Strains Of Murine Leukemia Virus Research Articles

An interleukin-1 beta-encoding retrovirus exhibits enhanced replication in vivo.

Interleukin-1 beta (IL-1β) is an inflammatory cytokine that is secreted in response to inflammasome activation by innate microbe-sensing pathways. Although some retroviruses can trigger IL-1β secretion through the DNA-sensing molecule IFI16, the effect of IL-1β on the course of infection is unknown. To test whether IL-1β secretion affects retroviral replication in vivo, I constructed a novel murine leukemia virus strain (FMLV-IL-1β) that encodes the mature form of IL-1β. This virus replicated with kinetics similar to that of wild-type virus in tissue culture but caused a dramatically more aggressive infection of both C57BL/6 and BALB/c mice. By 7 days postinfection (PI), mice infected with FMLV-IL-1β exhibited splenomegaly and viral loads 300-fold higher than those in mice infected with wild-type FMLV. Furthermore, the enlarged spleens of FMLV-IL-1β-infected mice correlated with a large expansion of Gr-1(+) CD11b(+) myeloid-derived suppressor cells, as well as elevated levels of immune activation. Although FMLV-IL-1β infection was controlled by C57BL/6 mice by 14 days p.i., FMLV-IL-1β was able to establish a significant persistent infection and immune activation in BALB/c mice. These results demonstrate that IL-1β secretion is a powerful positive regulator of retroviral infection and that FMLV-IL-1β represents a new model of proinflammatory retroviral infection. Interleukin-1 beta (IL-1β) is an inflammatory cytokine released in response to activation of innate pathogen-sensing pathways during microbial infection. To examine the potential impact of IL-1β on retroviral replication in vivo, I constructed a novel mouse retrovirus strain (FMLV-IL-1β) that encodes IL-1β and promotes abundant IL-1β secretion from infected cells. This virus replicates with normal kinetics in cultured cells but displays a dramatically enhanced ability to replicate in mice and caused persistent infection and immune activation in the BALB/c strain of mice. These results establish IL-1β as a positive regulator of retroviral replication and suggest that targeting this pathway may have therapeutic benefits in infections with proinflammatory retroviruses. This virus can also be used to further study the impact of inflammatory pathways on retroviral infection.

The protooncogene Vav1 regulates murine leukemia virus-induced T-cell leukemogenesis

Vav1 is expressed exclusively in hematopoietic cells and is required for T cell development and activation. Vav1-deficient mice show thymic hypocellularity due to a partial block during thymocyte development at the DN3 stage and between the double positive (DP) and single positive (SP) transition. Vav1 has been shown to play a significant role in several non-hematopoietic tumors but its role in leukemogenesis is unknown. To address this question, we investigated the role of Vav1 in retrovirus-induced T cell leukemogenesis. Infection of Vav1-deficient mice with the Moloney strain of murine leukemia virus (M-MuLV) significantly affected tumor phenotype without modulating tumor incidence or latency. M-MuLV-infected Vav1-deficient mice showed reduced splenomegaly, higher hematocrit levels and hypertrophic thymi. Notably, Vav1-deficient mice with M-MuLV leukemias presented with markedly lower TCRβ/CD3 levels, indicating that transformation occurred at an earlier stage of T cell development than in WT mice. Thus, impaired T cell development modulates the outcome of retrovirus-induced T cell leukemias, demonstrating a link between T cell development and T cell leukemogenesis.

Frequent detection of infectious xenotropic murine leukemia virus (XMLV) in human cultures established from mouse xenografts

Purpose: To investigate the frequency of xenotropic murine leukemia virus (MLV) presence in human cell lines established from mouse xenografts and to search for the evidence of horizontal viral spread to other cell lines. Methodology: We examined xenograft tumor cell lines from 7 independent laboratories and 128 non-xenografted tumor cell lines. Cell line DNA was examined for mouse DNA contamination, and by three Taqman qPCR assays targeting the gag, env or pol regions of MLV. Sequencing was used for viral strain identification. Supernatant fluids were tested for reverse transcriptase (RT) activity. Results: Six of 23 (26%) mouse DNA free xenograft cultures were strongly positive for MLV and their sequences had greater than 99% homology to known MLV strains. Four of five available supernatant fluids from these viral positive cultures were strongly positive for RT activity. Three of these supernatant fluids were studied to confirm the infectivity of the released virions for other human culture cells. Of the 78 non-xenograft derived cell lines maintained in the xenograft culture-containing facilities, 13 (17%) were positive for MLV, including XMRV, a virus strain first identified in human tissues. By contrast, all 50 cultures maintained in a xenograft culture-free facility were negative for viral sequences. Conclusions: Human cultures derived after mouse xenografting frequently contain and release highly infectious xenotropic MLV viruses. Laboratories working with xenograft-derived human cultures should be aware of the risk of contamination with potentially biohazardous human-tropic mouse viruses and their horizontal spread to other cultures.

