Journal of NeuroVirology

, Volume 7, Issue 3, pp 235–249 | Cite as

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

  • Heather L. Ross
  • Suzanne Gartner
  • Justin C. McArthur
  • John R. Corboy
  • John J. McAllister
  • Scott Millhouse
  • Brian Wigdahl
Article

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.

Keywords

Human Immunode Ciency Virus Long Terminal Repeat Long Terminal Repeat Sequence Human Immunode Ciency Virus Long Terminal Repeat Activity 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Ait-Khaled M, McLaughlin JE, Johnson MA, Emery VC (1995). Distinct HIV-1 long terminal repeat quasispecies present in nervous tissues compared to that in lung, blood and lymphoid tissues of an AIDS patient. Aids 9: 675–683.CrossRefPubMedGoogle Scholar
  2. Akira S, Isshiki H, Sugita T, Tanabe O, Kinoshita S, Nishio Y, Nakajima T, Hirano T, Kishimoto T (1990). A nuclear factor for IL-6 expression (NF-IL6) is a member of a C/EBP family. EMBO J 9: 1897–1906.PubMedGoogle Scholar
  3. Benson DA, Karsch-Mizrachi I, Lipman DJ, Ostell J, Rapp BA, Wheeler DL (2000). GenBank. Nucleic Acids Res 28: 15–18.CrossRefPubMedGoogle Scholar
  4. Bronstein I, Voyta JC, Murphy OJ, Bresnick L, Kricka LJ (1992). Improved chemiluminescent Western blotting procedure. Biotechniques 12: 748–753.PubMedGoogle Scholar
  5. Burnette WN (1981). “Western blotting”: electrophoretic transfer of proteins from sodium dodecyl sulfate—polyacrylamide gels to unmodified nitrocellulose and radiographic detection with antibody and radioiodinated protein A. Anal Biochem 112: 195–203.CrossRefPubMedGoogle Scholar
  6. Choe H, Farzan M, Sun Y, Sullivan N, Rollins B, Ponath PD, Wu L, Mackay CR, LaRosa G, Newman W, Gerard N, Gerard C, Sodroski J (1996). The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell 85: 1135–1148.CrossRefPubMedGoogle Scholar
  7. Corboy JR, Buzy JM, Zink MC, Clements JE (1992). Expression directed from HIV long terminal repeats in the central nervous system of transgenic mice. Science 258: 1804–1808.CrossRefPubMedGoogle Scholar
  8. Corboy JR, Garl PJ (1997). HIV-1 LTR DNA sequence variation in brain-derived isolates. J Neuro Virol 3: 331–341.Google Scholar
  9. Delwart EL, Sheppard HW, Walker BD, Goudsmit J, Mullins JI (1994). Human immunodeficiency virus type 1 evolution in vivo tracked by DNA heteroduplex mobility assays. J Virol 68: 6672–6683.PubMedGoogle Scholar
  10. Deng H, Liu R, Ellmeier W, Choe S, Unutmaz D, Burkhart M, Di Marzio P, Marmon S, Sutton RE, Hill CM, Davis CB, Peiper SC, Schall TJ, Littman DR, Landau NR (1996). Identification of a major co-receptor for primary isolates of HIV-1 [see comments]. Nature 381: 661–666.CrossRefPubMedGoogle Scholar
  11. Dignam JD, Lebovitz RM, Roeder RG (1983). Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res 11: 1475–1489.CrossRefPubMedGoogle Scholar
  12. Doranz BJ, Rucker J, Yi Y, Smyth RJ, Samson M, Peiper SC, Parmentier M, Collman RG, Doms RW (1996). A dual-tropic primary HIV-1 isolate that uses fusin and the beta-chemokine receptors CKR-5, CKR-3, and CKR-2b as fusion cofactors. Cell 85: 1149–1158.CrossRefPubMedGoogle Scholar
  13. Dragic T, Litwin V, Allaway GP, Martin SR, Huang Y, Nagashima KA, Cayanan C, Maddon PJ, Koup RA, Moore JP, Paxton WA (1996). HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5 [see comments]. Nature 381: 667–673.CrossRefPubMedGoogle Scholar
  14. Estable MC, Bell B, Merzouki A, Montaner JS, O’Shaughnessy MV, Sadowski IJ (1996). Human immunodeficiency virus type 1 long terminal repeat variants from 42 patients representing all stages of infection display a wide range of sequence polymorphism and transcription activity. J Virol 70: 4053–4062.PubMedGoogle Scholar
  15. Feng Y, Broder CC, Kennedy PE, Berger EA (1996). HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor [see comments]. Science 272: 872–877.CrossRefPubMedGoogle Scholar
  16. Gallo P, Frei K, Rordorf C, Lazdins J, Tavolato B, Fontana A (1989). Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system: an evaluation of cytokines in cerebrospinal fluid. J Neuroimmunol 23: 109–116.CrossRefPubMedGoogle Scholar
  17. Geleziunas R, Schipper HM, Wainberg MA (1992). Pathogenesis and therapy of HIV-1 infection of the central nervous system [editorial]. Aids 6: 1411–1126.CrossRefPubMedGoogle Scholar
  18. Gillespie PG, Hudspeth AJ (1991). Chemiluminescence detection of proteins from single cells. Proc Natl Acad Sci USA 88: 2563–2567.CrossRefPubMedGoogle Scholar
  19. Henderson AJ, Calame KL (1997). CCAAT/enhancer binding protein (C/EBP) sites are required for HIV-1 replication in primary macrophages but not CD4(+) T cells. Proc Natl Acad Sci USA 94: 8714–8719.CrossRefPubMedGoogle Scholar
