TAR-independent transactivation by Tat in cells derived from the CNS: a novel mechanism of HIV-1 gene regulation.
The Tat protein of human immunodeficiency virus type 1 (HIV-1) is essential for productive infection and is a potential target for antiviral therapy. Tat, a potent activator of HIV-1 gene expression, serves to greatly increase the rate of transcription directed by the viral promoter. This induction, which seems to be an important component in the progression of acquired immune deficiency syndrome (AIDS), may be due to increased transcriptional initiation, increased transcriptional elongation, or a combination of these processes. Much attention has been focused on the interaction of Tat with a specific RNA target termed TAR (transactivation responsive) which is present in the leader sequence of all HIV-1 mRNAs. This interaction is believed to be an important component of the mechanism of transactivation. In this report we demonstrate that in certain CNS-derived cells Tat is capable of activating HIV-1 through a TAR-independent pathway. A Tat-responsive element is found upstream within the viral promoter that in glial-derived cell lines allows transactivation in the absence of TAR. Deletion mapping and hybrid promoter constructs demonstrate that the newly identified Tat-responsive element corresponds to a sequence within the viral long terminal repeat (LTR) previously identified as the HIV-1 enhancer, or NF-kappa B domain. DNA band-shift analysis reveals NF-kappa B binding activity in glial cells that differs from that present in T lymphoid cells. Further, we observe that TAR-deleted mutants of HIV-1 demonstrate normal late gene expression in glial cells as evidenced by syncytia formation and production of viral p24 antigen.(ABSTRACT TRUNCATED AT 250 WORDS)
Taylor
J P
JP
Department of Biochemistry and Molecular Biology, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA 19107.
Pomerantz
R
R
Bagasra
O
O
Chowdhury
M
M
Rappaport
J
J
Khalili
K
K
Amini
S
S
D000818:Animals; D001483:Base Sequence; D002459:Cell Fusion; D002460:Cell Line; D015967:Gene Expression Regulation, Viral; D015696:Gene Products, tat / Q000378:metabolism*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D009457:Neuroglia / Q000382:microbiology; D011401:Promoter Regions, Genetic / Q000235:genetics; D012367:RNA, Viral / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics; D013601:T-Lymphocytes / Q000382:microbiology; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014779:Virus Replication / Q000235:genetics; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D016328:NF-kappa B; D012367:RNA, Viral; D054322:tat Gene Products, Human Immunodeficiency Virus