The members of the deltaretroviruses, which include human T-cell leukemia viruses type 1 and 2 (HTLV-1 and HTLV-2), are medically important because they cause cancers that cannot be cured and have no vaccines for prevention. The deltaretroviruses replicate to low titers in their natural hosts and are poorly infectious in cell culture. Cocultivation is typically used to infect permissive host cells. Because of these difficulties, information regarding the molecular details of their life cycles, including virus assembly and release, is limited. In a number of retroviruses, as well as in the matrix proteins of the rhabdoviruses and the filoviruses, a domain termed the """"""""late"""""""" or """"""""L"""""""" domain has been identified. These L domains play a critical role in the pinching-off of virus particles from the plasma membrane. In retroviruses, the L domain resides in the Gag protein. One of the most intriguing features of L domains is that they contain highly conserved motifs known to mediate protein-protein interactions between cellular proteins. To date, three classes of motifs have been identified: PTAP, PPPY, and YXXL. For each of these motifs, the integrity of the motif appears to be essential for L domain function, which suggests that L domain function relies on the interaction with host factor(s). The L domains for members of the deltaretroviruses have not been investigated to date. Preliminary data has associated L domain function for bovine leukemia virus, a closely related deltaretrovirus, to a PPPY motif in Gag. A novel feature of the HTLV-1 Gag protein is that it contains both a PTAP and PPPY motif.
Two specific aims will be pursued in this study. First, it will be determined whether both the PPPY and PTAP motifs function as HTLV-1 L domains. Second, it will be tested whether the PTAP and PPPY domains can be functionally replaced and if they are positionally independent. Completion of these aims should provide new clues regarding HTLV-1 L domain function and provide important preliminary data for more extensive studies that will investigate the host factor(s) involved in HTLV-1 release. In addition, the analysis of HTLV- 1 L domain function could have implications not only for the development of new inhibitors to block HTLV-1 particle release, but is also likely to contribute important information regarding the interplay between ubiquitination, internalization, endosomal sorting, and virus budding.
| Chen, Renxiang; Quinones-Mateu, Miguel E; Mansky, Louis M (2005) HIV-1 mutagenesis during antiretroviral therapy: implications for successful drug treatment. Front Biosci 10:743-50 |
| Spidel, Jared L; Craven, Rebecca C; Wilson, Carol B et al. (2004) Lysines close to the Rous sarcoma virus late domain critical for budding. J Virol 78:10606-16 |
| Wang, Huating; Machesky, Nicholas J; Mansky, Louis M (2004) Both the PPPY and PTAP motifs are involved in human T-cell leukemia virus type 1 particle release. J Virol 78:1503-12 |
| Chen, Renxiang; Quinones-Mateu, Miguel E; Mansky, Louis M (2004) Drug resistance, virus fitness and HIV-1 mutagenesis. Curr Pharm Des 10:4065-70 |
| Jewell, Nancy A; Chen, Renxiang; Raices, Raquel et al. (2003) Nucleoside reverse transcriptase inhibitors and HIV mutagenesis. J Antimicrob Chemother 52:547-50 |
