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Ancient, independent evolution and distinct molecular features of the novel human T-lymphotropic virus type 4

William M Switzer1*, Marco Salemi2, Shoukat H Qari1, Hongwei Jia1, Rebecca R Gray2, Aris Katzourakis3, Susan J Marriott4, Kendle N Pryor4, Nathan D Wolfe56, Donald S Burke7, Thomas M Folks8 and Walid Heneine1

  • * Corresponding author: William M Switzer

  • † Equal contributors

Author Affiliations

1 Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA

2 Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA

3 Department of Zoology, University of Oxford, Oxford, OX1 3PS, UK

4 Department of Molecular Virology & Microbiology, Baylor College of Medicine, Houston, Texas 77030, USA

5 Stanford University, Program in Human Biology, Stanford, CA 94305, USA

6 Global Viral Forecasting Initiative, San Francisco, CA 94105, USA

7 Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA

8 Southwest National Primate Research Center, San Antonio, TX 78227, USA

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Retrovirology 2009, 6:9  doi:10.1186/1742-4690-6-9

Published: 2 February 2009



Human T-lymphotropic virus type 4 (HTLV-4) is a new deltaretrovirus recently identified in a primate hunter in Cameroon. Limited sequence analysis previously showed that HTLV-4 may be distinct from HTLV-1, HTLV-2, and HTLV-3, and their simian counterparts, STLV-1, STLV-2, and STLV-3, respectively. Analysis of full-length genomes can provide basic information on the evolutionary history and replication and pathogenic potential of new viruses.


We report here the first complete HTLV-4 sequence obtained by PCR-based genome walking using uncultured peripheral blood lymphocyte DNA from an HTLV-4-infected person. The HTLV-4(1863LE) genome is 8791-bp long and is equidistant from HTLV-1, HTLV-2, and HTLV-3 sharing only 62–71% nucleotide identity. HTLV-4 has a prototypic genomic structure with all enzymatic, regulatory, and structural proteins preserved. Like STLV-2, STLV-3, and HTLV-3, HTLV-4 is missing a third 21-bp transcription element found in the long terminal repeats of HTLV-1 and HTLV-2 but instead contains unique c-Myb and pre B-cell leukemic transcription factor binding sites. Like HTLV-2, the PDZ motif important for cellular signal transduction and transformation in HTLV-1 and HTLV-3 is missing in the C-terminus of the HTLV-4 Tax protein. A basic leucine zipper (b-ZIP) region located in the antisense strand of HTLV-1 and believed to play a role in viral replication and oncogenesis, was also found in the complementary strand of HTLV-4. Detailed phylogenetic analysis shows that HTLV-4 is clearly a monophyletic viral group. Dating using a relaxed molecular clock inferred that the most recent common ancestor of HTLV-4 and HTLV-2/STLV-2 occurred 49,800 to 378,000 years ago making this the oldest known PTLV lineage. Interestingly, this period coincides with the emergence of Homo sapiens sapiens during the Middle Pleistocene suggesting that early humans may have been susceptible hosts for the ancestral HTLV-4.


The inferred ancient origin of HTLV-4 coinciding with the appearance of Homo sapiens, the propensity of STLVs to cross-species into humans, the fact that HTLV-1 and -2 spread globally following migrations of ancient populations, all suggest that HTLV-4 may be prevalent. Expanded surveillance and clinical studies are needed to better define the epidemiology and public health importance of HTLV-4 infection.