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HIV-1 LTR C/EBP binding site sequence configurations preferentially encountered in brain lead to enhanced C/EBP factor binding and increased LTR-specific activity

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Abstract

Recent studies have shown that two CAAT/enhancer binding protein (C/EBP) sites are critically important for efficient human immunodeficiency virus (HIV) type 1 (HIV-l) replication within cells of the monocyte/macrophage lineage, a primary cell type infected by HIV-1 and a potentially important vehicle for transport of virus to the central nervous system (CNS). Given the relevance of HIV-1 LTR sequence variation with respect to HIV-1 replication within monocyte populations and the important role that monocyte tropism likely plays in HIV-1 infection of the brain, C/EBP site sequence variation was examined within peripheral blood- and brain-derived LTR populations. Brain-derived LTRs commonly possessed a C/EBP site I configuration (6G, comprised of a thymidine to guanosine substitution with respect to the clade B consensus sequence at position 6 of C/EBP site I) that leads to enhanced binding of C/EBP proteins over that observed with the HIV-1 clade B consensus sequence at this site. In contrast, the 6G C/EBP site I configuration appeared infrequently within sequenced peripheral blood-derived LTRs. In addition, C/EBP site II was even more highly conserved in brain-derived HIV-1 LTR populations than site I. This was not the case with peripheral blood-derived LTR C/EBP site II sequences. The high degree of C/EBP site II conservation in brain-derived LTRs was likely important in LTR regulation since the clade B consensus sequence conserved at C/EBP site II recruited high amounts of C/EBP family members. Transient transfection analyses indicated that conservation of the strong C/EBP site II in brain-derived LTRs was likely due to important interactions with Tat. Overall, brain-derived HIV-1 LTRs preferentially contained two highly reactive C/EBP binding sites, which may suggest that these sites play important roles in LTR-directed transcription during invasion and maintenance of HIV-1 in the central nervous system.

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Authors and Affiliations

  1. Department of Microbiology and Immunology (H107), The Pennsylvania State University College of Medicine, 500 University Drive, P. O. Box 850, 17033, Hershey, PA, USA

    Heather L. Ross, John J. McAllister, Scott Millhouse & Brian Wigdahl

  2. Department of Neurology, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA

    Suzanne Gartner & Justin C. McArthur

  3. Department of Neurology, The University of Colorado, Health Sciences Center, Denver, Colorado, USA

    John R. Corboy

Authors
  1. Heather L. Ross
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  2. Suzanne Gartner
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  3. Justin C. McArthur
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  4. John R. Corboy
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  5. John J. McAllister
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  6. Scott Millhouse
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  7. Brian Wigdahl
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Correspondence to Brian Wigdahl.

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Ross, H.L., Gartner, S., McArthur, J.C. et al. HIV-1 LTR C/EBP binding site sequence configurations preferentially encountered in brain lead to enhanced C/EBP factor binding and increased LTR-specific activity. Journal of NeuroVirology 7, 235–249 (2001). https://doi.org/10.1080/13550280152403281

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  • DOI: https://doi.org/10.1080/13550280152403281

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