- Open Access
Use of different but overlapping determinants in a retrovirus receptor accounts for non-reciprocal interference between xenotropic and polytropic murine leukemia viruses
© Van Hoeven and Miller; licensee BioMed Central Ltd. 2005
Received: 13 September 2005
Accepted: 15 December 2005
Published: 15 December 2005
Retrovirus infection depends on binding of the retroviral envelope (Env) protein to specific cell-surface protein receptors. Interference, or superinfection resistance, is a frequent consequence of retroviral infection, and occurs when newly-synthesized Env binds to receptor proteins resulting in a block to entry by retroviruses that use the same receptors. Three groups of viruses demonstrate a non-reciprocal pattern of interference (NRI), which requires the existence of both a common receptor utilized by all viruses within the group, and a specific receptor that is used by a subset of viruses. In the case of amphotropic and 10A1 murine leukemia viruses (MLV), the common and specific receptors are the products of two related genes. In the case of avian sarcoma and leukosis virus types B, D, and E, the two receptors are distinct protein products of a single gene. NRI also occurs between xenotropic and polytropic MLV. The common receptor, Xpr1, has been identified, but a specific receptor has yet to be described.
Using chimeric receptor proteins and interference studies, we have identified a region of Xpr1 that is uniquely utilized by xenotropic MLV and show that this receptor domain is required for non-reciprocal interference.
We propose a novel pattern of receptor usage by xenotropic and polytropic MLV to explain the NRI observed between these viruses. We propose that the specific and common receptor determinants for xenotropic and polytropic viruses are simultaneously present in discreet domains of a single Xpr1 protein.
Retroviral infection of a host cell is initiated by interaction of the retroviral Env protein surface (SU) subunit with a specific host cell receptor. This interaction triggers conformational changes within the Env protein that bring the virus and host cell membranes in close proximity, resulting in fusion and delivery of the viral capsids into the host cell cytoplasm (reviewed in [1, 2]). In addition to promoting virus entry, the intracellular interaction of a viral Env and its cognate receptor can limit subsequent infection by subsequent viruses that bind the same receptor. This phenotype is referred to as interference or superinfection resistance because it prevents reinfection of a cell by the same virus strain, and has been used to classify viruses that utilize common cell surface receptors. Currently, mammalian retroviruses are divided into at least 10 different interference groups [3, 4]. Within these groups, several retroviruses show a non-reciprocal interference pattern (NRI), where infection by one virus will block infection by a second virus, but infection by the second virus only slightly inhibits infection by the first virus.
As the receptors for different retroviruses have been identified, it has become clear that NRI occurs in cases where related viruses within an interference group utilize a partially overlapping set of receptors for entry. In the case of amphotropic and 10A1 MLV  these receptors are Pit1 (Slc20a1) and Pit2 (Slc20a2), the products of two different genes with similar sequence and function. The phosphate transporter Pit2 serves as the receptor for both amphotropic MLV [6, 7] and 10A1 . However, 10A1 also binds to the closely related phosphate transporter Pit1, the receptor for gibbon ape leukemia virus (GALV)  and feline leukemia virus subtype B (FeLV-B) . Because the amphotropic Env cannot bind to Pit1, it cannot block 10A1 infection of cells that express both receptors, while the 10A1 Env can block amphotropic MLV infection .
NRI also occurs among avian sarcoma and leukosis viruses (ASLV) types B, D, and E. Viruses of types B and D can interfere with each other as well as type E viruses, whereas ASLV-E can interfere with itself, but not with types B or D. This group of viruses have all been shown to utilize a common receptor, CAR1 [11, 12]. Immunoprecipitation studies with different viral Env proteins have shown that this protein, encoded by the tv-b locus in chickens, produces two distinct protein products that differ in their disulfide bond pattern. One form, designated the type 1 receptor, can interact with ASLV-B and ASLV-E, whereas an additional form, the type 2 receptor, is specific for ASLV-B .
