Fighting fire with fire: endogenous retrovirus envelopes as restriction factors

Abstract

A considerable portion of vertebrate genomes are made up of endogenous retroviruses (ERVs). While aberrant or uncontrolled ERV expression has been perceived as a potential cause of disease, there is mounting evidence that some ERVs have become integral components of normal host development and physiology. Here, we revisit the longstanding concept that some of the gene products encoded by ERVs and other endogenous viral elements may offer to the host protection against viral infection. Notably, proteins produced from envelope (env) genes have been shown to act as restriction factors against related exogenous retroviruses in chickens, sheep, mice, and cats. Based on the proposed mode of restriction and the domain architecture of known antiretroviral env, we argue that many more env gene-derived restriction factors await discovery in vertebrate genomes, including the human genome.

FIG 1

Domain comparison of endogenous Envs proposed to restrict via receptor interference. Domains were determined based on previous characterizations of Refrex-1 (12), Suppressyn (17), Fv4 (11), Rmcf (11), Rmcf2 (11), enJS56A1 (9), Phobius (http://phobius.sbc.su.se/), and UniProt (http://www.uniprot.org/). White boxes, signal peptide; gray boxes, surface subunit; gray and white checkered boxes, transmembrane subunit. †, complete Envs are not displayed. Numbers in brackets indicate length (in amino acids).

FIG 2

Suppressyn as a candidate restriction factor. (A) As reported by Sugimoto et al. (17), Suppressyn (SUP) is secreted to the extracellular surface to block Syncytin-1 from host receptor ASCT2. (B) This interaction between Sup and ASCT2 may also lead to a receptor interference-type defense of the host cell receptor from exogenous retroviruses of the same interference group. SU, surface subunit; TM, transmembrane subunit.