Study

AU - Sgadari, Cecilia

AU - Monini, Paolo

AU - Tripiciano, Antonella

AU - Picconi, Orietta

AU - Casabianca, Anna

AU - Orlandi, Chiara

AU - Moretti, Sonia

AU - Francavilla, Vittorio

AU - Arancio, Angela

AU - Paniccia, Giovanni

AU - Campagna, Massimo

AU - Bellino, Stefania

AU - Meschiari, Marianna

AU - Nozza, Silvia

AU - Sighinolfi, Laura

AU - Latini, Alessandra

AU - Muscatello, Antonio

AU - Saracino, Annalisa

AU - Di Pietro, Massimo

AU - Galli, Massimo

AU - Cafaro, Aurelio

AU - Magnani, Mauro

AU - Ensoli, Fabrizio

AU - Ensoli, Barbara

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Introduction: Tat, a key HIV virulence protein, has been targeted for the development of a therapeutic vaccine aimed at cART intensification. Results from phase II clinical trials in Italy (ISS T-002) and South Africa (ISS T-003) indicated that Tat vaccination promotes increases of CD4+ T-cells and return to immune homeostasis while reducing the virus reservoir in chronically cART-treated patients. Here we present data of 92 vaccinees (59% of total vaccinees) enrolled in the ISS T-002 8-year extended follow-up study (ISS T-002 EF-UP, ClinicalTrials.gov NCT02118168). Results: Anti-Tat antibodies (Abs) induced upon vaccination persisted for the entire follow-up in 34/92 (37%) vaccinees, particularly when all 3 Ab classes (A/G/M) were present (66% of vaccinees), as most frequently observed with Tat 30 μg regimens. CD4+ T cells increased above study-entry levels reaching a stable plateau at year 5 post-vaccination, with the highest increase (165 cells/μL) in the Tat 30 μg, 3 × regimen. CD4+ T-cell increase occurred even in subjects with CD4+ nadir ≤ 250 cells/uL and in poor immunological responders and was associated with a concomitant increase of the CD4+/CD8+ T-cell ratio, a prognostic marker of morbidity/mortality inversely related to HIV reservoir size. Proviral DNA load decreased over time, with a half-life of 2 years and an estimated 90% reduction at year 8 in the Tat 30 μg, 3 × group. In multivariate analysis the kinetic and amplitude of both CD4+ T-cell increase and proviral DNA reduction were fastest and highest in subjects with all 3 anti-Tat Ab classes and in the 30 μg, 3 × group, irrespective of drug regimens (NNRTI/NRTI vs. PI). HIV proviral DNA changes from baseline were inversely related to CD4+/CD8+ T-cell ratio and CD4+ T-cell changes, and directly related to the changes of CD8+ T cells. Further, HIV DNA decay kinetics were inversely related to the frequency and levels of intermittent viremia. Finally, Tat vaccination was similarly effective irrespective of the individual immunological status or HIV reservoir size at study entry. Conclusions: Tat immunization induces progressive immune restoration and reduction of virus reservoirs above levels reached with long-term cART, and may represent an optimal vaccine candidate for cART intensification toward HIV reservoirs depletion, functional cure, and eradication strategies.

AB - Introduction: Tat, a key HIV virulence protein, has been targeted for the development of a therapeutic vaccine aimed at cART intensification. Results from phase II clinical trials in Italy (ISS T-002) and South Africa (ISS T-003) indicated that Tat vaccination promotes increases of CD4+ T-cells and return to immune homeostasis while reducing the virus reservoir in chronically cART-treated patients. Here we present data of 92 vaccinees (59% of total vaccinees) enrolled in the ISS T-002 8-year extended follow-up study (ISS T-002 EF-UP, ClinicalTrials.gov NCT02118168). Results: Anti-Tat antibodies (Abs) induced upon vaccination persisted for the entire follow-up in 34/92 (37%) vaccinees, particularly when all 3 Ab classes (A/G/M) were present (66% of vaccinees), as most frequently observed with Tat 30 μg regimens. CD4+ T cells increased above study-entry levels reaching a stable plateau at year 5 post-vaccination, with the highest increase (165 cells/μL) in the Tat 30 μg, 3 × regimen. CD4+ T-cell increase occurred even in subjects with CD4+ nadir ≤ 250 cells/uL and in poor immunological responders and was associated with a concomitant increase of the CD4+/CD8+ T-cell ratio, a prognostic marker of morbidity/mortality inversely related to HIV reservoir size. Proviral DNA load decreased over time, with a half-life of 2 years and an estimated 90% reduction at year 8 in the Tat 30 μg, 3 × group. In multivariate analysis the kinetic and amplitude of both CD4+ T-cell increase and proviral DNA reduction were fastest and highest in subjects with all 3 anti-Tat Ab classes and in the 30 μg, 3 × group, irrespective of drug regimens (NNRTI/NRTI vs. PI). HIV proviral DNA changes from baseline were inversely related to CD4+/CD8+ T-cell ratio and CD4+ T-cell changes, and directly related to the changes of CD8+ T cells. Further, HIV DNA decay kinetics were inversely related to the frequency and levels of intermittent viremia. Finally, Tat vaccination was similarly effective irrespective of the individual immunological status or HIV reservoir size at study entry. Conclusions: Tat immunization induces progressive immune restoration and reduction of virus reservoirs above levels reached with long-term cART, and may represent an optimal vaccine candidate for cART intensification toward HIV reservoirs depletion, functional cure, and eradication strategies.

KW - anti-Tat antibodies

KW - cART

KW - CD4+ T cells

KW - CD4+/CD8+ T-cell ratio

KW - HIV reservoirs

KW - HIV therapeutic vaccine

KW - proviral DNA

KW - Tat

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U2 - 10.3389/fimmu.2019.00233

DO - 10.3389/fimmu.2019.00233

M3 - Article

C2 - 30815001

AN - SCOPUS:85062395998

VL - 10

JO - Frontiers in Immunology

JF - Frontiers in Immunology

SN - 1664-3224

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