Another set of retroviruses that show NRI are xenotropic and polytropic MLV (X-MLV and P-MLV, respectively). Studies in cells derived from mink and the wild mouse Mus dunni demonstrated NRI between X-MLV and P-MLV [4, 14], implying the existence of a common receptor. In both cases, initial infection of cells with X-MLV strains resulted in complete resistance to subsequent infection by P-MLV isolates. However, initial infection of cells with P-MLV strains did not block infection by X-MLV, although the X-MLV titers observed were decreased [4, 14]. The hypothesis that these viruses share a common receptor was confirmed by the identification of a single cDNA from humans [15, 16] and mice  that could mediate infection of both viruses when expressed in resistant cells. However, the identification of a single cell surface receptor is inconsistent with the interference patterns observed between these two viruses. Previously established mechanisms of NRI would suggest the existence of a specific X-MLV receptor that cannot be utilized by P-MLV. Screening of cDNA libraries by three groups independently failed to identify additional genes encoding a xenotropic specific receptor. Furthermore, genetic studies in mice have mapped susceptibility loci for xenotropic and polytropic viruses to the same region of mouse chromosome 1, and it is currently believed that these studies have identified alleles of the same gene [18, 19]. These studies collectively argue against the existence of a separate locus encoding an X-MLV specific receptor, and suggest that the specific and the common receptor are encoded by the same gene.
Role of the putative third and fourth ECL of Xpr1 in xenotropic and polytropic virus entry
To identify regions of human Xpr1 (hXpr1) that are required for xenotropic and polytropic virus receptor function, chimeric receptors combining coding sequences from hXpr1 and from the non-functional hamster receptor (haXpr1) were made and tested for receptor function following expression in Chinese hamster ovary (CHO) cells (Figure 1). Chimeric receptors were named based on the order of human (U) and hamster (A) sequences that include the putative extracellular domains of the receptor. Because CHO cells can be infected by some X-MLV strains, we used the Env from an X-MLV strain (AKR6) that was unable to mediate transduction of CHO cells even when haXpr1 was overexpressed in the cells (Figure 1, construct AAAA). We also tested the Env from a P-MLV strain (1E) of Friend mink cell focus-forming virus (FrMCF) that mediates only a low rate of transduction of CHO cells overexpressing haXpr1 (Figure 1, construct AAAA). Both Env proteins could mediate relatively efficient transduction of CHO cells expressing hXpr1 (Figure 1, construct UUUU).
CHO cells expressing the Xpr1 chimeras were exposed to xenotropic [LAPSN(AKR6)] or polytropic [LAPSN(1E)] vectors and vector titers were determined (Figure 1). Cells expressing the UUAA chimera were poorly transduced by LAPSN(AKR6) or LAPSN(1E). Conversely, cells expressing the AAUU chimera were transduced at levels only slightly lower than those observed for hXpr1, indicating that the third and fourth loops of hXpr1 are important for both xenotropic and polytropic virus receptor function. Additional analysis of the determinants in this region shows that either the third or the fourth ECL is sufficient for xenotropic virus entry, but that only the fourth ECL can mediate polytropic virus entry. In particular, the AKR6 xenotropic vector could efficiently transduce cells expressing the AAAU or the AAUA chimeras, while the 1E polytropic vector could infect cells expressing the AAAU chimera but not the AAUA chimera.
Xenotropic and polytropic Env show reciprocal interference on some chimeric receptors
In previous interference studies, infection with a xenotropic virus blocks subsequent infection by viruses bearing either xenotropic or polytropic Env. In contrast, expression of a polytropic Env blocks subsequent infection by other polytropic viruses, but only slightly inhibits xenotropic infection [4, 14]. Using our chimeric Xpr1 proteins, we examined the requirement for different regions of Xpr1 in interference between AKR6 and 1E pseudotype vectors.
