- Open Access
Distinctive receptor binding properties of the surface glycoprotein of a natural Feline Leukemia Virus isolate with unusual disease spectrum
© Bolin et al; licensee BioMed Central Ltd. 2011
- Received: 20 December 2010
- Accepted: 13 May 2011
- Published: 13 May 2011
Feline leukemia virus (FeLV)-945, a member of the FeLV-A subgroup, was previously isolated from a cohort of naturally infected cats. An unusual multicentric lymphoma of non-T-cell origin was observed in natural and experimental infection with FeLV-945. Previous studies implicated the FeLV-945 surface glycoprotein (SU) as a determinant of disease outcome by an as yet unknown mechanism. The present studies demonstrate that FeLV-945 SU confers distinctive properties of binding to the cell surface receptor.
Virions bearing the FeLV-945 Env protein were observed to bind the cell surface receptor with significantly increased efficiency, as was soluble FeLV-945 SU protein, as compared to the corresponding virions or soluble protein from a prototype FeLV-A isolate. SU proteins cloned from other cohort isolates exhibited increased binding efficiency comparable to or greater than FeLV-945 SU. Mutational analysis implicated a domain containing variable region B (VRB) to be the major determinant of increased receptor binding, and identified a single residue, valine 186, to be responsible for the effect.
The FeLV-945 SU protein binds its cell surface receptor, feTHTR1, with significantly greater efficiency than does that of prototype FeLV-A (FeLV-A/61E) when present on the surface of virus particles or in soluble form, demonstrating a 2-fold difference in the relative dissociation constant. The results implicate a single residue, valine 186, as the major determinant of increased binding affinity. Computational modeling suggests a molecular mechanism by which residue 186 interacts with the receptor-binding domain through residue glutamine 110 to effect increased binding affinity. Through its increased receptor binding affinity, FeLV-945 SU might function in pathogenesis by increasing the rate of virus entry and spread in vivo, or by facilitating entry into a novel target cell with a low receptor density.
- Long Terminal Repeat
- Increase Binding Affinity
- Feline Leukemia Virus
- Reciprocal Mutant
- Amino Acid Sequence Difference
Feline leukemia virus (FeLV) is a naturally occurring gammaretrovirus that infects domestic cats. The outcome of FeLV infection is variable, including malignant, proliferative and degenerative diseases of lymphoid, myeloid and erythroid origin. Determinants of disease outcome are not well understood, but likely involve both viral and host factors. FeLV, like other natural retroviruses, does not occur as a single genomic species but as a closely related, genetically complex family. Sequence variation among natural isolates occurs most commonly in the viral long terminal repeat (LTR) and in the surface-exposed envelope glycoprotein (SU) [1, 2]. An unusual natural isolate, designated FeLV-945, was previously identified as the predominant isolate in a geographic and temporal cohort of naturally infected cats [3, 4]. The predominant disease presentation in the cohort was a multicentric lymphoma of non-T-cell origin detected in twelve cases, one of which was the original source of FeLV-945. The cohort also included four cases of thymic lymphoma, one case of mast cell leukemia, two cases of myeloproliferative disease and two cases of anemia [3–5]. FeLV-945 has been classified as a member of the FeLV-A subgroup, based on host range and analysis of superinfection interference and on sequence similarity of the envelope protein [3, 6]. Members of FeLV-A are ecotropic in host range and utilize feTHTR1, a thiamine transporter on the target cell surface, as a receptor for entry .
FeLV-945 differs in sequence from a prototype member of FeLV subgroup A, FeLV-A/61E, in the LTR and in the SU gene [3, 6, 8, 9]. Infection with 61E/945L, a mutant in which the FeLV-945 LTR was substituted for that of FeLV-A/61E, resulted in the relatively rapid induction of thymic lymphoma of T-cell origin. Thus, introduction of the FeLV-945 LTR induced the same tumor as FeLV-A/61E, but did so more rapidly . By contrast, infection with 61E/945SL, a mutant in which both the FeLV-945 LTR and SU gene were substituted for those of FeLV-A/61E, resulted in the rapid induction of multicentric lymphoma of B-cell origin, thus recapitulating the predominant disease detected in the natural cohort . Taken together, these findings implicated the FeLV-945 LTR as a determinant of the rate of disease induction, and FeLV-945 SU as the determinant of disease spectrum. The mechanism by which FeLV-945 SU might influence disease outcome is not known.
