Analyses of HTLV-1 sequences suggest interaction between ORF-I mutations and HAM/TSP outcome

Abstract

The region known as pX in the 3′ end of the human T-cell lymphotropic virus type 1 (HTLV-1) genome contains four overlapping open reading frames (ORF) that encode regulatory proteins. HTLV-1 ORF-I produces the protein p12 and its cleavage product p8. The functions of these proteins have been linked to immune evasion and viral infectivity and persistence. It is known that the HTLV-1 infection does not necessarily imply the development of pathological processes and here we evaluated whether natural mutations in HTLV-1 ORF-I can influence the proviral load and clinical manifestation of HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). For that, we performed molecular characterization, datamining and phylogenetic analysis with HTLV-1 ORF-I sequences from 156 patients with negative or positive diagnosis for HAM/TSP. Our analyses demonstrated that some mutations may be associated with the outcome of HAM/TSP (C39R, L40F, P45L, S69G and R88K) or with proviral load (P34L and F61L). We further examined the presence of mutations in motifs of HBZ and observed that P45L mutation is located within the HBZ nuclear localization signal and was found more frequently between patients with HAM/TSP and high proviral load. These results indicate that some natural mutations are located in functional domains of ORF-I and suggests a potential association between these mutations and the proviral loads and development of HAM/TSP. Therefore it is necessary to conduct functional studies aimed at evaluating the impact of these mutations on the virus persistence and immune evasion.

Absence of accessory genes in a divergent simian T-lymphotropic virus type 1 isolated from a bonnet macaque (Macaca radiata)

“…Many PTLV-1 strains (Table C in S1 Text) were analyzed and the presence of P12, P13 et P30 were addressed, focusing mostly on the conservation of the splicing sites, the presence of the start codon and the absence of early stop codon (Tables D-F in S1 Text). * although the complete sequences of HTLV-1a all encode a 99 aa-long protein, many shorter versions of the proteins have been reported [16, 17]. …”

“…* although the complete sequences of HTLV-1a all encode a 99 aa-long protein, many shorter versions of the proteins have been reported [16, 17]. …”

Role of HTLV-1 orf-I encoded proteins in viral transmission and persistence

“…Interestingly, the authors found that the pattern of p12 and p8 expression correlated with proviral load [58]. In a second study using a computational approach to examine p12/p8 sequence variants (D26N, G29S, P34L, L40F, P45L, S63P, L66P, S69G, R83C) in healthy carriers of HTLV-1 and HAM/TSP patients, P45L, S69G, and R88K were found more frequently in patients positive for HAM/TSP, and D26N, P34L, C39R, F61L, and R83C were found to be associated with low proviral load [59].…”

“…This study did not exclude the possibility that orf - I could be expressed by an alternative doubly spliced mRNA in these patients (Table 1). It is important to note that studies that examine the p12 sequence from patient PBMCs in vivo have relied on PCR amplification and cloning of viral DNA regions, resulting in amplification of the most dominant clones [58, 59, 141] that may not be infectious. Therefore, it is possible that where premature termination of p12 was found, minor intact clones are also present that contribute to infection and/or viral persistence.…”

First report of HTLV-1 truncated p12 protein in Brazil

“…[2][3][4][5][6][7][8][9][10][11][12][13][14][15] Previous studies demonstrated that mutations in p12 may influence the HTLV-1 infection outcome. 3,5,8,16,17 Here, we identified, at the first time, a HTLV-1 strain with a premature stop codon in p12 infecting an individual from Brazil, presenting a very low proviral load. We hypothesize if this mutation would have a protective role against HTLV-1 replication.…”