View Full Version : 400 million year-old fish helps researchers understand HIV

25-05-18, 16:18


Evolution-guided structural and functional analyses of the HERC family reveals an ancient marine origin and determinants of antiviral activity.


In humans, ‘homologous to the E6-AP carboxyl terminus (HECT) and regulator of chromosome condensation 1 (RCC1)-like domain-containing protein 5’ (HERC5) is an interferon-induced protein that inhibits replication of evolutionarily diverse viruses including human immunodeficiency virus type 1 (HIV-1). To better understand the origin, evolution and function of HERC5, we performed phylogenetic, structural and functional analyses of the entire human small HERC family, which includes HERC3, HERC4, HERC5 and HERC6. We demonstrated that the HERC family emerged >595 million years ago and has undergone gene duplication and gene loss events throughout its evolution. The structural topology of the RCC1-like domain and HECT domains from all HERC paralogs are highly conserved among evolutionarily diverse vertebrates despite low sequence homology. Functional analyses showed that the human small HERCs exhibit different degrees of antiviral activity towards HIV-1 and that HERC5 provided the strongest level of inhibition. Notably, coelacanth HERC5 inhibited SIV, but not HIV-1, particle production suggesting that the antiviral activity of HERC5 emerged over 413 million years ago and exhibits species- and virus-specific restriction. In addition, we showed that both HERC5 and HERC6 are evolving under strong positive selection; particularly blade 1 of the RCC1-like domain, which we showed is a key determinant of antiviral activity. These studies provide insight into the origin, evolution and biological importance of the human restriction factor HERC5 and the other HERC family members.