The interference patterns on CHO/AAAU cells were markedly different from those described for CHO/AAUU cells. The AAAU receptor contains only a single entry determinant that can be utilized by both AKR6 and 1E pseudotyped viruses. In cells expressing this receptor, transduction by the LAPSN(AKR6) or LAPSN(1E) vectors was blocked by the presence of either AKR6 or 1E Env (Figure 2, right panels), thus showing a pattern of reciprocal interference. Although transduction by LAPSN(AKR6) was not completely blocked by 1E Env, a similar degree of interference was observed in two independent experiments, and the observed differences in titer were found to be statistically significant in both cases by using the Student's t-test (p < 0.05).
In summary, these experiments demonstrate a non-reciprocal interference pattern between AKR6 and polytropic viruses on the AAUU chimera, and a reciprocal pattern of interference in the AAAU chimera, which contains only the putative fourth ECL of human Xpr1. These results support the hypothesis that xenotropic virus can utilize either the third or fourth ECL of hXpr1 for cell entry, but that polytropic virus can only use the fourth ECL. When the third ECL is replaced with the non-functional loop from haXpr1, both viruses can only use the fourth ECL for entry and therefore show reciprocal interference.
SU domains of AKR6 and 1E Env show high sequence similarity to prototypical xenotropic and polytropic Env SU domains
A full-length env gene containing the cloned 1E SU sequence and the transmembrane (TM) subunit sequence from NZB X-MLV was constructed and was transfected into LGPS/LAPSN cells, but vector production from these cells was not detected. Examination of multiple 1E-SU PCR clones isolated from various Hirt preparations of 1E virus DNA indicated that the 1E-SU clone we used to construct the Env expression vector does not contain inactivating mutations. Attempts to clone the remaining TM sequence from 1E Env by PCR using primers to conserved regions of Env were unsuccessful, suggesting that 1E may have unique sequences present in the TM domain that are required for proper Env function.
To verify that the cloned 1E SU sequence had the properties of a polytropic virus SU domain, we generated a human IgG tagged version of 1E-SU (1E-SU-IgG). Following production of the protein by transient transfection and purification by FPLC, we examined the binding of 1E-SU-IgG to dunni cells by flow cytometry (Figure 4B). To address the binding specificity of this reagent, and by extension of our cloned SU sequence, we also examined the binding to dunni cells infected with replication competent 1E or with 4070A amphotropic viruses. Similar binding of 1E-SU-IgG was observed in both control and dunni/4070A, whereas reduced binding was observed in dunni/1E cells. As a control, we found that Ampho-SU-IgG protein binding to dunni cells was inhibited in cells infected by an amphotropic virus (Figure 4C). The ability of replication competent 1E virus to inhibit binding of 1E-SU-IgG to cells demonstrates that the cloned SU recognizes a protein that is also bound by the 1E virus isolate. From this result, we conclude that the cloned SU sequence is representative of the Env present in the 1E virus.
Analysis of xenotropic and polytropic Env binding to cells expressing human, hamster and chimeric receptors
Results obtained here with the hamster/human receptor chimeras are consistent with previous studies demonstrating the importance of residues within the putative third and fourth ECL of Mus dunni Xpr1 in xenotropic receptor function . In that study, mutations in both the third and fourth ECL of Mus dunni Xpr1 were required to abolish xenotropic receptor function while mutations in either ECL alone did not limit virus entry. In the current study, the ability of AKR6 pseudotyped vectors to utilize either the AAUA or the AAAU chimera as a receptor demonstrates that either the third or fourth human ECL is sufficient to support X-MLV entry.
Taken together, our experiments with chimeric receptors suggest a model for entry of X-MLV and P-MLV that is consistent with the NRI observed previously, given that no X-MLV specific receptor has been identified. We propose that two receptor functions are present simultaneously in different domains of Xpr1. One domain, which resides in the fourth ECL functions as a recognition site for both xenotropic and polytropic viruses, while the second receptor domain in the third ECL can only interact efficiently with xenotropic Env.
