A Naturally Occurring Domestic Cat APOBEC3 Variant Confers Resistance to Feline Immunodeficiency Virus Infection

Abstract

Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3; A3) DNA cytosine deaminases can be incorporated into progeny virions and inhibit lentiviral replication. On the other hand, viral infectivity factor (Vif) of lentiviruses antagonizes A3-mediated antiviral activities by degrading A3 proteins. It is known that domestic cat (Felis catus) APOBEC3Z3 (A3Z3), the ortholog of human APOBEC3H, potently suppresses the infectivity of vif-defective feline immunodeficiency virus (FIV). Although a recent report has shown that domestic cat encodes 7 haplotypes (hap I to hap VII) of A3Z3, the relevance of A3Z3 polymorphism in domestic cats with FIV Vif has not yet been addressed. In this study, we demonstrated that these feline A3Z3 variants suppress vif-defective FIV infectivity. We also revealed that codon 65 of feline A3Z3 is a positively selected site and that A3Z3 hap V is subject to positive selection during evolution. It is particularly noteworthy that feline A3Z3 hap V is resistant to FIV Vif-mediated degradation and still inhibits vif-proficient viral infection. Moreover, the side chain size, but not the hydrophobicity, of the amino acid at position 65 determines the resistance to FIV Vif-mediated degradation. Furthermore, phylogenetic analyses have led to the inference that feline A3Z3 hap V emerged approximately 60,000 years ago. Taken together, these findings suggest that feline A3Z3 hap V may have been selected for escape from an ancestral FIV. This is the first evidence for an evolutionary “arms race” between the domestic cat and its cognate lentivirus. IMPORTANCE Gene diversity and selective pressure are intriguing topics in the field of evolutionary biology. A direct interaction between a cellular protein and a viral protein can precipitate an evolutionary arms race between host and virus. One example is primate APOBEC3G, which potently restricts the replication of primate lentiviruses (e.g., human immunodeficiency virus type 1 [HIV-1] and simian immunodeficiency virus [SIV]) if its activity is not counteracted by the viral Vif protein. Here we investigate the ability of 7 naturally occurring variants of feline APOBEC3, APOBEC3Z3 (A3Z3), to inhibit FIV replication. Interestingly, one feline A3Z3 variant is dominant, restrictive, and naturally resistant to FIV Vif-mediated degradation. Phylogenetic analyses revealed that the ancestral change that generated this variant could have been caused by positive Darwinian selection, presumably due to an ancestral FIV infection. The experimental-phylogenetic investigation sheds light on the evolutionary history of the domestic cat, which was likely influenced by lentiviral infection.

A conflict of interest: the evolutionary arms race between mammalian APOBEC3 and lentiviral Vif

“…In addition, a two-domain A3Z2Z3 hybrid protein is generated through alternative splicing [70, 71]. Similar to the relationship between primate A3s and PLVs (see above), previous studies revealed that the feline A3Z3 and A3Z2Z3 proteins potently suppress the infectivity of vif -deleted FIVfca [70–75] and that the Vif proteins of FIVfca (strains Petaluma, C36 and Shizuoka) counteract the antiviral action of domestic cat A3Z3 and A3Z2Z3 [71, 74]. …”

Central and peripheral reservoirs of feline immunodeficiency virus in cats: a review

“…Although FIV has been associated with unfavourable outcomes such as opportunistic infections, neoplasia, wasting and death, the precise determinants of morbidity remain unclear. Contributory factors including viral/host genetics, age of host, viral load during acute virus infection, housing environment, stress, cohabitation with other cats and concurrent disease status have been proposed [7][8][9][10][11][12]. Efforts to control lentiviral infections primarily focus on two broad strategies: preventing new infections and suppressing viral replication in already infected individuals, both of which are particularly relevant for HIVinfected humans.…”

“…Multiple factors play roles in defining a cell's permissiveness to lentiviral infection and productive replication and include the appropriate membrane receptors for virus attachment, fusion and entry, a temporally appropriate milieu of nuclear transcription factors, activation state, target cell subset, tissue micro-environment, and presence of specific host cellular restriction factors like tetherin, APOBEC3 family and others [11,13,15,16]. These same factors also determine the identity of cells that serve as reservoirs for persistent latent virus [13].…”

Feline Immunodeficiency Virus Vif N-Terminal Residues Selectively Counteract Feline APOBEC3s

“…The product was cloned into pCR2.1 vector using a TOPO TA cloning kit (Thermo Fisher Scientific) and submitted to sequencing. The A3Z3 haplotype of each sample was determined according to a previously described protocol (48) using the primers A3H2F and A3H3R and named (see the recent report [57]). Sequences were analyzed with the Geneious software (Biomatters, Auckland, New Zealand).…”

“…In contrast to HIV-1 Vif, Vifs from the HIV-2/SIV lineage counteract and induce degradation of feline A3Z2Z3 (44,47). Residues in feline A3s that are functionally involved in the interaction with FIV Vif were identified by recent studies (44,48,57). In contrast, the determinants in FIV Vif that are important for inhibition of the antiviral activity of feline A3s are poorly understood (58).…”