Disruption of Thiamine Uptake and Growth of Cells by Feline Leukemia Virus Subgroup A

Abstract

Feline leukemia virus (FeLV) is still a major cause of morbidity and mortality in domestic cats and some wild cats despite the availability of relatively effective vaccines against the virus. FeLV subgroup A (FeLV-A) is transmitted in natural infections, and FeLV subgroups B, C, and T can evolve directly from FeLV-A by mutation and/or recombination with endogenous retroviruses in domestic cats, resulting in a variety of pathogenic outcomes. The cell surface entry receptor for FeLV-A is a putative thiamine transporter (THTR1). Here, we have addressed whether FeLV-A infection might disrupt thiamine uptake into cells and, because thiamine is an essential nutrient, whether this disruption might have pathological consequences. First, we cloned the cat ortholog of the other of the two known thiamine transporters in mammals, THTR2, and we show that feline THTR1 (feTHTR1) and feTHTR2 both mediate thiamine uptake, but feTHTR2 does not function as a receptor for FeLV-A. We found that feTHTR1 is widely expressed in cat tissues and in cell lines, while expression of feTHTR2 is restricted. Thiamine uptake mediated by feTHTR1 was indeed blocked by FeLV-A infection, and in feline fibroblasts that naturally express feTHTR1 and not feTHTR2, this blockade resulted in a growth arrest at physiological concentrations of extracellular thiamine. The growth arrest was reversed at high extracellular concentrations of thiamine. Our results show that FeLV-A infection can indeed disrupt thiamine uptake with pathological consequences. A prediction of these experiments is that raising the plasma levels of thiamine in FeLVinfected cats may ameliorate the pathogenic effects of infection.

The Avian Retroviral Receptor Tva Mediates the Uptake of Transcobalamin Bound Vitamin B 12 (Cobalamin)

“…Future studies are required to clarify whether Cbl metabolism is altered in infected chickens. The cytopathic effects of FeLV-A, which uses the vitamin B 1 receptor, are partly caused by vitamin B 1 deficiency and can be reversed by high doses of the vitamin (54). However, the existence of a Tva-independent uptake of TC-Cbl may also ensure a sufficient delivery of Cbl in the infected cells.…”

Refrex-1, a Soluble Restriction Factor against Feline Endogenous and Exogenous Retroviruses

“…For example, interaction between FeLV-A Env protein and its receptor, thiamine transporter (THTR1), blocks thiamine uptake mediated by THTR1 and induces growth arrest of cells (50). It has also been shown that interaction between FeLV-C Env protein and its receptor, FLVCR-1, causes abnormal erythroid differentiation (51).…”

Identification of a Novel Subgroup of Koala Retrovirus from Koalas in Japanese Zoos

“…We found that lacZ(KoRV-J) interfered with FeLV-A on FEA cells (feline fibroblasts). The receptor for FeLV-A is known to be THTR1 (29,30). As shown in Fig.…”