As the receptor-binding protein of the virus, natural variation in SU is associated with significant functional impact on receptor utilization, thereby influencing cell tropism, rate of spread, and disease outcome [1, 2, 10–14]. The FeLV SU protein, analogous to the closely related murine leukemia viruses, contains two amino-terminal hypervariable regions, designated variable region A (VRA) and variable region B (VRB), that comprise the receptor binding domain . Previous work has demonstrated that the VRA domain is the primary determinant of receptor interaction and is sufficient for receptor binding, while the VRB domain is necessary for efficient infection [15–21]. Secondary determinants for receptor binding have also been identified in the carboxy-terminal region of SU and in a central proline-rich region (PRR) known to mediate conformational changes required for virus entry [17, 22–24]. FeLV-945 SU differs from that of FeLV-A/61E to a larger extent than other known FeLV-A isolates differ among themselves . Point mutations in FeLV-945 SU, relative to FeLV-A/61E, are largely contained within protein domains having roles in receptor recognition and entry [3, 6].
In the present study, unique properties of FeLV-945 SU were characterized that may play a role in its ability to direct disease outcome. Target cell receptor binding was compared between the FeLV-945 and FeLV-A/61E SU proteins. FeLV-945 SU was shown to exhibit an increased efficiency of receptor binding as compared to FeLV-A/61E using a variety of experimental conditions, both when presented in virus particles and in soluble form. The SU proteins of other isolates from the cohort were also found to exhibit an increase in receptor binding efficiency that was comparable to or greater than that observed with FeLV-945 SU. Mutational analyses implicated a region containing the VRB domain of FeLV-945 SU as the major determinant of the distinctive receptor-binding phenotype, and identified a single amino acid residue as primarily responsible for the effect.
Relative binding activity of virus particles bearing FeLV-945 Env and of soluble SU proteins
Mutational analysis does not implicate the consensus VRA domain of FeLV-945 SU as a determinant of binding phenotype
Substitutional analysis implicates a VRB-containing region as the major determinant of the binding phenotype
Mutational analysis implicates a single residue as the major determinant of binding phenotype
Summary of comparative flow cytometric binding assays performed using soluble SU proteins of FeLV-A/61E, 61E/945-VRB or mutant FeLV-A/61E SU proteins substituted of specific amino acids within and surrounding the consensus VRB domain of FeLV-945
Soluble SU Proteina
Average GMF of Replicate Binding Assaysb
Comparable Binding Phenotype
Computational modeling predicts a mechanism by which residue 186 influences the increased binding affinity of FeLV-945 SU
FeLV-945 was isolated from a natural cohort of infected cats in which the predominant disease presentation was a distinctive multicentric lymphoma of non-T-cell origin [3–5]. FeLV-945 was assigned through studies of host range and superinfection interference to FeLV subgroup A , although the FeLV-945 LTR and SU gene were shown to contain unique sequence elements [3, 6, 8]. Indeed, when substituted into FeLV-A prototype isolate, FeLV-A/61E, the unique LTR and SU gene of FeLV-945 were shown to redirect the outcome of infection from T-cell lymphoma of the thymus occurring after prolonged latency to a relatively rapid induction of multicentric lymphoma of B-cell origin, thus recapitulating the natural disease outcome seen with FeLV-945. Further studies demonstrated that FeLV-945 SU is strictly required for the shift in pathogenesis . The mechanism by which FeLV-945 SU acts to determine the outcome of disease induction is not known. In the present study, FeLV-945 SU was observed to bind feline cells, or murine cells expressing the FeLV-A receptor, with significantly increased efficiency as compared to FeLV-A/61E SU, when present either in virus particles (Figure 1) or in soluble form (Figure 2). These findings were documented by flow cytometric binding assay using a monoclonal antibody, C11D8, that recognizes an epitope conserved between FeLV-A/61E and FeLV-945 SU proteins . Thus, the enhanced receptor binding phenotype of FeLV-945 SU is not likely to represent differential binding of the C11D8 antibody. Confirmatory results were obtained using an antibody that recognizes the HA epitope tag fused to the C-terminus of the soluble SU proteins (Figure 2 and 8).
