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Journal of Virology, August 2006, p. 7427-7438, Vol. 80, No. 15
0022-538X/06/$08.00+0     doi:10.1128/JVI.00690-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Ancient Origin and Molecular Features of the Novel Human T-Lymphotropic Virus Type 3 Revealed by Complete Genome Analysis

William M. Switzer,1* Shoukat H. Qari,1 Nathan D. Wolfe,2,3,4 Donald S. Burke,2,3 Thomas M. Folks,1 and Walid Heneine1

Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia 30333,1 Departments of Epidemiology,2 International Health,3 Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 212054

Received 5 April 2006/ Accepted 8 May 2006

Human T-lymphotropic virus type 3 (HTLV-3) is a new virus recently identified in two primate hunters in Central Africa. Limited sequence analysis shows that HTLV-3 is distinct from HTLV-1 and HTLV-2 but is genetically similar to simian T-lymphotropic virus type 3 (STLV-3). We report here the first complete HTLV-3 sequence obtained by PCR-based genome walking using uncultured peripheral blood lymphocytes from an HTLV-3-infected person. The HTLV-3(2026ND) genome is 8,917 bp long and is genetically equidistant from HTLV-1 and HTLV-2, sharing about 62% identity. Phylogenetic analysis of all gene regions confirms this relationship and shows that HTLV-3 falls within the diversity of STLV-3, suggesting a primate origin. However, HTLV-3(2026ND) is unique, sharing only 87% to 92% sequence identity with STLV-3. SimPlot and phylogenetic analysis did not reveal any evidence of genetic recombination with either HTLV-1, HTLV-2, or STLV-3. Molecular dating estimates that the ancestor of HTLV-3 is as old as HTLV-1 and HTLV-2, with an inferred divergence time of 36,087 to 54,067 years ago. HTLV-3 has a prototypic genomic structure, with all enzymatic, regulatory, and structural proteins preserved. Like STLV-3, HTLV-3 is missing a third 21-bp transcription element found in the long terminal repeats of HTLV-1 and HTLV-2 but instead contains a unique activator protein-1 transcription factor upstream of the 21-bp repeat elements. A PDZ motif, like that in HTLV-1, which is important for cellular signal transduction and transformation, is present in the C terminus of the HTLV-3 Tax protein. A basic leucine zipper region located in the antisense strand of HTLV-1, believed to play a role in viral replication and oncogenesis, was also found in the complementary strand of HTLV-3. The ancient origin of HTLV-3, the broad distribution of STLV-3 in Africa, and the propensity of STLVs to cross species into humans all suggest that HTLV-3 may be prevalent and support the need for expanded surveillance for this virus.

* Corresponding author. Mailing address: Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention, 1600 Clifton Rd., MS G-45, Atlanta, GA 30333. Phone: (404) 639-0219. Fax: (404) 639-1174. E-mail: bis3{at}cdc.gov.

Journal of Virology, August 2006, p. 7427-7438, Vol. 80, No. 15
0022-538X/06/$08.00+0     doi:10.1128/JVI.00690-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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