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 κB (NF-κB) 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-κB/p65. A third NF-κB binding site increases infectious virus yield in primary CD4⁺ T cells in an γ-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-κB binding site in the LTR confers resistance to nuclear PYHIN proteins helps to explain the dominance of clade C HIV-1 strains.

C 亚型是全球最流行的 1 型人类免疫缺陷病毒 (HIV-1) 分支。其原因尚不清楚。在这里，我们证明长末端重复（LTR）启动子中的一个特征性额外的第三核因子κB（NF-κB）结合位点允许C亚型HIV-1病毒株逃避核PYHIN蛋白的限制，该蛋白隔离转录因子Sp1。此外，其他 LTR 改变也是 B 亚型病毒罕见的 PYHIN 耐药性的原因。赋予抗性的突变通常会降低 HIV-1 对 Sp1 病毒产生的依赖性，并使 LTR 转录对 NF-κB/p65 的刺激高度敏感。第三个 NF-κB 结合位点以 γ-干扰素诱导蛋白 16 (IFI16) 依赖性方式增加原代 CD4 ⁺ T 细胞中感染性病毒的产量。综合序列分析表明，循环中的 PYHIN 抗性 HIV-1 病毒株的频率正在增加。我们发现 LTR 中额外的 NF-κB 结合位点赋予了对核 PYHIN 蛋白的抗性，这有助于解释 C 分支 HIV-1 毒株的优势。