Utilization of HIV-1 envelope V3 to identify X4- and R5-specific Tat and LTR sequence signatures

Gregory C. Antell; Will Dampier; Benjamas Aiamkitsumrit; Michael R. Nonnemacher; Jeffrey M. Jacobson; Vanessa Pirrone; Wen Zhong; Katherine Kercher; Shendra Passic; Jean W. Williams; Gregory Schwartz; Uri Hershberg; Fred C. Krebs; Brian Wigdahl

doi:10.1186/s12977-016-0266-9

Utilization of HIV-1 envelope V3 to identify X4- and R5-specific Tat and LTR sequence signatures

Gregory C. Antell, Will Dampier, Benjamas Aiamkitsumrit, Michael R. Nonnemacher, Jeffrey M. Jacobson, Vanessa Pirrone, Wen Zhong, Katherine Kercher, Shendra Passic, Jean W. Williams, Gregory Schwartz, Uri Hershberg, Fred C. Krebs, Brian Wigdahl

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	1-14
Journal	Retrovirology
Volume	13
Issue number	1
DOIs	https://doi.org/10.1186/s12977-016-0266-9
State	Published - 3 May 2016
Externally published	Yes

Bibliographical note

Funding Information:
We would like to thank all patients who are part of the Drexel Medicine CARES Cohort. We would also like to thank the clinical staff within the Division of Infectious Diseases and HIV Medicine and Center for Clinical and Translational Medicine in the Institute for Molecular Medicine and Infectious Disease at the Drexel University College of Medicine who are involved in recruitment, enrollment, obtaining consent, obtaining clinical histories, venipuncture, and delivery of peripheral blood to the research laboratories in the Center for Molecular Virology and Translational Neuroscience in the Institute for Molecular Medicine and Infectious Disease. These studies were funded in part by the Public Health Service, National Institutes of Health, through grants from the National Institute of Neurological Disorders and Stroke (NS32092 and NS46263, Dr. Brian Wigdahl, Principal Investigator; NS089435, Dr. Michael R. Nonnemacher, Principal Investigator), the National Institute of Drug Abuse (DA19807, Dr. Brian Wigdahl, Principal Investigator), National Institute of Mental Health Comprehensive NeuroAIDS Center (CNAC) (P30 MH-092177, Kamel Khalili, PI; Brian Wigdahl, PI of the Drexel subcontract; Michael Nonnemacher, PI, Developmental Grant), and under the Ruth L. Kirschstein National Research Service Award 5T32MH079785 (Jay Rappaport, PI; Brian Wigdahl, PI of the Drexel subcontract). The contents of the paper are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Drs. Michael Nonnemacher, Will Dampier, and Fred Krebs were also supported by faculty development funds provided by the Department of Microbiology and Immunology and the Institute for Molecular Medicine and Infectious Disease.

Publisher Copyright:
© 2016 Antell et al..

Keywords

Co-receptor
Divergence
Diversity
Gp120
HIV-1
LTR
Tat
Transcription factor
Tropism
V3

ASJC Scopus subject areas

Virology
Infectious Diseases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1186/s12977-016-0266-9

Cite this

Antell, G. C., Dampier, W., Aiamkitsumrit, B., Nonnemacher, M. R., Jacobson, J. M., Pirrone, V., Zhong, W., Kercher, K., Passic, S., Williams, J. W., Schwartz, G., Hershberg, U., Krebs, F. C., & Wigdahl, B. (2016). Utilization of HIV-1 envelope V3 to identify X4- and R5-specific Tat and LTR sequence signatures. Retrovirology, 13(1), 1-14. https://doi.org/10.1186/s12977-016-0266-9

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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.",

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author = "Antell, {Gregory C.} and Will Dampier and Benjamas Aiamkitsumrit and Nonnemacher, {Michael R.} and Jacobson, {Jeffrey M.} and Vanessa Pirrone and Wen Zhong and Katherine Kercher and Shendra Passic and Williams, {Jean W.} and Gregory Schwartz and Uri Hershberg and Krebs, {Fred C.} and Brian Wigdahl",