Significantly increased efficiency of receptor binding by soluble FeLV-945 SU was observed using different feline cell lines, including 3201 T-lymphoid cells, AH927 and FEA fibroblast lines (Figure 2 and data not shown). Increased binding was observed over a 100-fold range of SU concentration, with a statistically significant difference observed at all but the highest concentration (Figure 3A - E). These findings indicate that FeLV-945 SU binds receptor with greater affinity, and predicts that FeLV-945 SU would bind the cell surface receptor more efficiently under physiological conditions where the amount of receptor and/or virus may be limiting. By virtue of this phenotype, FeLV-945 SU might then act as a determinant of pathogenesis by increasing the rate of virus entry and spread in vivo, or by facilitating entry into a novel target cell with a low receptor density. The analysis further demonstrated a 2-fold difference in dissociation constant (Kd; Figure 3F), which, while seemingly modest, might have a major impact during an exponentially spreading infection in vivo. While we do not yet know the functional impact of increased binding affinity of FeLV-945 SU, it is useful to consider the quantitative modeling of replicative advantage that may be conferred by a mutation in the virus genome. Others have calculated that a newly arising virus mutation which affords a 1% replicative advantage would represent 50% of the virus population within 400 replication cycles . These observations indicate that a replicative advantage (or in this case, increased affinity for receptor-binding) need not be large to impact an exponentially spreading infection.
The cohort from which FeLV-945 was isolated was collected from a single veterinary practice in Pasadena, California over a period of six years [3, 4]. Considering the limited geographic and temporal spread of the cohort, the animals were presumably infected by a similar spectrum of natural FeLV isolates circulating among the population. This possibility is supported by the observation that SU genes isolated from other disease cases in the cohort were found to share most of the unique sequence features of FeLV-945 SU, and to exhibit greater sequence identity to each other than to other members of FeLV subgroup A across the functional domains of SU (Figure 4A). This observation is particularly remarkable since other previously described members of FeLV subgroup A demonstrate near identity across SU despite having been isolated from across the world over a period of many years [1, 2, 27]. Pseudotype virus particles bearing Env protein from cohort isolates were shown to exhibit a receptor-binding phenotype comparable to that of FeLV-945 SU, or in the case of 922 and 1046A pseudotypes, significantly more efficient binding (Figure 4B). These results support the hypothesis that distinctive SU sequences across the functional domains confer the increased binding efficiency characteristic of FeLV-945 SU and other cohort isolates. To test this hypothesis, and to determine which of the functional domains confers the binding phenotype, computational modeling was first performed to examine the potential functional impact of amino acid differences in the receptor-binding domain of FeLV-945 as compared to FeLV-A/61E. While the crystal structure of the receptor-binding domain of FeLV subgroup A is not available, such structure is available for FeLV subgroup B . Using the FeLV-B structure as a modeling template, a cysteine-delimited loop of 31 amino acids was predicted to occur in both FeLV-945 and FeLV-A/61E SU at a position likely to involve the receptor-binding surface (Figure 5A - B). This loop, contained fully within the VRA domain, harbors five amino acid differences between the two sequences (Figure 5B). The possible impact of these changes was of interest, considering the several demonstrations of VRA as the primary determinant of receptor interaction in murine and feline gammaretroviral SU proteins [15–21]. Reciprocal substitution of all five residues between the SU proteins of FeLV-945 and FeLV-A/61E, however, failed to influence the binding phenotype (Figure 5C). These findings indicate that the sequence of the predicted VRA loop is not sufficient to determine the binding phenotype.
