The TATAA box binds the TATAA binding protein (TBP) and other host proteins that comprise the RNA polymerase transcription complex. The core region includes the TATAA element and three GC rich binding sites for the Sp family of transcription factors. The core region is required for HIV-1 basal transcription and is positioned approximately from 20 to 60 bp upstream of the transcriptional start site. The U3 region is further subdivided into the core, enhancer, and modulatory regions and their associated transcription factor binding sites that guide the DNA–protein and protein–protein interactions important for LTR activity and regulated viral gene expression. The HIV-1 LTR is approximately 640 bp in length and is divided into the unique 3 (U3), repeat (R), and unique 5 (U5) regions. Located at both ends of the integrated genome are two identical viral long terminal repeat (LTR) sequences, with the 5′ LTR serving as the promoter for HIV-1 transcription and the 3′ LTR providing for nascent viral RNA polyadenylation. 1HIV-1 sequence variation within the LTR and other viral genes, such as env, Tat, and others, impacts viral gene expression and replication as well as viral tropism, which may affect overall HIV disease severity based on the relative fitness of the virus. The molecular diversity of HIV-1 is a critical mediator of viral replication and overall viral fitness. The production of human immunodeficiency virus type 1 (HIV-1) RNA and protein subsequent to infection is achieved using the integrated provirus as a template to guide production of both regulatory and structural gene products. Keywords:HIV-1, LTR, TAR, Tat, Transactivation, Genetic variation, Sp binding sites Introduction These studies indicate that a vast majority of LTRs derived from the integrated provirus in the peripheral blood compartment of a number of infected patients maintained the ability to drive basal and Tat-mediated transcription but that just a small number of nucleotides were shown to have a detrimental impact on LTR activation in both T cells and cells of the monocyte-macrophage lineage. In this regard, site-directed mutagenesis indicated that optimal Tat-mediated transactivation depended on both position 32 of the TAR element and binding of Sp to all three Sp binding sites within the LTR. After inspection of the sequence of the patient-derived LTR clone defective with respect to Tat-mediated transactivation, additional alterations within the LTR were identified in a number of transcription factor binding sites in the LTR core region as well as in the TAR element that suggested that these sites may also contribute to the Tat non responsiveness. These results demonstrated that one of 4 clones could not be transactivated by Tat derived from laboratory strain IIIB or from the patient. As one simple approach to examine the impact of sequence variation on LTR fitness, LTR clones from a single patient (patient 19) were used in transient expression studies in both T-cell and monocyte-macrophage cell lines. HIV-1 LTRs and Tat were amplified and cloned from patients in the Drexel Medicine CNS AIDS Research and Eradication Study (CARES) Cohort. Studies conducted pre- and post antiretroviral therapy identified HIV-1-infected patients harboring a C-to-T change at position 5 of the consensus B sequence of Sp binding site III (a knockout configuration with respect to binding of Sp1). HIV-1 Tat-mediated transactivation of the long terminal repeat (LTR) requires an interaction with the transactivation response element (TAR) and is facilitated by NF-κB and Sp factors binding to sequences upstream of the transcriptional start site. (2015) Impact of Naturally Occurring Genetic Variation in the HIV-1 LTR TAR Region and Sp Binding Sites on Tat-Mediated Transcription. Please type the correct Captcha word to see email ID.ġDepartment of Microbiology and Immunology, Drexel University College of Medicine, USAĢCenter for Molecular Virology and Translational Neuroscience, Drexel University College of Medicine, USAģCenter for Clinical and Translational Medicine, Drexel University College of Medicine, USAĤDivision of Infectious Disease and HIV Medicine, Drexel University College of Medicine, USAĥB-Tech Consulting, Ltd., Philadelphia, USAĦDepartment of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, USAĬorrespondence: Brian Wigdahl, Department of Microbiology and Immunology, Drexel University College of Medicine, 245 N 15th St, Room 18301, Philadelphia, Pennsylvania 19102, USA, Tel 1-21, Fax 1-21Ĭitation: Luna LI, Parikh N, Liu Y, Kercher K, Dampier W, et al. Regret for the inconvenience: we are taking measures to prevent fraudulent form submissions by extractors and page crawlers.
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