Retroviral restriction and dependency factors in primates and carnivores

Abstract

Recent studies have extended the rapidly developing retroviral restriction factor field to cells of carnivore species. Carnivoran genomes, and the domestic cat genome in particular, are revealing intriguing properties vis-à-vis the primate and feline lentiviruses, not only with respect to their repertoires of virus-blocking restriction factors but also replication-enabling dependency factors. Therapeutic application of restriction factors is envisioned for human immunodeficiency virus (HIV) disease and the feline immunodeficiency virus (FIV) model has promise for testing important hypotheses at the basic and translational level. Feline cell-tropic HIV-1 clones have also been generated by a strategy of restriction factor evasion. We review progress in this area in the context of what is known about retroviral restriction factors such as TRIM5α, TRIMCyp, APOBEC3 proteins and BST-2/Tetherin.

Figure 1. Carnivoran, artiodactyl, mouse and human A3 repertoires

Z domain names are shown above A–H names. Schematically, the figure follows those in LaRue et al. (LaRue et al., 2009; LaRue et al., 2008) and synthesizes findings from there and elsewhere (Münk et al., 2008; Munk et al., 2009; Münk et al., 2007; Stern et al., 2010; Zielonka et al., 2010). Dogs but not cats have a Z1 protein, suggesting that this gene was lost in cats after Caniformia and Feliformia diverged. The dog genomic locus has not been fully characterized but cDNAs for Z1 and Z3 proteins were cloned and relatively low-level activities against FIV were observed (Münk et al., 2008). The canine Z3 protein (A3H) restricted SIVagm approximately 10-fold in a single round assay (Münk et al., 2008). Antiretroviral activities of fA3H (Z3) and fA3CH (Z2–Z3) are inhibited by FIV Vif (Münk et al., 2008; Stern et al., 2010) and also by SIVmac Vif (Stern et al., 2010), while those of the fA3C (Z2) proteins are inhibited by the foamy virus accessory protein Bet (Lochelt et al., 2005; Münk et al., 2008; Perkovic et al., 2009)