note = "Funding Information: We would like to thank all patients who are part of the Drexel Medicine CARES Cohort. We would also like to thank the clinical staff within the Division of Infectious Diseases and HIV Medicine and Center for Clinical and Translational Medicine in the Institute for Molecular Medicine and Infectious Disease at the Drexel University College of Medicine who are involved in recruitment, enrollment, obtaining consent, obtaining clinical histories, venipuncture, and delivery of peripheral blood to the research laboratories in the Center for Molecular Virology and Translational Neuroscience in the Institute for Molecular Medicine and Infectious Disease. These studies were funded in part by the Public Health Service, National Institutes of Health, through grants from the National Institute of Neurological Disorders and Stroke (NS32092 and NS46263, Dr. Brian Wigdahl, Principal Investigator; NS089435, Dr. Michael R. Nonnemacher, Principal Investigator), the National Institute of Drug Abuse (DA19807, Dr. Brian Wigdahl, Principal Investigator), National Institute of Mental Health Comprehensive NeuroAIDS Center (CNAC) (P30 MH-092177, Kamel Khalili, PI; Brian Wigdahl, PI of the Drexel subcontract; Michael Nonnemacher, PI, Developmental Grant), and under the Ruth L. Kirschstein National Research Service Award 5T32MH079785 (Jay Rappaport, PI; Brian Wigdahl, PI of the Drexel subcontract). The contents of the paper are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Drs. Michael Nonnemacher, Will Dampier, and Fred Krebs were also supported by faculty development funds provided by the Department of Microbiology and Immunology and the Institute for Molecular Medicine and Infectious Disease. Publisher Copyright: {\textcopyright} 2016 Antell et al..",

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doi = "10.1186/s12977-016-0266-9",

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Antell, GC, Dampier, W, Aiamkitsumrit, B, Nonnemacher, MR, Jacobson, JM, Pirrone, V, Zhong, W, Kercher, K, Passic, S, Williams, JW, Schwartz, G, Hershberg, U, Krebs, FC & Wigdahl, B 2016, 'Utilization of HIV-1 envelope V3 to identify X4- and R5-specific Tat and LTR sequence signatures', Retrovirology, vol. 13, no. 1, pp. 1-14. https://doi.org/10.1186/s12977-016-0266-9

TY - JOUR

T1 - Utilization of HIV-1 envelope V3 to identify X4- and R5-specific Tat and LTR sequence signatures

AU - Antell, Gregory C.

AU - Dampier, Will

AU - Aiamkitsumrit, Benjamas

AU - Nonnemacher, Michael R.

AU - Jacobson, Jeffrey M.

AU - Pirrone, Vanessa

AU - Zhong, Wen

AU - Kercher, Katherine

AU - Passic, Shendra

AU - Williams, Jean W.

AU - Schwartz, Gregory

AU - Hershberg, Uri

AU - Krebs, Fred C.

AU - Wigdahl, Brian

N1 - Funding Information: We would like to thank all patients who are part of the Drexel Medicine CARES Cohort. We would also like to thank the clinical staff within the Division of Infectious Diseases and HIV Medicine and Center for Clinical and Translational Medicine in the Institute for Molecular Medicine and Infectious Disease at the Drexel University College of Medicine who are involved in recruitment, enrollment, obtaining consent, obtaining clinical histories, venipuncture, and delivery of peripheral blood to the research laboratories in the Center for Molecular Virology and Translational Neuroscience in the Institute for Molecular Medicine and Infectious Disease. These studies were funded in part by the Public Health Service, National Institutes of Health, through grants from the National Institute of Neurological Disorders and Stroke (NS32092 and NS46263, Dr. Brian Wigdahl, Principal Investigator; NS089435, Dr. Michael R. Nonnemacher, Principal Investigator), the National Institute of Drug Abuse (DA19807, Dr. Brian Wigdahl, Principal Investigator), National Institute of Mental Health Comprehensive NeuroAIDS Center (CNAC) (P30 MH-092177, Kamel Khalili, PI; Brian Wigdahl, PI of the Drexel subcontract; Michael Nonnemacher, PI, Developmental Grant), and under the Ruth L. Kirschstein National Research Service Award 5T32MH079785 (Jay Rappaport, PI; Brian Wigdahl, PI of the Drexel subcontract). The contents of the paper are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Drs. Michael Nonnemacher, Will Dampier, and Fred Krebs were also supported by faculty development funds provided by the Department of Microbiology and Immunology and the Institute for Molecular Medicine and Infectious Disease. Publisher Copyright: © 2016 Antell et al..

PY - 2016/5/3

Y1 - 2016/5/3

N2 - 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.

AB - 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.

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KW - Divergence

KW - Diversity

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KW - HIV-1

KW - LTR

KW - Tat

KW - Transcription factor

KW - Tropism

KW - V3

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IS - 1

ER -

Utilization of HIV-1 envelope V3 to identify X4- and R5-specific Tat and LTR sequence signatures

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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