Journal
CELL REPORTS
Volume 36, Issue 12, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2021.109735
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Funding
- National Institutes of Health [R01 AI 162646, UM1 AI 164570, P30 AI 045008]
- German Research Foundation [DFG CRC 1279, SPP 1923, DFG KM 5/1-1]
- Baden-Wurttemberg Foundation [BWST-ISF2018-032]
- German Federal Ministry of Research and Education (BMBF Junior Research Group IMMUNOMOD)
- Heisenberg Program of the German Research Foundation
- Canon Foundation Europe
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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.
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.
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