Feline Pit2 Functions as a Receptor for Subgroup B Feline Leukemia Viruses

Different subgroups of feline leukemia virus (FeLV) use different host cell receptors for entry. Subgroup A FeLV (FeLV-A) is the virus that is transmitted from cat to cat, suggesting that cells expressing the FeLV-A receptor are important targets at the earliest stages of infection. FeLV-B evolves from FeLV-A in the infected cat through acquisition of cellular sequences that are related to the FeLV envelope gene. FeLV-Bs have been shown to infect cells using the Pit1 receptor, and some variants can infect cells at a lower efficiency using Pit2. Because these observations were made using receptor proteins of human or rodent origin, the role that Pit1 and Pit2 may play in FeLV-B replication in the cat is unclear. In this study, the feline Pit receptors were cloned and tested for their ability to act as receptors for different FeLV-Bs. Some FeLV-Bs infected cells expressing feline Pit2 and feline Pit1 with equal high efficiency. Variable region A (VRA) in the putative receptor-binding domain (RBD) was a critical determinant for both feline Pit1 and feline Pit2 binding, although other domains in the RBD appear to influence how efficiently the FeLV-B surface unit can bind to feline Pit2 and promote entry via this receptor. An arginine residue at position 73 in VRA was found to be important for envelope binding to feline Pit2 but not feline Pit1. Interestingly, this arginine is not found in endogenous FeLV sequences or in recombinant viruses recovered from feline cells infected with FeLV-A. Thus, while FeLV-Bs that are able to use feline Pit2 can evolve by recombination with endogenous sequences, a subsequent point mutation during reverse transcription may be needed to generate a virus that can efficiently enter the cells using the feline Pit2 as its receptor. These studies suggest that cells expressing the feline Pit2 protein are likely to be targets for FeLV-B infection in the cat.

猫白血病病毒（feline leukemia virus, FeLV）的不同亚型依靠不同宿主细胞受体完成入侵。A亚型猫白血病病毒（FeLV-A）可在猫之间传播，这表明表达FeLV-A受体的细胞是感染早期的关键靶标。FeLV-B由受感染猫体内的FeLV-A演化而来，通过获取与FeLV包膜基因相关的细胞序列实现变异。已有研究证实，FeLV-B可借助Pit1受体感染细胞，部分变异株还能以较低效率通过Pit2受体感染细胞。由于上述结论均基于人类或啮齿类来源的受体蛋白得出，因此Pit1与Pit2在猫体内FeLV-B复制过程中所发挥的作用仍不明确。本研究克隆了猫源Pit受体，并检测其作为不同FeLV-B受体的能力。结果显示，部分FeLV-B可通过猫源Pit1与猫源Pit2以同等高效的水平感染细胞。推定的受体结合结构域（receptor-binding domain, RBD）中的可变区A（variable region A, VRA）是介导FeLV-B结合猫源Pit1与猫源Pit2的关键决定因素，尽管RBD中的其他结构域也会影响FeLV-B表面亚单位结合猫源Pit2并通过该受体完成入侵的效率。研究发现，VRA第73位的精氨酸残基对包膜蛋白结合猫源Pit2至关重要，但对结合猫源Pit1并无此必要性。值得注意的是，内源性FeLV序列以及从FeLV-A感染的猫源细胞中回收的重组病毒均不携带该精氨酸残基。由此可见，尽管可通过与内源性序列重组演化出能够利用猫源Pit2的FeLV-B，但还需要在逆转录过程中发生后续点突变，才能生成可借助猫源Pit2作为受体高效入侵细胞的病毒。本研究结果表明，表达猫源Pit2蛋白的细胞极有可能是猫体内FeLV-B感染的靶标。