Molecular and functional interactions of cat APOBEC3 and feline foamy and immunodeficiency virus proteins: different ways to counteract host-encoded restriction.

Defined host-encoded feline APOBEC3 (feA3) cytidine deaminases efficiently restrict the replication and spread of exogenous retroviruses like Feline Immunodeficiency Virus (FIV) and Feline Foamy Virus (FFV) which developed different feA3 counter-acting strategies. Here we characterize the molecular interaction of FFV proteins with the diverse feA3 proteins. The FFV accessory protein Bet is the virus-encoded defense factor which is shown here to bind all feA3 proteins independent of whether they restrict FFV, a feature shared with FIV Vif that induces degradation of all feA3s including those that do not inactivate FIV. In contrast, only some feA3 proteins bind to FFV Gag, a pattern that in part reflects the restriction pattern detected. Additionally, one-domain feA3 proteins can homo- and hetero-dimerize in vitro, but a trans-dominant phenotype of any of the low-activity feA3 forms on FFV restriction by one of the highly-active feA3Z2 proteins was not detectable.

Restriction of feline retroviruses: lessons from cat APOBEC3 cytidine deaminases and TRIM5alpha proteins.

The interplay between viral and cellular factors determines the outcome of an initial contact between a given virus and its natural host or upon encounter of a novel host. Thus, the potential of inducing disease as well as crossing host species barriers are the consequences of the molecular interactions between the parasite and its susceptible, tolerant or resistant host. Cellular restriction factors, for instance APOBEC3 and TRIM5 proteins, targeting defined pathogens or groups of pathogens as well as viral genes counter-acting these cellular defense systems are of prime importance in this respect and may even represent novel targets for prevention and therapy of virus infections. Due to the importance of host-encoded antiviral restriction and viral counter-defense for pathogenicity and host tropism, the responsible molecular factors and mechanisms are currently under intense investigation. In this review we will introduce host restriction and retroviral counter-defense systems with a special emphasis on the cat and its naturally occurring exogenous retroviruses which is a valid model for human disease, a model that will contribute to increase our basic understanding and potential applications of these important aspects of host-virus interaction.

Functions, structure, and read-through alternative splicing of feline APOBEC3 genes.

BACKGROUND: Over the past years a variety of host restriction genes have been identified in human and mammals that modulate retrovirus infectivity, replication, assembly, and/or cross-species transmission. Among these host-encoded restriction factors, the APOBEC3 (A3; apolipoprotein B mRNA-editing catalytic polypeptide 3) proteins are potent inhibitors of retroviruses and retrotransposons. While primates encode seven of these genes (A3A to A3H), rodents carry only a single A3 gene. RESULTS: Here we identified and characterized several A3 genes in the genome of domestic cat (Felis catus) by analyzing the genomic A3 locus. The cat genome presents one A3H gene and three very similar A3C genes (a-c), probably generated after two consecutive gene duplications. In addition to these four one-domain A3 proteins, a fifth A3, designated A3CH, is expressed by read-through alternative splicing. Specific feline A3 proteins selectively inactivated only defined genera of feline retroviruses: Bet-deficient feline foamy virus was mainly inactivated by feA3Ca, feA3Cb, and feA3Cc, while feA3H and feA3CH were only weakly active. The infectivity of Vif-deficient feline immunodeficiency virus and feline leukemia virus was reduced only by feA3H and feA3CH, but not by any of the feA3Cs. Within Felidae, A3C sequences show significant adaptive selection, but unexpectedly, the A3H sequences present more sites that are under purifying selection. CONCLUSION: Our data support a complex evolutionary history of expansion, divergence, selection and individual extinction of antiviral A3 genes that parallels the early evolution of Placentalia, becoming more intricate in taxa in which the arms race between host and retroviruses is harsher.