Emerging viral pathogens have either invaded a new host species or expanded into new geographic populations of host species. As represented by the human immunodeficiency virus epidemic or the Spanish influenza outbreak in the early 1920s, viruses can be highly transmissible and virulent. These episodes appear to be unpredictable. A viral pathogen may be benign while residing within a reservoir species, yet on entering a new host, it increases in virulence (41
Until recently, the HTLV family comprised only two members: HTLV-1, known as the etiological agent of adult T-cell leukemia/lymphoma, which is one of the worst leukemia viruses; and HTLV-2, which although very similar in sequence to HTLV-1, is barely leukemogenic. We and others have recently discovered a third member of the HTLV group (4
), and our next challenge is to determine whether HTLV-3 is more similar to HTLV-1 than to HTLV-2 in terms of pathogenicity. Of note, studies of the first STLV-3-infected animals were reported almost a decade ago (14
), but those animals as well as the STLV-3-infected monkeys described more recently (24
) were never studied longitudinally. For this reason, it is not possible to determine whether, as is the case for some STLV-1-infected animals, animals can suffer from adult T-cell leukemia/lymphoma-like or other diseases (9
). We have now sequenced the HTLV-3 provirus, which is very similar to a central African STLV-3 strain (STLV-3CTO604
). Furthermore, HTLV-3Pyl43
shares some sequence features with all STLV-3 strains (24
). As an example, the viral promoter contains only two Tax-responsive elements. Together with the phylogenetic analyses, these results confirm that, as is the case for HTLV-1 (21
), HTLV-3 arose in humans from interspecies transmissions, which, according to our molecular-clock analysis, is estimated to have occurred within the last 3,800 years. Of note, this estimate is not without precedent, as HTLV-1 subtypes B, D, and F were previously estimated to have arisen in humans between 3,000 and 13,600 years ago (50
Unexpectedly, however, the proximal pX region of HTLV-3, in which the RorfII sequence is removed, is shorter than that of its simian counterpart. For this reason, it would be of interest to compare the proximal pX region of HTLV-3Pyl43
with that of the strain reported by Wolfe et al. (52
). This would allow us to determine whether this feature is common to all HTLV-3 or whether it is specific to HTLV-3Pyl43
The STLV-3 minus strand is predicted to contain an ORF that encodes a 221-amino-acid-long protein (data not shown). Similar to HTLV-1 HBZ, this protein would possess several NLS sequences. The NLS sequences that are present in HTLV-1 HBZ are critical for its localization and, likely, for its functions (18
). On the other hand, the putative HTLV-3 antisense protein would be only 103 amino acids long due to the 366-bp deletion in the proximal pX region. This protein would lack the NLS domains and would probably be functionally impaired. Because an HTLV-3-infected cell line is not available for analysis, the existence and the putative role of such a protein cannot be investigated at this point. The lack of a protein in a PTLV genome is not without precedent. Various studies have shown that defective proviruses comprise 25 to 40% of all HTLV-1 genomes present in lymphocytes from infected individuals or in cells infected with HTLV-1 in vitro (8
). These viruses retain different parts of the genomes, i.e., both LTRs, the amino terminus of gag
, and the portions of pX encoding the Tax, Rex, p12, and p30 proteins (16
). Whether or not these defective viruses are the only genomes that are present in these individuals is very difficult to determine.
Full-length genomes that lack the expression of some viral proteins were also reported. As an example, apart from HTLV-1 subtype A, which has always been used for molecular studies, the other HTLV-1 genomes that are available for analysis (subtypes B and C) lack the p12 ATG codon. Therefore, it is very unlikely that the p12 protein is present in individuals infected with HTLV-1 subtypes B and C (A. Vandamme and S. Van Dooren, personal communication).
Because Tax is one of the key players in HTLV-1 pathogenicity, we examined HTLV-3 Tax properties. Sequence analysis first revealed that, as with Tax1 but not Tax2, Tax3Pyl43
contains a PDZ binding motif. Such a domain, which is absent from Tax2, is critical for the ability of the viral protein to induce T-cell proliferation and to persist in vivo (54
). This is one argument that strongly suggests that HTLV-3 possesses some of the HTLV-1 properties. We show here that Tax3Pyl43
is capable of inducing the CREB/ATF and the NF-κB pathways. We also provide evidence that Tax3Pyl43
transactivates both the HTLV-1 and the HTLV-2 promoters. This is of importance as HTLV-3Pyl43
was discovered in a population in whom both HTLV-1 and HTLV-2 are endemic. Interestingly, central African monkeys that were coinfected by STLV-1 and STLV-3 were described earlier (7
). Whether coinfection would accelerate the occurrence of a PTLV-associated disease remains to be determined. So far, both cases of HTLV-3 infection were reported in individuals who were not coinfected with other types of HTLV.
Unexpectedly, we have also found that, even if Tax3Pyl43, like Tax1, ultimately transrepresses some cellular gene products (p53 or c-Myb) and transactivates others (IL-8 and Bcl-XL), the mechanisms that are involved might be slightly different. In particular, we have demonstrated here that the activation of NF-κB by Tax3Pyl43 is not sufficient for transactivating the interleukin-8 and the Bcl-XL promoters.
For these reasons, the construction of both an HTLV-3 and an STLV-3 molecular clone is now needed to investigate viral expression in the context of a provirus. This will allow us to determine in particular whether the 366-bp deletion has an impact on the HTLV-3 viral life cycle. Indeed, earlier analyses have allowed us to conclude that not only Tax but other pX-encoded proteins (p12, p13, p30, and HBZ) are involved in viral pathogenesis. Due to the deletion in the putative HTLV-3 AEP sequence, we anticipate that HTLV-3 is likely to encode a nonfunctional protein compared to its STLV-3 counterpart. Based on HTLV-1 data (2
) and the possibility that STLV-3 AEP is functionally related to HBZ, it is expected that a loss of the HTLV-3 AEP functions would result in a lower proviral load in vivo.