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In This Issue, The Journal of Immunology, Volume 176, Issue 7, April 2006, Pages 3851–3852, https://doi.org/10.4049/jimmunol.176.7.3851
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HIV-1 Inhibition of TNF
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Subtypes of HIV-1 differ with regard to their geographical prevalence and viral gene sequences. To date, no definitive relationship between subtype and pathogenic potential has established. Ranjbar et al. (p. 4182 ) found several amino acid differences within the transactivator of transcription (Tat) protein between viral subtypes B and C compared with subtype E based on nucleotide sequences. Tryptophan at aa 32 was found only in subtype E isolates. In stimulated CD4+ T cells or monocytes, vector-expressed subtype B or C, but not E, Tat enhanced activity of a cotransfected luciferase reporter gene controlled by the region of the TNF gene that binds Tat. A subtype E variant in which tryptophan at aa 32 of the wild-type subtype E isolate was replaced with glycine had partial TNF reporter activity. TNF gene DNase I hypersensitivity patterns of stimulated CD4+ T cells differed between cells stably transfected with subtype B and subtype E Tat. Intracellular TNF protein levels were repressed in stimulated subtype E Tat-transfected cells but elevated in stimulated subtype B Tat-transfected cells; levels in cells transfected with the subtype E Tat variant were 30% of subtype B Tat-transfected cell levels. Chromatin immunoprecipitation assays revealed decreased inducible recruitment to the TNF promoter of histone acetyltransferase p300/CBP-associating factor (P/CAF) and another enhanceosome protein and lower H3 acetylation only in cells transfected with subtype E Tat. Increased TNF reporter activity occurred in cells cotransfected with subtype E Tat plus a P/CAF expression plasmid. The authors present structural models of Tat and P/CAF interactions to support their interpretation that the aa 32 mutation in HIV-1 subtype E Tat inhibits chromatin remodeling and TNF expression in stimulated cells.