Our model for NRI predicts that the xenotropic and polytropic viruses should show a reciprocal pattern of interference in a receptor lacking the X-MLV specific receptor domain. The interference experiments described here using the AAAU and AAUU chimeras confirm this prediction. The interference pattern on the AAUU chimera, which contains both entry domains, is non-reciprocal due to the presence of the third extracellular loop. If the xenotropic specific determinant is removed, as in the AAAU chimera, X-MLV entry is markedly inhibited in cells expressing the 1E Env. This finding demonstrates that the third ECL is required for NRI, and that a chimeric receptor lacking this region serves as a common receptor for both P-MLV and X-MLV.
In the interference experiments described here, 1E Env was sometimes unable to completely block infection by a 1E-pseudotype challenge vector (Table 2). Previous work suggests that such incomplete interference may reflect an inherent inability of P-MLV to completely block their cellular receptor. In vitro studies specifically examining the mechanism of P-MLV pathogenesis have shown that infection of cells by polytropic/MCF viruses results in accumulation of unintegrated extrachromosomal viral DNA, suggesting that P-MLV are capable of superinfecting cells in culture . This finding is consistent with studies from other oncoretroviral systems showing that pathogenic viral stains can often superinfect cells [27–29]. Given that receptor mediated interference is the primary mechanism by which viruses prevent superinfection, the demonstrated ability of P-MLV to initiate multiple rounds of infection suggests that some polytropic Env proteins are inherently incapable of blocking certain receptors. However, it should be noted that strong interference by polytropic Env proteins can be observed in some cases (Table 2) .
It is tempting to speculate that the regions we have identified through our chimera analyses represent the motifs within Xpr1 that are responsible for binding to the viral Env. The critical portions of the molecule are believed to lie outside of the cell, and therefore represent candidates for SU binding domains. However, it is difficult to accurately predict the topology of transmembrane receptors, as was shown in the case of Pit1 and Pit2. Initial predictions of receptor topology were used to design a number of chimeras similar to those described here. Regions within those chimeras were identified that enhanced infection by GALV or amphotropic MLV respectively, and it was suggested that these regions were responsible for virus binding [30–33]. However, recent experiments have provided a new, experimentally verified topology for Pit2 , and several of the previously identified critical regions were found to lie on the inner surface of the cell membrane. Therefore, before a specific role can be firmly assigned to the third and fourth ECL of Xpr1, the topology of the protein must be established.
Results presented here indicate that the non-reciprocal interference between polytropic and xenotropic retroviruses can be explained by a common receptor domain in the putative fourth ECL of Xpr1 and a specific receptor domain for xenotropic virus in the third ECL of the same Xpr1 protein.
Virus and cell line nomenclature
Cell lines containing integrated retroviral vectors are indicated by the name of the cell line, followed by a slash, followed by the name of the integrated vector (e.g. dunni/LAPSN, or CHO/LN). Retroviral vectors in the viral form are described by the vector name followed, in parentheses, by the name of the replication-competent virus or packaging cell line used to produce the vector [e.g. LAPSN(AKR6), LAPSN(PA317)]. Where packaging cell lines have been used, the Gag and Pol proteins are from Moloney murine leukemia virus.
Chinese hamster ovary (CHO) cells (CHO-K1, ATCC CCL 61) were grown in minimum essential medium-alpha (α-MEM) (Gibco) supplemented with 10% fetal bovine serum (FBS) (Hyclone). All other cell lines were grown in Dulbecco's minimal essential medium (DMEM) (Gibco) supplemented with 10% FBS. CHO cells expressing chimeric receptors were generated by calcium phosphate-mediated transfection of receptor expression constructs. One day post-transfection, cells were trypsinized and seeded at 1:10 dilution into medium containing G418 (750 μg active compound per ml) and were maintained in selection medium for 7 to 10 days. Surviving cells were pooled and utilized in subsequent transduction assays. Mus dunni tail fibroblasts (dunni cells), the generation of dunni/LN, dunni/LAPSN, and helper virus-infected derivatives have been described . LGPS/LAPSN cells  are a clone of NIH 3T3 cells that express Moloney MLV Gag and Pol proteins and contain the retroviral vector LAPSN . Retrovirus packaging cell lines used included PA317 , PD223  and FlyRD . All cells were grown in a 37°C incubator at 10% CO2 and 100% relative humidity.
