Definition of an Amino-terminal Domain of the Human T-cell Leukemia Virus Type 1 Envelope Surface Unit That Extends the Fusogenic Range of an Ecotropic Murine Leukemia Virus

Abstract

Murine leukemia viruses (MuLV) and human T-cell leukemia viruses (HTLV) are phylogenetically highly divergent retroviruses with distinct envelope fusion properties. The MuLV envelope glycoprotein surface unit (SU) comprises a receptor-binding domain followed by a proline-rich region which modulates envelope conformational changes and fusogenicity. In contrast, the receptor-binding domain and SU organization of HTLV are undefined. Here, we describe an HTLV/MuLV envelope chimera in which the receptor-binding domain and proline-rich region of the ecotropic MuLV were replaced with the potentially corresponding domains of the HTLV-1 SU. This chimeric HTLV/MuLV envelope was processed, specifically interfered with HTLV-1 envelope-mediated fusion, and similar to MuLV envelopes, required cleavage of its cytoplasmic tail to exert significant fusogenic properties. Furthermore, the HTLV domain defined here broadened ecotropic MuLV envelopeinduced fusion to human and simian cell lines.

HTLV-1 tropism and envelope receptor

“…Functional evaluation of different SU domains, as delineated in Figure 2, allowed us to demonstrate that, paradoxically to its 'complex' genetic organization, the HTLV SU has a modular organization that is identical to that of simple retroviruses (Battini et al, 1995), with the RBD residing at the SU amino terminal (Kim et al, 2000(Kim et al, , 2004b. Furthermore, we found that this domain was sufficient for receptor binding, as measured by FACS analysis, fusion, infection and interference to infection (Kim et al, 2000(Kim et al, , 2004b, and did not require the central proline-rich region (PRR) of HTLV Env to exert these properties (Kim et al, 2000(Kim et al, , 2004b.…”

“…Notably though, alignment of the HTLV-1 SU with that of the Friend-murine leukemia virus (F-MLV) reveals highly conserved microdomains within the SU and underscores a similar general organization of the SU (Kim et al, 2000(Kim et al, , 2004a (Figure 2). Functional evaluation of different SU domains, as delineated in Figure 2, allowed us to demonstrate that, paradoxically to its 'complex' genetic organization, the HTLV SU has a modular organization that is identical to that of simple retroviruses (Battini et al, 1995), with the RBD residing at the SU amino terminal (Kim et al, 2000(Kim et al, , 2004b.…”

Cell Surface Expression of the Bovine Leukemia Virus-Binding Receptor on B and T Lymphocytes Is Induced by Receptor Engagement

“…Medium containing the various soluble RBD was harvested 48 -72 h after transfection, filtered through a 0.45-m filter, and frozen at Ϫ20°C until further use. Fusion proteins harboring the HTLV-2 RBD, H RBD rFc and H RBD eGFP, were similarly produced, as previously described (17,19). Quantification of a B RBD rFc preparation, as assessed by ELISA (Zeptometrix), revealed levels of Ͼ100 ng/ml.…”

“…Accordingly, the gag and pol genes of HTLV-1 and BLV show strong homologies, indicative of their close evolutionary relationship (16). Deltaretroviruses, including BLV, share the same modular envelope organization as gammaretroviruses, even in the variable regions of the protein surface unit (SU) (17)(18)(19), oligomerizing as a trimer (20 -22). Although the SU has been hypothesized to harbor the putative receptor-binding domain (RBD) (18,23,24), it is significant that the cellular receptor for BLV has yet to be identified.…”

“…We previously determined that the 183-and 178-amino-terminal residues of the HTLV-1 and -2 envelope glycoprotein (Env), respectively, are sufficient to efficiently bind target cells of different species (17,19). This region of the SU, immediately upstream of the so-called proline-rich region (PRR), confers HTLV tropism to heterologous envelopes.…”