An additional NF-κB site allows HIV-1 subtype C to evade restriction by nuclear PYHIN proteins

Subtype C is the most prevalent clade of human immunodeficiency virus type 1 (HIV-1) worldwide. The reasons for this are poorly understood. Here, we demonstrate that a characteristic additional third nuclear factor kappa B (NF-kappa B) binding site in the long terminal repeat (LTR) promoter allows subtype C HIV-1 strains to evade restriction by nuclear PYHIN proteins, which sequester the transcription factor Sp1. Further, other LTR alterations are responsible for rare PYHIN resistance of subtype B viruses. Resistance-conferring mutations generally reduce the dependency of HIV-1 on Sp1 for virus production and render LTR transcription highly responsive to stimulation by NF-kappa B/p65. A third NF-kappa B binding site increases infectious virus yield in primary CD4+ T cells in an gamma-interferon-inducible protein 16 (IFI16)-dependent manner. Comprehensive sequence analyses suggest that the frequency of circulating PYHIN-resistant HIV-1 strains is increasing. Our finding that an additional NF-kappa B binding site in the LTR confers resistance to nuclear PYHIN proteins helps to explain the dominance of clade C HIV-1 strains.

Automated summary

Subtype C HIV-1 strains, the most prevalent worldwide, possess an additional third NF-kappa B binding site in the LTR promoter that confers resistance to nuclear PYHIN proteins, which helps explain their dominance.