  20. Henderson AJ, Connor RI, Calame KL (1996). C/EBP activators are required for HIV-1 replication and proviral induction in monocytic cell lines. Immunity 5: 91–101.CrossRefPubMedGoogle Scholar
  21. Henderson AJ, Zou X, Calame KL (1995). C/EBP proteins activate transcription from the human immunodeficiency virus type 1 long terminal repeat in macrophages/monocytes. J Virol 69: 5337–5347.PubMedGoogle Scholar
  22. Ho DD, Bredesen DE, Vinters HV, Daar ES (1989). The acquired immunodeficiency syndrome (AIDS) dementia complex [clinical conference]. Ann Intern Med 111: 400–410.PubMedGoogle Scholar
  23. Kim FM, Kolson DL, Balliet JW, Srinivasan A, Collman RG (1995). V3-independent determinants of macrophage tropism in a primary human immunodeficiency virus type 1 isolate. J Virol 69: 1755–1761.PubMedGoogle Scholar
  24. Kirchhoff F, Greenough TC, Hamacher M, Sullivan JL, Desrosiers RC (1997). Activity of human immunodeficiency virus type 1 promoter/TAR regions and tat1 genes derived from individuals with different rates of disease progression. Virology 232: 319–331.CrossRefPubMedGoogle Scholar
  25. Korber BT, Kunstman KJ, Patterson BK, Furtado M, McEvilly MM, Levy R, Wolinsky SM (1994). Genetic differences between blood- and brain-derived viral sequences from human immunodeficiency virus type 1-infected patients: evidence of conserved elements in the V3 region of the envelope protein of brain-derived sequences. J Virol 68: 7467–7481.PubMedGoogle Scholar
  26. Lipton SA, Gendelman HE (1995). Seminars in medicine of the Beth Israel Hospital, Boston. Dementia associated with the acquired immunodeficiency syndrome [see comments]. N Engl J Med 332: 934–940.CrossRefPubMedGoogle Scholar
  27. Liu Y, Tang XP, McArthur JC, Scott J, Gartner S (2000). Analysis of human immunodeficiency virus type 1 gp 160 sequences from a patient with HIV dementia: evidence for monocyte trafficking into brain. J NeuroVirol 6 Suppl 1: S70-S81.PubMedGoogle Scholar
  28. Lukashov VV, Kuiken CL, Goudsmit J (1995). Intrahost human immunodeficiency virus type 1 evolution is related to length of the immunocompetent period. J Virol 69: 6911–6916.PubMedGoogle Scholar
  29. Maxam AM, Gilbert W (1980). Sequencing end-labeled DNA with base-specific chemical cleavages. Methods Enzymol 65: 499–560.CrossRefPubMedGoogle Scholar
  30. McAllister JJ, Phillips D, Millhouse S, Conner J, Hogan T, Ross HL, Wigdahl B (2000). Analysis of the HIV-1 LTR NF-kappaB-proximal Sp site III: evidence for cell typespecific gene regulation and viral replication. Virology 274: 262–277.CrossRefPubMedGoogle Scholar
  31. McArthur JC, Hoover DR, Bacellar H, Miller EN, Cohen BA, Becker JT, Graham NM, McArthur JH, Selnes OA, Jacobson LP (1993). Dementia in AIDS patients: incidence and risk factors. Multicenter AIDS Cohort Study. Neurology 43: 2245–2252.PubMedGoogle Scholar
  32. Michael NL, D’Arcy L, Ehrenberg PK, Redfield RR (1994). Naturally occurring genotypes of the human immunodeficiency virus type 1 long terminal repeat display a wide range of basal and Tat-induced transcriptional activities. J Virol 68: 3163–3174.PubMedGoogle Scholar
  33. Pang S, Shlesinger Y, Daar ES, Moudgil T, Ho DD, Chen IS (1992). Rapid generation of sequence variation during primary HIV-1 infection [published erratum appears in AIDS 1992 Jun;6(6):following 606]. Aids 6: 453–460.CrossRefPubMedGoogle Scholar
  34. Perelson AS, Essunger P, Cao Y, Vesanen M, Hurley A, Saksela K, Markowitz M, Ho DD (1997). Decay characteristics of HrV-1-infected compartments during combination therapy [see comments]. Nature 387: 188–191.CrossRefPubMedGoogle Scholar
  35. Perrella O, Carrieri PB, Guarnaccia D, Soscia M (1992). Cerebrospinal fluid cytokines in AIDS dementia complex. J Neurol 239: 387–388.PubMedGoogle Scholar
  36. Sandhu GS, Eckloff BW, Kline BC (1991). Chemiluminescent substrates increase sensitivity of antigen detection in Western blots. Biotechniques 11: 14–16.PubMedGoogle Scholar
  37. Sokal RR, Rohlf FJ (1995). Biometry (3rd ed). New York: W. H. Freeman.Google Scholar
  38. Tesmer VM, Rajadhyaksha A, Babin J, Bina M (1993). NF-IL6-mediated transcriptional activation of the long terminal repeat of the human immunodeficiency virus type 1. Proc Natl Acad Sci USA 90: 7298–7302.CrossRefPubMedGoogle Scholar

Copyright information

© Journal of NeuroVirology, Inc. 2001

Authors and Affiliations

  • Heather L. Ross
    • 1
  • Suzanne Gartner
    • 2
  • Justin C. McArthur
    • 2
  • John R. Corboy
    • 3
  • John J. McAllister
    • 1
  • Scott Millhouse
    • 1
  • Brian Wigdahl
    • 1
  1. 1.Department of Microbiology and Immunology (H107)The Pennsylvania State University College of MedicineHersheyUSA
  2. 2.Department of NeurologyThe Johns Hopkins School of MedicineBaltimoreUSA
  3. 3.Department of NeurologyThe University of Colorado, Health Sciences CenterDenverUSA

Personalised recommendations