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. 2013 Jul 9;110(28):11547-52.
doi: 10.1073/pnas.1304704110. Epub 2013 Jun 24.

An exogenous retrovirus isolated from koalas with malignant neoplasias in a US zoo

Wenqin Xu  1 , Cynthia K Stadler, Kristen Gorman, Nathaniel Jensen, David Kim, HaoQiang Zheng, Shaohua Tang, William M Switzer, Geoffrey W Pye, Maribeth V Eiden
Affiliations

An exogenous retrovirus isolated from koalas with malignant neoplasias in a US zoo

Wenqin Xu et al. Proc Natl Acad Sci U S A. .

Abstract

Leukemia and lymphoma account for more than 60% of deaths in captive koalas (Phascolarctos cinereus) in northeastern Australia. Although the endogenizing gammaretrovirus koala endogenous retrovirus (KoRV) was isolated from these koalas, KoRV has not been definitively associated with leukemogenesis. We performed KoRV screening in koalas from the San Diego Zoo, maintained for more than 45 y with very limited outbreeding, and the Los Angeles Zoo, maintained by continuously assimilating captive-born Australian koalas. San Diego Zoo koalas are currently free of malignant neoplasias and were infected with only endogenous KoRV, which we now term subtype "KoRV-A," whereas Los Angeles Zoo koalas with lymphomas/leukemias are infected in addition to KoRV-A by a unique KoRV we term subtype "KoRV-B." KoRV-B is most divergent in the envelope protein and uses a host receptor distinct from KoRV-A. KoRV-B also has duplicated enhancer regions in the LTR associated with increased pathology in gammaretroviruses. Whereas KoRV-A uses the sodium-dependent phosphate transporter 1 (PiT1) as a receptor, KoRV-B employs a different receptor, the thiamine transporter 1 (THTR1), to infect cells. KoRV-B is transmitted from dam to offspring through de novo infection, rather than via genetic inheritance like KoRV-A. Detection of KoRV-B in native Australian koalas should provide a history, and a mode for remediation, of leukemia/lymphoma currently endemic in this population.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Organization of KoRV proviral genome shows locations of primers used to clone KoRV-B. Gray triangles represent primers specific to KoRV-B. Asterisks indicate primers used in previous studies (5).
Fig. 2.
Fig. 2.
Experimental design used to detect KoRV in koala blood samples.
Fig. 3.
Fig. 3.
KoRV-B differs from KoRV-A in the LTR U3. An alignment of the nucleotides comprising the LTR regions of KoRV-A and KoRV-B. Nucleotide insertions in KoRV-B LTR are highlighted in gray. U3, R, and U5 boundaries are defined according to those described for the LTR of the KoRV-A genome (GenBank accession no. AF151794). Transcription regulatory signals such as the CAAT sequence, the promoter (TATAAAA), and polyadenylation signals AATAAA are shown within boxes.
Fig. 4.
Fig. 4.
KoRV-B and KoRV-A differ in their envelope regions: alignment of amino acid residues encoded by the KoRV-A and KoRV-B env genes. Consensus amino acid sequences appear with an asterisk below the residue alignment. Residues that differ between KoRV-A and KoRV-B are highlighted in light gray. The boundary between the surface unit (SU) and transmembrane domain (TM) is shown. Proposed receptor-binding domain (RBD) region is indicated in boxes. The CETAG sequence present in KoRV-A and the canonical motif CETTG found in KoRV-B are highlighted in dark gray.
Fig. 5.
Fig. 5.
(A) Schematic representation of the replication competent retrovirus containing a KoRV-A or GALV as an env gene. IRES, internal ribosome entry site. A replication-competent MoMLV with an IRES-GFP cassette between the env and 3′LTR was used as a template to construct GALV-GFP replacing the MLV env with the GALV env (18). An insertion of TCC just upstream of the splice acceptor (SA) provides the GALV-GFP with improved infection and replication properties (18). Replacement of the GALV env with the KoRV-A env gives rise to replication competent MLV using KoRV-A as an envelope. (B) Plasmids used in transient transfection in 293T cells to produce GALV, KoRV-A, or KoRV-B pseudotyped retroviral vectors referenced in Table 2. After transfection CMV promoter drives the transient expression of MoMLV gagpol, GALV, KoRV-A, or KoRV-B env, and MoMLV LTR-based viral vector genomic RNA encoding nuclear localized β-gal gene.
Fig. 6.
Fig. 6.
Dam to offspring transmission of KoRV-B, but not sire to offspring transmission. Standard sex symbols denoting male and female are used in the family tree.
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References

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