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

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).

Phylogenetic analysis of HIV-1 archived DNA in blood and gut-associated lymphoid tissue in patients receiving antiretroviral therapy: a study from Provir/Latitude45 project

“…Provir/Latitude 45 project is based on the identification of conserved epitopes in the provirus with potential affinity for the dominant alleles of the population; therefore, more than 200 patients at successful ART have been investigated for these conserved epitopes [27] and a peptide cocktail has been proposed ; it must be noted that this project is based on the study of the blood compartment and the question has been raised whether another compartment could yield different results ; as the GALT is a major reservoir, we have then focused on a simulation of the CTL epitopes of the nine patients in both compartments with a high affinity for the corresponding HLA I alleles ;…”

“…It links the sequence data, the identity of the HLA alleles, the Los Alamos HIV database for CTL epitopes and the International Immune Epitope Database (IEDB) simulator. It does not only identify CTL epitopes in the LANL database but also proposes predictive epitopes as previously published [27].…”

Antiretroviral treatment, government policy and economy of HIV/AIDS in Brazil: is it time for HIV cure in the country?

“…Based on these preliminary data, the researchers suggest that NA + auranofin administration in combination with intensified ART is well tolerated, and an impact on the proviral reservoir size is possible using this combination [47]. Other studies by the same group also focused on the epigenetic factors associated with HIV latency [48] and HIV purging from latent reservoirs [49], all aiming to reduce HIV load from those compartments. Functional cure has also been approached by the Soares lab in Brazil, through the development of a multi-epitopic CTL therapeutic vaccine based on archived HIV-1 proviruses and according to prevalent HLA class I alleles in the Brazilian population.…”

Phylogenetic analysis of HIV-1 archived DNA in blood and gut-associated lymphoid tissue in two patients under antiretroviral therapy

“…Cure strategies for HIV-1 include therapeutic vaccination [ 12 ], although immune response observed was not able to control viral replication after ART discontinuation [ 13 ]. In this context, we launched the Provir/Latitude 45 project to identify conserved CTL epitopes in the proviral HIV-1 DNA of patients with long-term ART [ 14 ]. The study involves in silico modeling based on the HIV-1 proviral DNA sequences, the HLA alleles and the HIV-1 CTL epitopes following sequencing of the archived DNA from peripheral blood mononuclear cells (PBMC), i.e., from circulating blood.…”