heptad repeat 1-heptad repeat 2 region (ectodomain) of the gp41 subunit of human immunodeficiency virus (HIV-1), and related domains
This domain family spans both heptad repeats of the glycoprotein (gp)/transmembrane subunit of various endogenous retroviruses (ERVs) and infectious retroviruses, including human, simian, and feline immunodeficiency viruses (HIV, SIV, and FIV), bovine immunodeficiency-like virus (BIV), equine infectious anaemia virus (EIAV), and Jaagsiekte sheep retrovirus (JSRV), mouse mammary tumour virus (MMTV) and various ERVs including sheep enJSRV-26, and human ERVs (HERVs): HERV-K_c1q23.3 and HERV-K_c12q14.1. This domain belongs to a larger superfamily containing the HR1-HR2 domain of ERVs and infectious retroviruses, including Ebola virus, and Rous sarcoma virus. Proteins in this family lack the canonical CSK17-like immunosuppressive sequence, and the intrasubunit disulfide bond-forming CX6C motif found in linker region between HR1 and HR2 in the Ebola_RSV-like_HR1-HR2 family. N-terminal to the HR1-HR2 region is a fusion peptide (FP), and C-terminal is a membrane-spanning region (MSR). Viral infection involves the formation of a trimer-of-hairpins structure (three HR1 helices, buttressed by three HR2 helices lying in antiparallel orientation). In this structure, the FP (inserted in the host cell membrane) and MSR (inserted in the viral membrane) are in close proximity. ERVs are likely to originate from ancient germ-line infections by active retroviruses. Some modern ERVs, those that integrated into the host genome post-speciation, have a currently active exogenous counterpart, such as JSRV. Some ERVs play specific roles in the host, including placental development, protection of the host from infection by related pathogenic and exogenous retroviruses, and genome plasticity. Included in this subgroup are ERVs from domestic sheep that are related to JSRV, the agent of transmissible lung cancer in sheep, for example enJSRV-26 that retains an intact genome. These endogenous JSRVs protect the sheep against JSRV infection and are required for sheep placental development. HERV-K_c12q14.1 is potentially a complete envelope protein; however, it does not appear to be fusogenic.