Acquisition of an Additional NF-κB Site Allows HIV-1 Subtype C to Evade Restriction by Nuclear PYHIN Proteins

Abstract

Subtype C is the most prevalent clade of HIV-1 worldwide. The reasons for this are poorly understood. Here, we demonstrate that a characteristic additional third NF-κB binding site in the LTR promoter allows subtype C HIV-1 strains to evade restriction by nuclear PYHIN proteins, which sequester the transcription factor Sp1. We also show that 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-κB/p65. A third NF-κB binding site increased infectious virus yield in primary CD4+ T cells in an 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-κB binding site in the LTR confers resistance to nuclear PYHIN proteins helps to explain the dominance of clade C HIV-1 strains.