Elevated Tumor Necrosis Factor—α Activation of Human Immunodeficiency Virus Type 1 Subtype C in Southern Africa Is Associated with an NF-κ B Enhancer Gain-of-Function

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-κB binding sites, unlike other subtypes, which have only 1 or 2 sites. A correlation was shown between NF-κB enhancer configuration and responsiveness to the proinflammatory cytokine tumor necrosis factor (TNF)-α within the context of naturally occurring subtype LTRs, subtype-specific NF-κB 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-α activation was correlated with the subtype configuration of the NF-κB enhancer. Whether the naturally occurring gain-of-function in the NF-κB 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.