Chimeric receptor plasmids and retroviral vectors
Receptor chimeras are named to indicate the origin of the sequence in each putative extracellular loop, based on the receptor topology model provided in Figure 1. This model has been suggested in previous studies , and was confirmed for this study by using a number of topology prediction algorithms located on the ExPASy proteomics server . For the human/hamster Xpr1 receptor chimeras (Figure 1), "A" indicates sequence from the Cricetulus griseus hamster receptor [GenBank:AF198106], while a "U" is used for the human sequence derived from a HeLa cell cDNA library [GenBank:AF099082]. Chimeric Xpr1 proteins were constructed by exchanging restriction fragments as indicated in Figure 1. The 2 kb DNA fragments containing the hXpr1 or haXpr1 coding regions were blunt ended with Klenow and was cloned into SmaI digested pBluescript II (Stratagene, La Jolla CA). Following the exchange of fragments required to generate chimeric receptors, all constructs were confirmed by sequencing using primers internal to the receptor sequence. Retroviral vectors expressing the chimeric receptors were made by insertion of 2 kb XhoI-BamHI fragments containing the receptor coding regions from pBluescript into the retroviral expression plasmid LXSN  after digestion of pLXSN with HpaI and BamHI. Additional retroviral vectors used here included LAPSN , which encodes AP and Neo, and LN , which encodes Neo.
Viruses and infection assays
The AKR6 xenotropic and 1E polytropic virus isolates were a kind gift from Bruce Chesebro . LAPSN(AKR6) and LAPSN(1E) retroviral vectors were generated by infecting dunni/LAPSN cells with AKR6 or 1E helper virus, as described previously . LAPSN(AKR6env) and LAPSN(1Eenv) vectors were generated by transfection of pSX2-AKR6env and pSX2-1Eenv into LGPS/LAPSN cells using standard calcium phosphate protocols. Briefly, LGPS/LAPSN cells were plated into 6-cm-diameter culture dishes at 5 × 105 cells per dish approximately16 h prior to transfection. The following day, 9 μg of the Env expression plasmid was transfected into the cells with 1 μg of pCMV-βgal as a control for transfection efficiency. The following day cells were rinsed with PBS, and incubated with 4 ml culture medium per plate overnight. The conditioned medium was collected, filtered through a 0.45 μm pore-size filter, and was frozen at -80°C. Vector titers were determined by limiting dilution assay on dunni cells. Additional viral vectors, including LAPSN (PA317), LAPSN (PD223), and LAPSN(FlyRD), were obtained by collecting conditioned medium from established producer lines.
Transduction assays in cell lines expressing chimeric receptors were carried out as follows. Approximately 16 h before infection, cell lines were plated at 7 × 104 cells/well into 6-well (d = 3.4 cm) tissue culture dishes. Immediately prior to infection, medium was changed to include 4 μg/ml Polybrene. Virus was added at appropriate dilutions, and the cells incubated for 48 h to allow expression of the alkaline phosphatase protein from the integrated LAPSN vector. Cells were then fixed in 3.7% formaldehyde in phosphate-buffered saline for 8 min at room temperature. Fixed cells were washed three times with phosphate-buffered saline. Endogenous alkaline phosphatase was inactivated by incubating the cells at 68°C for 1 h. Cells were then stained for alkaline phosphatase activity by incubating the cells over night in AP staining buffer (100 mM Tris pH 8.5, 100 mM NaCl, 50 mM MgCl2, 1mg/ml Nitro Blue tetrazolium, 100 μg/ml X-Phos). Transduction events were measured by counting AP+ foci.
