title: 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.
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-1) 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 6GC/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.
authors.affiliation: Department of Microbiology and Immunology, The Pennsylvania State University, College of Medicine, Hershey, Pennsylvania 17033, USA.
authors.forename: H L
authors.initials: HL
authors.lastname: Ross
authors.forename: S
authors.initials: S
authors.lastname: Gartner
authors.forename: J C
authors.initials: JC
authors.lastname: McArthur
authors.forename: J R
authors.initials: JR
authors.lastname: Corboy
authors.forename: J J
authors.initials: JJ
authors.lastname: McAllister
authors.forename: S
authors.initials: S
authors.lastname: Millhouse
authors.forename: B
authors.initials: B
authors.lastname: Wigdahl
mesh_terms: D015526:AIDS Dementia Complex / Q000378:metabolism / Q000821:virology*; D000074183:ATPases Associated with Diverse Cellular Activities; D001483:Base Sequence; D001665:Binding Sites / Q000502:physiology; D001921:Brain / Q000378:metabolism / Q000821:virology*; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D016384:Consensus Sequence; D004268:DNA-Binding Proteins / Q000378:metabolism; D015967:Gene Expression Regulation, Viral / Q000502:physiology; D016325:HIV Long Terminal Repeat / Q000502:physiology*; D015497:HIV-1 / Q000254:growth & development*; D006801:Humans; D009000:Monocytes / Q000166:cytology / Q000821:virology; D046988:Proteasome Endopeptidase Complex; D014158:Transcription, Genetic / Q000502:physiology; D014779:Virus Replication
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D046988:Proteasome Endopeptidase Complex; D000074183:ATPases Associated with Diverse Cellular Activities; C064757:PSMC3 protein, human