To further delineate the responsible domain, substitution mutants were created in which regions containing the VRA, PRR, and VRB domains of FeLV-945 SU and FeLV-A/61E SU were reciprocally replaced (Figure 6A). Comparative binding assays using equivalent mass amounts of soluble SU protein confirmed that substitution of VRA, or VRA and PRR, did not influence the binding phenotype of mutant SU proteins (Figure 6B). By contrast, the reciprocal substitution of VRA and VRB (Figure 6C - D), or of VRB alone (Figure 7A - B) generated mutant SU proteins whose binding phenotype recapitulated the parent SU of the introduced domain. Taken together, the comparative binding assays implicate the VRB-containing substitution as the major determinant of binding phenotype, but also indicate a contribution of the VRA domain. Specifically, the substitution of both VRA and VRB from FeLV-945 into FeLV-A/61E was shown to recapitulate the FeLV-945 binding phenotype (Figure 6C) but the substitution of VRB alone does not (Figure 7A), thus suggesting a role for VRA in conferring the full activity. The effect of VRA on determining binding phenotype is apparently dependent on interaction with VRB, since substitution of FeLV-945 VRA into FeLV-A/61E did not affect binding in the absence of FeLV-945 VRB (Figure 6B). The 124-amino acid VRA-containing substitution constructed for these studies includes eight amino acid sequence differences between FeLV-945 and FeLV-A/61E, seven of which are localized within the consensus VRA domain (positions 55, 58, 60, 63, 69, 98, 99; Figure 4A). All of these substitutions are shared among cohort isolates, and five of them represent the residues identified by computational modeling as potential contributors to binding phenotype (Figure 5). However, substitution of the FeLV-945 sequence into FeLV-A/61E at all five positions failed to recapitulate the FeLV-945 binding phenotype, consistent with the observation that replacement of the entire VRA domain from FeLV-945 into FeLV-A/61E did not influence binding in the absence of VRB substitution. These results indicate that FeLV-945 VRB can positively impact SU binding in the context of VRA from either FeLV-A/61E or FeLV-945, but the optimal binding interaction is achieved in the presence of FeLV-945 VRA.
Within the VRB-containing segment implicated as the major determinant of binding phenotype are eight amino acid sequence differences between FeLV-945 and FeLV-A/61E, three of which (positions 143, 147, and 149) are localized within consensus VRB. Mutational analysis, however, demonstrated that these residues could not confer the enhanced binding phenotype of FeLV-945 VRB. Mutational analysis of four other residues (positions 128, 130, 156, 164) that neighbor consensus VRB and are shared among other cohort isolates similarly demonstrated that these do not influence relative binding affinity. Indeed, only when the isoleucine-to-valine change at position 186 was incorporated into the mutants was the binding phenotype affected (Table 1), and point mutation implicated the single valine residue at position 186 in FeLV-945 SU as the major determinant of increased binding affinity (Figure 8). Computational modeling sheds light on the mechanism by which valine 186 as represented in FeLV-945 may influence increased binding affinity as compared to isoleucine 186 as represented in FeLV-A/61E (Figure 9). Acting through an effect on position of the neighboring residue Q110, the relatively bulky isoleucine side chain at position 186 results in a narrowing of the predicted receptor-binding cleft at its lower end (Figure 9A). By contrast, the relatively compact valine side chain at position 186 allows Q110 to assume an orientation out of the receptor-binding cleft thus widening the lower end approximately two-fold (Figure 9B). The impact on conformation of the receptor-binding cleft is then predicted to influence the relative binding affinity for FeLV-A receptor. This influence of valine 186 is apparently further influenced by residues in VRA that make contact with receptor, since a more optimal binding phenotype is observed in the presence of VRA from FeLV-945 as compared to that of FeLV-A/61E. This may explain why FeLV-922 and FeLV-1046 SU proteins showed an even greater binding affinity than FeLV-945, since both contain valine 186 and additional sequence differences within VRA that are not shared between the two or with other cohort isolates (Figure 4). This hypothesis will be further examined in future studies. While several studies have shown the VRA domain to be sufficient for infection, efficient infection is known to require the VRB domain as well [15–21]. The present findings implicate a single residue in the influence of VRB on FeLV-945 SU binding affinity, and suggest a mechanism by which that residue interacts with the VRA domain to effect its influence.
