Zhang Z, Gu Q, Jaguva Vasudevan AA, et al. Determinants of FIV and HIV Vif sensitivity of feline APOBEC3 restriction factors. Retrovirology 2016 Jul 1;13(1):46.
APOBEC super-family of mammalian proteins plays an important role in innate anti-viral immunity. These proteins are cytidine deaminases that catalyze the deamination of cytidine to uridine in single stranded DNA substrates. This enzymatic activity provides an innate antiretroviral immune activity against retroviruses by disrupting viral reverse transcription and by interfering with viral DNA integration into the host genome. On the other hand, lentiviruses of the family Retroviridae, such as FIV and HIV, have evolved the Viral infectivity factor (Vif) protein in order to counteract this effect. Vif interacts with APOBEC and triggers its degradation making its antiviral activity ineffective.
Specifically, the domestic cat, and likely all Felidae, encodes APOBEC3 (A3) genes that translate into single- domain proteins A3Z2s, A3Z3, and a double-domain protein, A3Z2Z3. A3Z2Z3 is uniquely expressed in the feline genome via read-through transcription and alternative splicing encoding an additional domain insertion called linker. FIV Vif readily degrades A3Z2s, A3Z3, and A3Z2Z3.
Researchers from Clinic for Gastroenterology, Hepatology, and Infectiology at Heinrich-Heine-University Dusseldorf, Germany and their collaborators used chimeric human-feline APOBEC3 (A3) to identify residues in feline A3s that FIV Vifs needs for interaction and degradation. A human A3 protein (A3H) and feline A3 protein (A3Z3) were used to construct various human-feline chimeric proteins. Human A3H is resistant to FIV Vif degradation. Feline regions important for FIV Vif resistance were identified. Further selective specific mutations within feline regions were made. Protein residues were identified that when mutated induce complete or partial FIV ViF degradation resistance. Similar chimeric constructs were made with human A3C and feline A3Z2s and protein residues were also identified that when mutated lead to FIV ViF degradation resistance. Observations demonstrated that FIV Vif binding feline A3s is not sufficient for A3 degradation; i.e., FIV Vif could bind to A3 but not degrade it. In addition to finding important feline A3s binding residues, a unique protein domain insertion (linker) was identified. Lastly, comparative modeling of feline A3s showed that HIV Vif binds human A3s differently than FiV Vif binds feline A3s suggesting a different trajectory in human-HIV and feline-FIV evolution. Feline A3s residue sites important for FIV Vif interaction may provide therapeutic targets. (GO)
Yoshikawa R, Izumi T, et al. A Naturally Occurring Domestic Cat APOBEC3 Variant Confers Resistance to Feline Immunodeficiency Virus Infection. J Virol. 2015 Oct 21;90(1):474-85.
feline immunodeficiency virus