Human T-Cell Lymphotropic Virus Type 3: Complete Nucleotide Sequence and Characterization of the Human Tax3 Protein

Four types of primate T-cell lymphotropic viruses (PTLVs) have been discovered. While three of them, i.e., PTLV-1, PTLV-2, and PTLV-3, include human T-cell lymphotropic viruses (HTLV-1, HTLV-2, and HTLV-3) and simian T-cell lymphotropic viruses (STLV-1, STLV-2, and STLV-3), the fourth type (HTLV-4) has so far been found to consist only of a unique human isolate (4, 52). STLV-3 (formerly named PTLV-L) was isolated shortly before STLV-2 (14). The STLV-3 lineage is composed of at least two subtypes that correspond more or less to the geographical sources of the isolates (East Africa and west-central Africa) (7, 14, 24, 25, 27, 46, 47, 49, 51). Although STLV-3 is much more widespread than STLV-2 in African monkeys, STLV-3 infection has not been linked to any pathology so far, yet neither longitudinal follow-up nor clinical studies have been performed. Sequence comparisons of STLV-3 full-length proviruses pointed out that these strains are highly divergent from HTLV-1, HTLV-2, and STLV-2 (40%, 38%, and 38% divergence, respectively) (7, 14, 24, 25, 27, 46, 47, 49, 51). The overall STLV-3 genomic organization is similar to that of HTLV-1 and HTLV-2; the gag, pro, pol, env, tax, and rex genes are present (24, 25, 46, 47, 51). Sequence analyses also revealed that STLV-3 long terminal repeat (LTR) sequences possess only two 21-bp repeats (or Tax-responsive elements [TREs]), while HTLV-1 and HTLV-2 LTRs retain three of these sequences (24, 25, 46). The impact of the lack of a TRE on viral transcription is not known. Interestingly, apart from Tax and Rex, the STLV-3 prototype (STLV-3PH969) pX region was reported to contain only one additional open reading frame (ORF) whose corresponding mRNA can be amplified by reverse transcriptase (RT)-PCR (47). This mRNA could be translated into a putative 84-amino-acid-long protein designated RorfII, which shares some similarities with the HTLV-1 p12 protein (47). Of note, the RorfII mRNA was not detected in the two other STLV-3 strains (PPAF3 and CTO604) that have been analyzed lately by RT-PCR. In fact, sequence analysis of these isolates revealed either a mutation in the splice acceptor sequence and/or a stop codon in the RorfII sequence (24, 25). At this point, it is therefore not clear whether, apart from Tax and Rex, additional ORFs are commonly present in the STLV-3 pX sequence. We and others have uncovered the existence of HTLV-3, a third member of the HTLV family, in two Cameroonian individuals (4, 52). We therefore ought to obtain the complete sequence of HTLV-3Pyl43 in order to determine its genomic organization and to characterize its Tax protein. Full-length genome comparisons and phylogenetic analyses allow us to demonstrate that the HTLV-3 genome organization is similar to that of HTLV-1 and HTLV-2 and is related to some central African STLV-3 strains. Like STLV-3, HTLV-3 LTRs contain only two Tax-responsive elements. Unexpectedly, a 366-bp sequence is lacking in the HTLV-3 proximal pX region. This sequence corresponds in part to the RorfII sequence that was previously described for STLV-3PH969 and also to the 3′ end of a putative antisense transcript. We have lately demonstrated that HTLV-3 Tax protein is expressed in vivo (6). Our results now reveal that Tax3Pyl43 is functionally more closely related to the transforming HTLV-1 Tax protein than to HTLV-2 Tax, suggesting that HTLV-3, like HTLV-1, might be pathogenic in vivo.