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Provir/Latitude 45 study: A step towards a multi-epitopic CTL vaccine designed on archived HIV-1 DNA and according to dominant HLA I alleles
research-article
Author(s):
Camille Tumiotto
1 ,
Bruna M. Alves
2 ,
Patricia Recordon-Pinson
1 ,
Marine Jourdain
1 ,
Pantxika Bellecave
1 ,
Gwenda-Line Guidicelli
1 ,
Jonathan Visentin
1 ,
Fabrice Bonnet
1 ,
Mojdan Hessamfar
1 ,
Didier Neau
1 ,
Jorge Sanchez
3 ,
Christian Brander
4
,
5
,
6 ,
Mohammad Sajadi
7 ,
Lindsay Eyzaguirre
7 ,
Esmeralda A. Soares
2 ,
Jean-Pierre Routy
8 ,
Marcelo A. Soares
2 ,
Hervé Fleury
1
,
*
Publication date (Electronic):
27 February 2019
Journal:
PLoS ONE
Publisher:
Public Library of Science
Read this article at
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Abstract
One of the approaches by which the scientific community is seeking to cure HIV is the use of therapeutic vaccination. Previous studies have highlighted the importance of the virus-specific CD8+ T cell cytotoxic responses for the immune control of HIV and have oriented research on vaccine constructs based on CTL epitopes from circulating HIV-1 strains. The clinical trials with therapeutic vaccines to date have had limited success likely due to (i) a discrepancy between archived CTL epitopes in the viral reservoir and those in circulating viruses before antiretroviral therapy (ART) initiation and (ii) the lack of strong affinity between the selected CTL epitopes and the HLA grooves for presentation to CD8+ cells. To overcome these limitations, we launched the Provir/Latitude 45 study to identify conserved CTL epitopes in archived HIV-1 DNA according to the HLA class I alleles of aviremic patients, most of whom are under ART. The near full-length genomes or Gag, Pol and Nef regions of proviral DNA were sequenced by Sanger and/or Next Generation Sequencing (NGS). The HLA-A and B alleles were defined by NGS or molecular analysis. The TuTuGenetics software, which moves a sliding window of 8 to 10 amino acids through the amino acid alignment, was combined with the Immune Epitope Data Base (IEDB) to automatically calculate the theoretical binding affinity of identified epitopes to the HLA alleles for each individual. We identified 15 conserved epitopes in Pol (11), Gag (3), and Nef (1) according to their potential presentation by the dominant HLA-A and B alleles and now propose to use the corresponding conserved peptides in a multi-epitopic vaccine (HLA-fitted VAC, HFVAC).
Related collections
Most cited references26
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- Article: not found
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J. Gallant, R Brookmeyer, J Margolick … (1998)
The hypothesis that quiescent CD4+ T lymphocytes carrying proviral DNA provide a reservoir for human immunodeficiency virus-type 1 (HIV-1) in patients on highly active antiretroviral therapy (HAART) was examined. In a study of 22 patients successfully treated with HAART for up to 30 months, replication-competent virus was routinely recovered from resting CD4+ T lymphocytes. The frequency of resting CD4+ T cells harboring latent HIV-1 was low, 0.2 to 16.4 per 10(6) cells, and, in cross-sectional analysis, did not decrease with increasing time on therapy. The recovered viruses generally did not show mutations associated with resistance to the relevant antiretroviral drugs. This reservoir of nonevolving latent virus in resting CD4+ T cells should be considered in deciding whether to terminate treatment in patients who respond to HAART.
- Record: found
- Abstract: found
- Article: not found
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Hiromi Imamichi, Robin Dewar, Joseph Adelsberger … (2016)
Despite years of plasma HIV-RNA levels <40 copies per milliliter during combination antiretroviral therapy (cART), the majority of HIV-infected patients exhibit persistent seropositivity to HIV-1 and evidence of immune activation. These patients also show persistence of proviruses of HIV-1 in circulating peripheral blood mononuclear cells. Many of these proviruses have been characterized as defective and thus thought to contribute little to HIV-1 pathogenesis. By combining 5'LTR-to-3'LTR single-genome amplification and direct amplicon sequencing, we have identified the presence of "defective" proviruses capable of transcribing novel unspliced HIV-RNA (usHIV-RNA) species in patients at all stages of HIV-1 infection. Although these novel usHIV-RNA transcripts had exon structures that were different from those of the known spliced HIV-RNA variants, they maintained translationally competent ORFs, involving elements of gag, pol, env, rev, and nef to encode a series of novel HIV-1 chimeric proteins. These novel usHIV-RNAs were detected in five of five patients, including four of four patients with prolonged viral suppression of HIV-RNA levels <40 copies per milliliter for more than 6 y. Our findings suggest that the persistent defective proviruses of HIV-1 are not "silent," but rather may contribute to HIV-1 pathogenesis by stimulating host-defense pathways that target foreign nucleic acids and proteins.
- Record: found
- Abstract: found
- Article: not found
Rebound of plasma viremia following cessation of antiretroviral therapy despite profoundly low levels of HIV reservoir: implications for eradication.
