Authors

Gregory C Antell, Drexel University College of Medicine, Department of Microbiology and Immunology; Drexel University College of Medicine, Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease; Drexel University, School of Biomedical Engineering, Science, and Health Systems
Will Dampier, Drexel University College of Medicine, Department of Microbiology and Immunology; Drexel University College of Medicine, Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease; Drexel University, School of Biomedical Engineering, Science, and Health Systems
Benjamas Aiamkitsumrit, Drexel University College of Medicine, Department of Microbiology and Immunology; Drexel University College of Medicine, Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease
Michael R Nonnemacher, Drexel University College of Medicine, Department of Microbiology and Immunology; Drexel University College of Medicine, Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease
Jeffrey M Jacobson, Drexel University College of Medicine, Department of Microbiology and Immunology; Drexel University College of Medicine, Division of Infectious Diseases and HIV Medicine, Department of Medicine; Drexel University College of Medicine, Center for Clinical and Translational Medicine, Institute for Molecular Medicine and Infectious Disease
Vanessa Pirrone, Drexel University College of Medicine, Department of Microbiology and Immunology; Drexel University College of Medicine, Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease
Wen Zhong, Drexel University College of Medicine, Department of Microbiology and Immunology; Drexel University College of Medicine, Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease
Katherine Kercher, Drexel University College of Medicine, Department of Microbiology and Immunology; Drexel University College of Medicine, Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease
Shendra Passic, Drexel University College of Medicine, Department of Microbiology and Immunology; Drexel University College of Medicine, Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease
Jean W Williams, Drexel University College of Medicine, Department of Microbiology and Immunology; Drexel University College of Medicine, Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease
Gregory Schwartz, Drexel University, School of Biomedical Engineering, Science, and Health Systems
Uri Hershberg, Drexel University College of Medicine, Department of Microbiology and Immunology; Drexel University, School of Biomedical Engineering, Science, and Health Systems
Fred C Krebs, Drexel University College of Medicine, Department of Microbiology and Immunology; Drexel University College of Medicine, Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease
Brian Wigdahl, Drexel University College of Medicine, Department of Microbiology and Immunology; Drexel University College of Medicine, Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease; Thomas Jefferson University, Sidney Kimmel Cancer Center

Document Type

Article

Publication Date

5-3-2016

Comments

This article has been peer reviewed. It was published in: Retrovirology.

Volume 13, Issue 1, 3 May 2016, Article number 32.

The published version is available at DOI: 10.1186/s12977-016-0266-9

Copyright © Antell et al. 2016

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Abstract

BACKGROUND: HIV-1 entry is a receptor-mediated process directed by the interaction of the viral envelope with the host cell CD4 molecule and one of two co-receptors, CCR5 or CXCR4. The amino acid sequence of the third variable (V3) loop of the HIV-1 envelope is highly predictive of co-receptor utilization preference during entry, and machine learning predictive algorithms have been developed to characterize sequences as CCR5-utilizing (R5) or CXCR4-utilizing (X4). It was hypothesized that while the V3 loop is predominantly responsible for determining co-receptor binding, additional components of the HIV-1 genome may contribute to overall viral tropism and display sequence signatures associated with co-receptor utilization.

RESULTS: The accessory protein Tat and the HlV-1 long terminal repeat (LTR) were analyzed with respect to genetic diversity and compared by Jensen-Shannon divergence which resulted in a correlation with both mean genetic diversity as well as the absolute difference in genetic diversity between R5- and X4-genome specific trends. As expected, the V3 domain of the gp120 protein was enriched with statistically divergent positions. Statistically divergent positions were also identified in Tat amino acid sequences within the transactivation and TAR-binding domains, and in nucleotide positions throughout the LTR. We further analyzed LTR sequences for putative transcription factor binding sites using the JASPAR transcription factor binding profile database and found several putative differences in transcription factor binding sites between R5 and X4 HIV-1 genomes, specifically identifying the C/EBP sites I and II, and Sp site III to differ with respect to sequence configuration for R5 and X4 LTRs.

CONCLUSION: These observations support the hypothesis that co-receptor utilization coincides with specific genetic signatures in HIV-1 Tat and the LTR, likely due to differing transcriptional regulatory mechanisms and selective pressures applied within specific cellular targets during the course of productive HIV-1 infection.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

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