Env SU sequences from the AKR6 [GenBank:DQ199948] and 1E [GenBank:DQ199949] viruses were obtained by PCR from low molecular weight DNA obtained from infected cells. Specifically, dunni cells were plated at 105 cells in 6-cm-diameter tissue culture dishes. Following overnight incubation, the cells were infected at high multiplicity of infection (~100) with helper virus-containing stocks of LAPSN(AKR6) and LAPSN(1E) in the presence of 4 μg/ml Polybrene (Sigma). 16 h post-infection, low molecular weight DNA was isolated using the method of Hirt . Env sequences corresponding to the SU portion of Env were isolated by PCR using primers Xeno5'env (5'-ATGGAAGGTTCAGCGTTCTCAAAACCCC-3') and Xeno3'Env (5'-TGCCGCCCATAGTAAGTCCTCC-3'). Following gel purification using a Qiaquick gel purification kit (Qiagen), fragments were cloned into pCR2.1 using a Topo-TA cloning strategy (Invitrogen, Carlsbad CA). Full length Env coding regions were generated by ligation of a SacI-XhoI fragments into pBS-TM, a pBluescript-based vector containing a C-terminal fragment from the NZB env gene [GenBank:K02730]. The pBS-TM plasmid was made by insertion of a SacI-NotI fragment from pCSI-ENZB  into pBluescript II. Expression plasmids were generated by subcloning of XhoI-NotI fragments into pCR3.1 (Invitrogen) to generate pCR3.1-AKR6env and pCR3.1-1Eenv. To improve expression in murine and CHO cells, a BamHI-HincII fragment containing the human cytomegalovirus immediate early promoter was replaced with a BamHI-NheI fragment containing the Moloney MLV LTR promoter and enhancer from pSX2 , to generate pSX2-AKRenv and pSX2-1Eenv. These plasmids were sequenced to confirm the presence of complete Env open reading frames.
The 1E-SU-IgG plasmid was generated by ligation of a SacI-XhoI fragment from pCR2.1-1E-Env into pCI-NSU?9-hFc . To confirm the identity and integrity of the resulting fusion protein, the construct was sequenced using primers internal to the 1E-SU.
Virus and Env SU binding assays
Production and purification of 1E-SU-IgG for binding assays was carried out as described for other similar proteins [43, 44]. For flow cytometry assays, 106 cells were incubated with 1–2 μg of purified fusion protein in a final volume of 100 μl for 2 h. Following washing, cells were incubated with a fluorescent anti human-IgG secondary antibody (DAKO F0315) for 1 h. Cell fluorescence was determined by flow cytometry on a FACSCalibur (BD Biosciences), and data was analyzed using CellQuest software.
For virus binding assays, 106 cells expressing the indicated receptor chimeras were incubated with LAPSN(AKR6) virus at 4°C for two h. Cells were washed three times with phosphate-buffered saline containing 2% FBS and were incubated with 1 ml hybridoma supernatant containing 83A25 antibody for 2 h. Following two additional washes and incubation with a FITC-conjugated anti-Rat-IgG secondary antibody, cell fluorescence was determined by flow cytometry using a FACSCalibur.
To establish CHO cell lines expressing high levels of AKR6 and 1E Env, cells were maintained in conditioned medium from dunni/LN cells (mock), or dunni/LN cells productively infected with AKR6 or 1E helper viruses. Conditioned medium (α-MEM with 10% FBS) was collected, centrifuged at 1,000 × g for 10 min to remove cells and debris, and frozen at -80°C for 24 h. Prior to addition to CHO cells, a 1:1 mixture of dunni conditioned medium and fresh α-MEM with 10% FBS was supplemented with 4 μg/ml Polybrene to facilitate infection. The conditioned medium mix was added to cells every 24 h. As CHO cultures reached confluence (approximately every 3 days) cells were removed from the culture dish with trypsin/EDTA and split 1:10 into new 6-cm-diameter dishes. After 6 weeks, cells were trypsinized, counted on a hemacytometer and plated at 105 cells/well in 6 well dishes. Cells were then transduced with LAPSN(AKR) or LAPSN(1E) viral vectors. The titer of each vector was determined by limiting dilution. The degree of interference can be determined by comparing the vector titer on mock infected cells to that obtained on cells infected with AKR6 or 1E viruses.
This study was supported by grants HL54881, DK47754, and HL36444 from the NIH.
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