title: Human T lymphotropic virus type 1 SU residue 195 plays a role in determining the preferential CD4+ T cell immortalization/transformation tropism.
abstract: Human T lymphotropic virus type 1 (HTLV-1) mainly causes adult T cell leukemia and predominantly immortalizes/transforms CD4(+) T cells in culture. HTLV-2 is aleukemic and predominantly immortalizes/transforms CD8(+) T cells in culture. We have shown previously that the viral envelope is the genetic determinant of the differential T cell tropism in culture. The surface component (SU) of the HTLV-1 envelope is responsible for binding to the cellular receptors for entry. Here, we dissect the HTLV-1 SU further to identify key domains that are involved in determining the immortalization tropism. We generated HTLV-1 envelope recombinant virus containing the HTLV-2 SU domain. HTLV-1/SU2 was capable of infecting and immortalizing freshly isolated peripheral blood mononuclear cells in culture. HTLV-1/SU2 shifted the CD4(+) T cell immortalization tropism of wild-type HTLV-1 (wtHTLV-1) to a CD8(+) T cell preference. Furthermore, a single amino acid substitution, N195D, in HTLV-1 SU (Ach.195) resulted in a shift to a CD8(+) T cell immortalization tropism preference. Longitudinal phenotyping analyses of the in vitro transformation process revealed that CD4(+) T cells emerged as the predominant population by week 5 in wtHTLV-1 cultures, while CD8(+) T cells emerged as the predominant population by weeks 4 and 7 in wtHTLV-2 and Ach.195 cultures, respectively. Our results indicate that SU domain independently influences the preferential T cell immortalization tropism irrespective of the envelope counterpart transmembrane (TM) domain. We further showed that asparagine at position 195 in HTLV-1 SU is involved in determining this CD4(+) T cell immortalization tropism. The slower emergence of the CD8(+) T cell predominance in Ach.195-infected cultures suggests that other residues/domains contribute to this tropism preference.
authors.affiliation: Center for Retrovirus Research, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Priya
authors.initials: P
authors.lastname: Kannian
authors.forename: Soledad
authors.initials: S
authors.lastname: Fernandez
authors.forename: Kathryn S
authors.initials: KS
authors.lastname: Jones
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Green
mesh_terms: D019943:Amino Acid Substitution; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D015686:Gene Products, env / Q000235:genetics / Q000378:metabolism*; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology*; D006801:Humans; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics / Q000378:metabolism*; D056189:Viral Tropism; D037521:Virulence Factors / Q000378:metabolism*
chemical_list: D015686:Gene Products, env; D050505:Mutant Proteins; D011993:Recombinant Fusion Proteins; D015682:Retroviridae Proteins, Oncogenic; D037521:Virulence Factors; C055266:gp46 protein, Human T-cell leukemia virus type I