The SU protein of FeLV-945, a unique natural isolate of feline leukemia virus, directs the induction of non-T-cell multicentric lymphoma through an as yet unknown mechanism. FeLV-945 SU is shown here to bind its cell surface receptor, feTHTR1, with significantly greater efficiency than does prototype FeLV-A SU when present on the surface of virus particles or in soluble form. The increased binding activity demonstrates a 2-fold difference in Kd relative to prototype FeLV-A SU. Computational modeling and mutational analyses implicate a region containing the VRB domain of FeLV-945 SU as the major determinant of increased binding affinity, although a region containing the VRA domain appears to play a role. The results implicate a single residue adjacent to consensus VRB, valine 186, as the major determinant of increased binding affinity. Computational modeling suggests a molecular mechanism by which residue 186 interacts with residue Q110 to effect increased binding affinity.
Cells and viruses
Feline 3201 cells, an FeLV-negative T-lymphoid line derived from a natural thymic lymphoma, were maintained in a medium of 50% Leibovitz L-15 and 50% RPMI 1640 with 15% fetal bovine serum (FBS). FEA cells, a continuous line of feline embryonic fibroblasts, were maintained in Eagle's minimum essential medium with 10% FBS and nonessential amino acids. AH927, a continuous line of feline embryonic fibroblasts, was maintained in Dulbecco's Modified Eagle Medium (DMEM) with 10% FBS. Murine MDTF/H2 cells, a gift of Dr. Julie Overbaugh, represent a continuous line of Mus dunni tail fibroblasts engineered to express the FeLV-A receptor, feTHTR1, and were maintained in DMEM with 10% FBS and 0.6 mg/ml geneticin . Human embryonic kidney 293T/17 cells (ATCC CRL-11268) were maintained in DMEM with 10% FBS. Molecularly cloned, infectious proviral DNAs used in the study include FeLV-A/61E  and the infectious recombinant viruses 61E/945L and 61E/945SL. As described previously, 61E/945L was generated by replacement of the FeLV-A/61E LTR with that of FeLV-945 and 61E/945SL was generated by replacement of the FeLV-A/61E LTR and SU gene with corresponding sequences from FeLV-945 [6, 8]. Pseudoptyped virus particles bearing envelope proteins of FeLV-945, FeLV-922, FeLV-1049, FeLV-1306, or FeLV-1046 were constructed as previously described .
SU expression constructs
CS2-FeLV-A-61E-SU-HA , a gift of Dr. Julie Overbaugh, encodes the FeLV-A/61E SU gene corresponding to amino acids 1 to 435, fused at the carboxy terminus to a hemagglutinin (HA) epitope tag. CS2-FeLV-945-SU-HA was generated by replacing a MscI to NcoI fragment (basepair 100 to 1214) of the SU gene in CS2-FeLV-61E-SU-HA with the corresponding fragment from FeLV-945 [GenBank:AY662447]. An empty vector control, designated pCS2/Ctrl, was generated by religation of BamHI-digested CS2-FeLV-A-61E-SU-HA. 61E/945-VRA and 61E/945-VRA/VRB were generated by replacing a HindIII-to-HindIII fragment or an NdeI-to-Bsu36I fragment of CS2-FeLV-A-61E-SU-HA, respectively, with the corresponding fragment of CS2-FeLV-945-SU-HA. 61E/945-VRA/PRR was generated by replacing a Bsu36I-to-NcoI fragment of 61E/945-VRA with the corresponding fragment of CS2-FeLV-945-SU-HA. 945/61E-VRA/VRB was generated by replacing a NdeI-to-Bsu36I fragment of CS2-FeLV-945-SU-HA with the corresponding fragment of CS2-FeLV-61E-SU-HA. 61E/945-VRB was generated by replacing a HindIII-to-HindIII fragment of 61E/945-VRA/VRB with the corresponding fragment of CS2-FeLV-61E-SU-HA. A reciprocal mutant, 945/61E-VRB, was made by replacing a