Mapping the molecular characteristics of Brazilian human T-cell lymphotropic virus type 1 Env (gp46) and Pol amino acid sequences for vaccine design

Abstract

This study was carried out to evaluate the molecular pattern of all available Brazilian human T-cell lymphotropic virus type 1 Env (n = 15) and Pol (n = 43) nucleotide sequences via epitope prediction, physicochemical analysis, and protein potential sites identification, giving support to the Brazilian AIDS vaccine program. In 12 previously described peptides of the Env sequences we found 12 epitopes, while in 4 peptides of the Pol sequences we found 4 epitopes. The total variation on the amino acid composition was 9 and 17% for human leukocyte antigen (HLA) class I and class II Env epitopes, respectively. After analyzing the Pol sequences, results revealed a total amino acid variation of 0.75% for HLA-I and HLA-II epitopes. In 5 of the 12 Env epitopes the physico-chemical analysis demonstrated that the mutations magnified the antigenicity profile. The potential protein domain analysis of Env sequences showed the loss of a CK-2 phosphorylation site caused by D197N mutation in one epitope, and a N-glycosylation site caused by S246Y and V247I mutations in another epitope. Besides, the analysis of selection pressure have found 8 positive selected sites (w = 9.59) using the codon-based substitution models and maximum-likelihood methods. These studies underscore the importance of this Env region for the virus fitness, for the host immune response and, therefore, for the development of vaccine candidates.Key words: human T-cell lymphotropic virus type 1 -Env -Pol -epitopeThe human t-cell lymphotropic virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia lymphoma (ATLL) (Poiesz et al. 1980) and tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM) (Gessain et al. 1985, Osame et al. 1986). This infection is endemic in Japan, in the Caribbean Basin, some South American, and African regions (Mueller 1991), while there are 2.5 million HTLV-1 infected people in Brazil (Carneiro-Proietti et al. 2002). In contrast, only 5% of infected people develop the associated disease, and it is not yet known why 95-98% of them remain asymptomatic. The envelope glycoproteins of this virus are known to play a critical role in the infection process. The surface glycoprotein (gp46) subunit is involved in cellular receptor recognition, while the transmembrane glycoprotein (gp21) subunit anchors the gp46 to the cell and plays a major role in the post-binding steps of the fusion process, resulting in the formation of multinucleated giant cells named syncytia. These envelope proteins are expressed on the surface of virus-infected cells and on viral particles and they are the first to be recognized by the host in the course of the natural immune response (Nagy et al. 1983, Palker et al. 1989), in such a way that HTLV-1 infected individuals develop a strong immune response to the envelope (env) gene products. Several studies have focused on mapping linear immunodominant regions of the HTLV-1 surface glycoprotein that could elicit antibody responses, for the purpose of vaccine development and diagnostic screening (Tana...

Molecular characterization of HTLV-1 gp46 glycoprotein from health carriers and HAM/TSP infected individuals

“…Recent data revealed that patients with HAM/TSP recognized a significantly broader repertoire of Env epitopes, compared with health carriers, suggesting that the diversity, frequency and repertoire of HTLV-1 Env CD8 + T-cells may be related to the hyperimmune response in HAM/TSP disease [22]. Additionally, the identification of the Env epitopes associated with the immune system activation could be useful to vaccine design [23]. In a recent report, the immunogenicity and protective efficacy in squirrel monkeys of a B-cell env gene epitope and of a T-cell multiepitope derived from Tri-Tax were tested.…”

“…All models were implemented in the HYPHY program [35] and the ω and p values were estimated through maximum-likelihood optimization, in such a way that using the M3 model, sites with a posterior probability exceeding 90% and a ω value > 1 were labeled as being “positive selection sites”. Finally, Likelihood Ratio Test (LRT) analysis was used to determine: (1) if site heterogeneity selection was present and (2) if there were positively selected sites [23,36]. …”

Molecular Study of HBZ and gp21 Human T Cell Leukemia Virus Type 1 Proteins Isolated from Different Clinical Profile Infected Individuals

“…The protein domain analysis was also performed using GeneDoc software 13 and the Prosite tool, as previously described. 14 The gp21 and HBZ nucleotide sequences previously deposited in GenBank and used in this study as references are listed below with their corresponding accession number: AB219938 (HBZ), J02029 (gp21), and U81865-U81869 (gp21). The new gp21 and HBZ nucleotide sequences that were generated in this study were deposited in GenBank, and their corresponding accession number are KF053886-KF053893 (gp21) and KF053876-KF053885 (HBZ).…”