Abby C Collier, Colin Kovacs, J. Justement … (2010)
Sustained suppression of plasma viremia in HIV-infected individuals is attainable with antiretroviral therapy (ART); however, eradication of virus that would allow discontinuation of ART has been hampered by the persistence of HIV reservoirs. It is of great interest to identify individuals who had received ART for prolonged periods of time with extremely low or undetectable HIV reservoirs and monitor plasma viremia following discontinuation of therapy. We measured the size of HIV reservoirs in CD4(+) T cells of individuals on long-term ART and monitored plasma viremia following cessation of ART in one individual with an exceptionally low viral burden after a decade of therapy. We demonstrated undetectable levels of HIV DNA in the blood of eight of 45 infected individuals on long-term ART. Among those eight individuals, the frequency of cells carrying infectious virus was significantly lower in those who initiated ART during the early versus the chronic phase of infection. One individual with undetectable HIV DNA in both blood and tissue and a profoundly low level of infectious virus experienced plasma viral rebound 50 days following discontinuation of ART. Our data suggest that a significant reduction in the size of viral reservoirs may be achievable in selected individuals who initiate standard ART early in infection. However, given re-emergence of plasma viremia in an individual with an extraordinarily low viral burden, therapeutic strategies aimed at specifically targeting these extremely rare HIV-infected cells with novel interventions may be necessary in order to achieve eradication of virus.
Author and article information
Contributors
Camille Tumiotto: Role: Formal analysisRole: Methodology
Bruna M. Alves: Role: Methodology
Patricia Recordon-Pinson: Role: Methodology
Marine Jourdain:
ORCID: http://orcid.org/0000-0001-7312-3659
Role: Methodology
Pantxika Bellecave: Role: Methodology
Gwenda-Line Guidicelli: Role: Methodology
Jonathan Visentin: Role: Methodology
Fabrice Bonnet: Role: Data curationRole: Investigation
Mojdan Hessamfar:
ORCID: http://orcid.org/0000-0001-6475-1768
Role: Data curationRole: Investigation
Didier Neau: Role: Data curationRole: Investigation
Jorge Sanchez: Role: Data curationRole: Investigation
Christian Brander:
ORCID: http://orcid.org/0000-0002-0548-5778
Role: Data curationRole: InvestigationRole: Writing – review & editing
Mohammad Sajadi: Role: Data curationRole: InvestigationRole: Methodology
Lindsay Eyzaguirre: Role: Data curationRole: InvestigationRole: Methodology
Esmeralda A. Soares: Role: Data curationRole: InvestigationRole: Methodology
Jean-Pierre Routy: Role: Data curationRole: Investigation
Marcelo A. Soares:
ORCID: http://orcid.org/0000-0002-9013-2570
Role: Data curationRole: InvestigationRole: Methodology
Hervé Fleury:
ORCID: http://orcid.org/0000-0002-5318-489X
Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: Project
administrationRole: ResourcesRole: SupervisionRole: Writing – original draft
Cristian Apetrei: Role: Editor
Journal
Journal ID (nlm-ta): PLoS One
Journal ID (iso-abbrev): PLoS ONE
Journal ID (publisher-id): plos
Journal ID (pmc): plosone
Title:
PLoS ONE
Publisher:
Public Library of Science
(San Francisco, CA USA
)
ISSN
(Electronic):
1932-6203
Publication date
(Electronic):
27
February
2019
Publication date Collection: 2019
Volume: 14
Issue: 2
Electronic Location Identifier: e0212347
Affiliations
Author notes
Competing Interests: HF received a grant from Merck Sharp and Dohme (DS-2016-0005). This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development, or marketed products to declare.
* E-mail:
herve.fleury@
123456u-bordeaux.fr
Author information
Marine Jourdain
http://orcid.org/0000-0001-7312-3659
Mojdan Hessamfar
http://orcid.org/0000-0001-6475-1768
Christian Brander
http://orcid.org/0000-0002-0548-5778
Marcelo A. Soares
http://orcid.org/0000-0002-9013-2570
Hervé Fleury
http://orcid.org/0000-0002-5318-489X
Article
Publisher ID: PONE-D-18-36090DOI: 10.1371/journal.pone.0212347
PMC ID: 6392325
PubMed ID: 30811489
SO-VID: 5335936f-88c7-42f8-a50c-094e2a610e45
Copyright © © 2019 Tumiotto et al
License:
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
History
Date
received
: 19
December
2018
Date
accepted
: 22
January
2019
Page count
Figures: 1,
Tables: 3,
Pages: 11
Funding
Funded by: MSDAvenir
Award ID: DS-2016-0005
Award Recipient
:
ORCID: http://orcid.org/0000-0002-5318-489X
Hervé Fleury
HF received a grant from Merck Sharp and Dohme (DS-2016-0005) and financial contribution
from GERMATAN (groupe d'etudes et de recherche sur les maladies animales et les anthropozoonoses).
The funders had no role in study design, data collection and analysis, decision to
publish, or preparation of the manuscript.
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