HindIII-to-HindIII fragment of 945/61E-VRA/VRB with the corresponding fragment of CS2-FeLV-945-SU-HA. SU genes bearing point mutations were generated by site-directed mutagenesis (Stratagene, Agilent Technologies, Santa Clara, CA) using CS2-FeLV-61E-SU-HA as template and using the indicated primers where the introduced mutation in each case is underlined: 1) the mutant designated 61E/945-5 using primer 5'-ACTAGTGTTGGATCCTAACAACGTTCGGCATGGAGCTAGGTATAGCAGTAGCAAATATGGATGTAAAACTACAGATAG-3', 2) the mutant designated VRB3aa using primer 5'-GAGGGAGTAATCAGGACAATAGCTGCACAGGAAAATGCAACCCCC-3', 3) the mutant designated N147S using primer 5'-GGGAGTAGTCAGGACAATAGCTGTGAGGG-3', 4) the mutant designated K128N/S130T using primer 5'-GCAACCCCCTAGTCTTACAGTTCACCCAGAAGGGAAGACAAGCCTCTTGG-3', 5) the mutant designated I156V/K164R using primer 5'-GGAGAAGCTTGGTGGAATCCCACCTCCTCATGG-3', and 6) the mutant designated I186V using primer 5'-GGATATGACCCTGTCGCTTTATTCACGGTGTCCCGGCAGG-3'. The mutant designated V186I was generated using CS2-FeLV-945-SU-HA as template and using primer 5'-GGATATGACCCTATCGCCTTATTCACGGTATCCCGGCAGG-3'. The mutants designated K128N/S130T/I186V and I156V/K164R/I186V were generated using primer 5'-GGATATGACCCTGTCGCTTTATTCACGGTGTCCCGGCAGG-3' and using K128N/S130T or I156V/K164R as template, respectively.
Generation and titering of soluble SU proteins
293T/17 cells were transfected with SU expression plasmids using Lipofectamine LTX reagent (Invitrogen Corp., Carlsbad, CA) as per the manufacturer's instructions. Approximately 48 hours after transfection, SU-containing cell supernatants were collected and filtered to remove cellular debris. Cell-free supernatants were mixed with Laemmli Buffer (Bio-Rad Laboratories, Hercules, CA) and 2.5% beta-mercaptoethanol, boiled for 5 minutes, and electrophoresed under reducing conditions in NuPAGE Novex Bis-Tris Mini Gels (Invitrogen Corp., Carlsbad, CA). Proteins were transferred to nitrocellulose and western blot analysis was performed to detect SU proteins using either the primary antibody C11D8 (Custom Monoclonals International, West Sacramento, CA) or mouse anti-HA (Invitrogen, Camarillo, CA) and an infrared dye-conjugated secondary antibody (Li-Cor Biosciences, Lincoln, NE). SU protein preparations were thereby quantified using the Odyssey Infrared Imaging System (Li-Cor). Equivalent mass amounts of each SU protein were then visualized by western blot analysis using chemiluminescent detection (Thermo Scientific, Rockford, IL) to confirm the validity of the quantitation.
Flow cytometric target cell binding assays
Based on the previously reported crystal structure of the receptor binding domain of FeLV subgroup B , the corresponding residues of FeLV-A/61E and FeLV-945 were submitted for computational modeling by the SwissModel program [29–31]. The binding cleft domains of FeLV-A/61E and FeLV-945 SU were modeled using the SwissModel program [29–31] and the molecular surfaces were calculated and drawn using 3D Molecule Viewer (Vector NTI, Invitrogen Corp., Carlsbad, CA).
Statistical analysis of the data from replicate binding assays was performed using one-way ANOVA and Bonferroni post test.
This work was supported by U.S. Public Health Service grants R01CA083823 from the National Cancer Institute to L.S.L. and R01AI033410 from the National Institute of Allergy and Infectious Diseases to L.M.A., and by support from the Louisiana Cancer Research Consortium. The authors gratefully acknowledge Dr. Shamim Ahmad for valuable discussions.
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