title: Elevated tumor necrosis factor-alpha activation of human immunodeficiency virus type 1 subtype C in Southern Africa is associated with an NF-kappaB enhancer gain-of-function.
abstract: The human immunodeficiency virus type 1 (HIV-1) epidemic within southern Africa is predominantly associated with the HIV-1C subtype. Functional analysis of the enhancer region within the long terminal repeat (LTR) indicates that HIV-1C isolates have >/=3 NF-kappaB binding sites, unlike other subtypes, which have only 1 or 2 sites. A correlation was shown between NF-kappaB enhancer configuration and responsiveness to the proinflammatory cytokine tumor necrosis factor (TNF)-alpha within the context of naturally occurring subtype LTRs, subtype-specific NF-kappaB enhancer regions cloned upstream of an isogenic HXB2 core promoter or a heterologous SV40 minimal promoter, and full-genome subtype clones. In all cases, TNF-alpha activation was correlated with the subtype configuration of the NF-kappaB enhancer. Whether the naturally occurring gain-of-function in the NF-kappaB enhancer of HIV-1C observed in this study can provide a selective advantage for the virus in vivo remains to be determined and warrants further study.
authors.affiliation: Department of Immunology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Montano
authors.forename: C P
authors.initials: CP
authors.lastname: Nixon
authors.forename: T
authors.initials: T
authors.lastname: Ndung'u
authors.forename: H
authors.initials: H
authors.lastname: Bussmann
authors.forename: V A
authors.initials: VA
authors.lastname: Novitsky
authors.forename: D
authors.initials: D
authors.lastname: Dickman
authors.forename: M
authors.initials: M
authors.lastname: Essex
mesh_terms: D001665:Binding Sites; D001902:Botswana; D004742:Enhancer Elements, Genetic; D015658:HIV Infections / Q000453:epidemiology / Q000821:virology*; D015497:HIV-1 / Q000145:classification / Q000235:genetics*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D020079:Terminal Repeat Sequences; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015030:Zimbabwe
chemical_list: D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha