Human T-cell lymphotropic virus type 1 Tax mediates enhanced transcription in CD4+ T lymphocytes.
Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia/lymphoma and is associated with a variety of immunoregulatory disorders. HTLV-1 has been shown to bind to and infect a variety of hematopoietic and nonhematopoietic cells. However, both in vivo and in vitro, the provirus is mostly detected in and preferentially transforms CD4+ T cells. The molecular mechanism that determines the CD4+ T-cell tropism of HTLV-1 has not been determined. Using cocultures of purified CD4+ and CD8+ T cells with an HTLV-1 producing cell line, we measured viral transcription by using Northern (RNA) blot analysis, protein production by using a p24 antigen capture assay and flow cytometric analysis for viral envelope, and proviral integration by using DNA slot blot analysis. We further measured HTLV-1 long terminal repeat-directed transcription in purified CD4+ and CD8+ T cells by using transient transfection assays and in vitro transcription. We demonstrate a higher rate of viral transcription in primary CD4+ T cells than in CD8+ T cells. HTLV-1 protein production was 5- to 25-fold greater in CD4+ cocultures and mRNA levels were 5-fold greater in these cultures than in the CD8+ cocultures. Transient transfection and in vitro transcription indicated a modest increase in basal transcription in CD4+ T cells, whereas there was a 20-fold increase in reporter gene activity in CD4+ T cells cotransfected with tax. These data suggest that unique or activated transcription factors, particularly Tax-responsive factors in CD4+ T cells, recognize regulatory sequences within the HTLV-1 long terminal repeat, and this mediates the observed enhanced viral transcription and ultimately the cell tropism and leukemogenic potential of the virus.
Newbound
G C
GC
Center for Retrovirus Research, Ohio State University, Columbus, Ohio 43210, USA.
Andrews
J M
JM
O'Rourke
J P
JP
Brady
J N
JN
Lairmore
M D
MD
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D018414:CD8-Positive T-Lymphocytes / Q000821:virology; D002460:Cell Line; D015967:Gene Expression Regulation, Viral; D016356:Gene Products, tax / Q000502:physiology*; D017930:Genes, Reporter; D015368:Human T-lymphotropic virus 1 / Q000235:genetics* / Q000502:physiology; D006801:Humans; D012333:RNA, Messenger / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics*; D014158:Transcription, Genetic
D016356:Gene Products, tax; D012333:RNA, Messenger; D012367:RNA, Viral