Distinctive variation in the U3R region of the 5' Long Terminal Repeat from diverse HIV-1 strains.

Abstract

Functional mapping of the 5'LTR has shown that the U3 and the R regions (U3R) contain a cluster of regulatory elements involved in the control of HIV-1 transcription and expression. As the HIV-1 genome is characterized by extensive variability, here we aimed to describe mutations in the U3R from various HIV-1 clades and CRFs in order to highlight strain specific differences that may impact the biological properties of diverse HIV-1 strains. To achieve our purpose, the U3R sequence of plasma derived virus belonging to different clades (A1, B, C, D, F2) and recombinants (CRF02_AG, CRF01_AE and CRF22_01A1) was obtained using Illumina technology. Overall, the R region was very well conserved among and across different strains, while in the U3 region the average inter-strains nucleotide dissimilarity was up to 25%. The TAR hairpin displayed a strain-distinctive cluster of mutations affecting the bulge and the loop, but mostly the stem. Like in previous studies we found a TATAA motif in U3 promoter region from the majority of HIV-1 strains and a TAAAA motif in CRF01_AE; but also in LTRs from CRF22_01A1 isolates. Although LTRs from CRF22_01A1 specimens were assigned CRF01_AE, they contained two NF-kB sites instead of the single TFBS described in CRF01_AE. Also, as previously describe in clade C isolates, we found no C/EBP binding site directly upstream of the enhancer region in CRF22_01A1 specimens. In our study, one-third of CRF02_AG LTRs displayed three NF-kB sites which have been mainly described in clade C isolates. Overall, the number, location and binding patterns of potential regulatory elements found along the U3R might be specific to some HIV-1 strains such as clade F2, CRF02_AG, CRF01_AE and CRF22_01A1. These features may be worth consideration as they may be involved in distinctive regulation of HIV-1 transcription and replication by different and diverse infecting strains.

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10.1371/journal.pone.0195661

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Mbondji-Wonje, Christelle, Ming Dong, Xue Wang, Jiangqin Zhao, Viswanath Ragupathy, Ana M Sanchez, Thomas N Denny, Indira Hewlett, et al. (2018). Distinctive variation in the U3R region of the 5' Long Terminal Repeat from diverse HIV-1 strains. PloS one, 13(4). p. e0195661. 10.1371/journal.pone.0195661 Retrieved from https://hdl.handle.net/10161/17799.

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Denny

Thomas Norton Denny

Professor in Medicine

Thomas N. Denny, MSc, M.Phil, is the Chief Operating Officer of the Duke Human Vaccine Institute (DHVI), Associate Dean for Duke Research and Discovery @RTP, and a Professor of Medicine in the Department of Medicine at Duke University Medical Center. He is also an Affiliate Member of the Duke Global Health Institute. Previously, he served on the Health Sector Advisory Council of the Duke University Fuquay School of Business. Prior to joining Duke, he was an Associate Professor of Pathology, Laboratory Medicine and Pediatrics, Associate Professor of Preventive Medicine and Community Health and Assistant Dean for Research in Health Policy at the New Jersey Medical School, Newark, New Jersey. He has served on numerous committees for the NIH over the last two decades and currently is the principal investigator of an NIH portfolio in excess of 65 million dollars. Mr. Denny was a 2002-2003 Robert Wood Johnson Foundation Health Policy Fellow at the Institute of Medicine of the National Academies (IOM). As a fellow, he served on the US Senate Health, Education, Labor and Pensions Committee with legislation/policy responsibilities in global AIDS, bioterrorism, clinical trials/human subject protection and vaccine related-issues.

As the Chief Operating Officer of the DHVI, Mr. Denny has senior oversight of the DHVI research portfolio and the units/teams that support the DHVI mission. He has extensive international experience and previously was a consultant to the U.S. Centers for Disease Control and Prevention (CDC) for the President’s Emergency Plan for AIDS Relief (PEPFAR) project to oversee the development of an HIV and Public Health Center of Excellence laboratory network in Guyana. In September 2004, the IOM appointed him as a consultant to their Board on Global Health Committee studying the options for overseas placement of U.S. health professionals and the development of an assessment plan for activities related to the 2003 PEPFAR legislative act. In the 1980s, Mr. Denny helped establish a small laboratory in the Republic of Kalmykia (former Soviet Union) to improve the care of children with HIV/AIDS and served as a Board Member of the Children of Chernobyl Relief Fund Foundation. In 2005, Mr. Denny was named a consulting medical/scientific officer to the WHO Global AIDS Program in Geneva. He has also served as program reviewers for the governments of the Netherlands and South Africa as well as an advisor to several U.S. biotech companies. He currently serves as the Chair of the Scientific Advisory Board for Grid Biosciences.

Mr. Denny has authored and co-authored more than 200 peer-reviewed papers and serves on the editorial board of Communications in Cytometry and Journal of Clinical Virology. He holds an M.Sc in Molecular and Biomedical Immunology from the University of East London and a degree in Medical Law (M.Phil) from the Institute of Law and Ethics in Medicine, School of Law, University of Glasgow. In 1991, he completed a course of study in Strategic Management at The Wharton School, University of Pennsylvania. In 1993, he completed the Program for Advanced Training in Biomedical Research Management at Harvard School of Public Health. In December 2005, he was inducted as a Fellow into the College of Physicians of Philadelphia, the oldest medical society in the US.

While living in New Jersey, Mr. Denny was active in his community, gaining additional experience from two publicly elected positions. In 2000, Mr. Denny was selected by the New Jersey League of Municipalities to Chair the New Jersey Community Mental Health Citizens’ Advisory Board and Mental Health Planning Council as a gubernatorial appointment.


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