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      Impact of Genetic Variations in HIV-1 Tat on LTR-Mediated Transcription via TAR RNA Interaction

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          HIV-1 evades host defense through mutations and recombination events, generating numerous variants in an infected patient. These variants with an undiminished virulence can multiply rapidly in order to progress to AIDS. One of the targets to intervene in HIV-1 replication is the trans-activator of transcription (Tat), a major regulatory protein that transactivates the long terminal repeat promoter through its interaction with trans-activation response (TAR) RNA. In this study, HIV-1 infected patients ( n = 120) from North India revealed Ser46Phe (20%) and Ser61Arg (2%) mutations in the Tat variants with a strong interaction toward TAR leading to enhanced transactivation activities. Molecular dynamics simulation data verified that the variants with this mutation had a higher binding affinity for TAR than both the wild-type Tat and other variants that lacked Ser46Phe and Ser61Arg. Other mutations in Tat conferred varying affinities for TAR interaction leading to differential transactivation abilities. This is the first report from North India with a clinical validation of CD4 counts to demonstrate the influence of Tat genetic variations affecting the stability of Tat and its interaction with TAR. This study highlights the co-evolution pattern of Tat and predominant nucleotides for Tat activity, facilitating the identification of genetic determinants for the attenuation of viral gene expression.

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                Author and article information

                Front Microbiol
                Front Microbiol
                Front. Microbiol.
                Frontiers in Microbiology
                Frontiers Media S.A.
                21 April 2017
                : 8
                1Laboratory of Virology, National Institute of Immunology Delhi, India
                2Department of Microbiology, University College of Medical Sciences and Guru Teg Bahadur Hospital Delhi, India
                3Centre for Bioinformatics, School of Life Sciences, Pondicherry University Pondicherry, India
                4Department of Biochemistry and Molecular Biology, Pondicherry University Pondicherry, India
                5Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station TX, USA
                6Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences Delhi, India
                7Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston TX, USA
                8Department of Microbiology and Immunology, Rosalind Franklin University of Medicine and Science, Chicago IL, USA
                9Department of Microbiology, All India Institute of Medical Sciences Delhi, India
                10Department of Neurological Surgery, Northwestern University, Chicago IL, USA
                Author notes

                Edited by: Akio Adachi, Tokushima University, Japan

                Reviewed by: Hirotaka Ode, Nagoya Medical Center (NHO), Japan; Aurelio Cafaro, Istituto Superiore di Sanità, Italy; Takao Masuda, Tokyo Medical and Dental University, Japan

                Present address: Larance Ronsard, Ragon Institute of MGH, MIT and Harvard, 400 Technology Square, Cambridge, MA, USA

                Nilanjana Ganguli and Vivek K. Singh have joint 2nd authorship.

                § Kumaravel Mohankumar and Tripti Rai have joint 3rd authorship.

                This article was submitted to Virology, a section of the journal Frontiers in Microbiology

                Copyright © 2017 Ronsard, Ganguli, Singh, Mohankumar, Rai, Sridharan, Pajaniradje, Kumar, Rai, Chaudhuri, Coumar, Ramachandran and Banerjea.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 5, Tables: 0, Equations: 0, References: 71, Pages: 13, Words: 0
                Funded by: Department of Biotechnology, Ministry of Science and Technology 10.13039/501100001407
                Award ID: BT/PR10599/Med/29/76/2008
                Award ID: BT/246/NE/TBP/2011/77
                Funded by: Indian Council of Medical Research 10.13039/501100001411
                Award ID: HIV/50/142/9/2011-ECD-II
                Original Research

                Microbiology & Virology

                mutations, hiv-1 tat, transactivation, tar rna, genetic variations, recombination


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