SUMO-Interacting Motifs of Human TRIM5α are Important for Antiviral Activity

Human TRIM5α potently restricts particular strains of murine leukemia viruses (the so-called N-tropic strains) but not others (the B- or NB-tropic strains) during early stages of infection. We show that overexpression of SUMO-1 in human 293T cells, but not in mouse MDTF cells, profoundly blocks N-MLV infection. This block is dependent on the tropism of the incoming virus, as neither B-, NB-, nor the mutant R110E of N-MLV CA (a B-tropic switch) are affected by SUMO-1 overexpression. The block occurred prior to reverse transcription and could be abrogated by large amounts of restricted virus. Knockdown of TRIM5α in 293T SUMO-1-overexpressing cells resulted in ablation of the SUMO-1 antiviral effects, and this loss of restriction could be restored by expression of a human TRIM5α shRNA-resistant plasmid. Amino acid sequence analysis of human TRIM5α revealed a consensus SUMO conjugation site at the N-terminus and three putative SUMO interacting motifs (SIMs) in the B30.2 domain. Mutations of the TRIM5α consensus SUMO conjugation site did not affect the antiviral activity of TRIM5α in any of the cell types tested. Mutation of the SIM consensus sequences, however, abolished TRIM5α antiviral activity against N-MLV. Mutation of lysines at a potential site of SUMOylation in the CA region of the Gag gene reduced the SUMO-1 block and the TRIM5α restriction of N-MLV. Our data suggest a novel aspect of TRIM5α-mediated restriction, in which the presence of intact SIMs in TRIM5α, and also the SUMO conjugation of CA, are required for restriction. We propose that at least a portion of the antiviral activity of TRIM5α is mediated through the binding of its SIMs to SUMO-conjugated CA.

Murine double minute 2 as a modulator of retroviral restrictions mediated by TRIM5α

In human cells, endogenous TRIM5α strongly inhibits N-tropic strains of murine leukemia virus (N-MLV) but does not target the closely related B-MLV. We have used a shRNA-based loss-of-function screen to isolate factors other than TRIM5α involved in the restriction of N-MLV. In one of the isolated clones, the shRNA expressed was found to target the murine double minute-2 mRNA. Knocking down MDM2 increased N-MLV and EIAV infection of human cells by 2- to 5-fold while having little effect on B-MLV. Similarly, knocking down MDM2 in African green monkey cells diminished the restriction of both N-MLV and HIV-1. Dual knockdown experiments showed that MDM2 was involved in the restriction mediated by TRIM5α. Moreover, MDM2 knockdown decreased the sensitivity of N-MLV infection to treatment with MG132 and As2O3, two known TRIM5α pharmacological inhibitors. Altogether, our data suggest that MDM2 is a general but nonessential modulator of TRIM5α-mediated antiretroviral functions.

Interfering Residues Narrow the Spectrum of MLV Restriction by Human TRIM5α

TRIM5α is a restriction factor that limits infection of human cells by so-called N- but not B- or NB-tropic strains of murine leukemia virus (MLV). Here, we performed a mutation-based functional analysis of TRIM5α-mediated MLV restriction. Our results reveal that changes at tyrosine336 of human TRIM5α, within the variable region 1 of its C-terminal PRYSPRY domain, can expand its activity to B-MLV and to the NB-tropic Moloney MLV. Conversely, we demonstrate that the escape of MLV from restriction by wild-type or mutant forms of huTRIM5α can be achieved through interdependent changes at positions 82, 109, 110, and 117 of the viral capsid. Together, our results support a model in which TRIM5α-mediated retroviral restriction results from the direct binding of the antiviral PRYSPRY domain to the viral capsid, and can be prevented by interferences exerted by critical residues on either one of these two partners.

Non-identical patterns of proviral insertions around host transcription units in lymphomas induced by different strains of murine leukemia virus

In a small sample of 57 retrovirus integration sites (RISs) isolated from 23 end-stage lymphomas induced in NMRI mice by the B-lymphotropic Akv wt or an enhancer mutant hereof, Akv1–99, we identified 14 novel RISs and defined 9 novel CISs (common insertion sites). Moreover, when comparing with RISs from tumors induced by the T-lymphomagenic SL3-3, we observed that SL3-3 targets RefSeq promoter regions with a significantly higher frequency than Akv/Akv1–99 and in an orientation-dependent way. Altogether, our results strongly emphasize the importance of host genetic background and virus type for retroviral insertion mutagenesis screens and suggest that different types of MLV may favor specific genomic regions and orientations in order exert optimal effect on target gene expression during lymphoma induction and development.

Disruption of human TRIM5alpha antiviral activity by nonhuman primate orthologues.

TRIM5 is a determinant of species-specific differences in susceptibility to infection by retroviruses bearing particular capsids. Human immunodeficiency virus type 1 (HIV-1) infection is blocked by the alpha isoform of macaque TRIM5 (TRIM5alpha(rh)) or by the product of the owl monkey TRIM5-cyclophilin A gene fusion (TRIMCyp). Human TRIM5alpha potently restricts specific strains of murine leukemia virus (N-MLV) but has only a modest effect on HIV-1. The amino termini of TRIM5 orthologues are highly conserved and possess a coiled-coil domain that promotes homomultimerization. Here we show that heterologous expression of TRIM5alpha(rh) or TRIMCyp in human cells interferes with the anti-N-MLV activity of endogenous human TRIM5alpha (TRIM5alpha(hu)). Deletion of the cyclophilin domain from TRIMCyp has no effect on heteromultimerization or colocalization with TRIM5alpha(hu) but prevents interference with anti-N-MLV activity. These data demonstrate that TRIM5 orthologues form heteromultimers and indicate that C-terminal extensions alter virus recognition by multimers of these proteins.

Selection for loss of Ref1 activity in human cells releases human immunodeficiency virus type 1 from cyclophilin A dependence during infection.

Capsid (CA)-specific restrictions are determinants of retroviral tropism in mammalian cells. One such restriction, human Ref1, targets strains of murine leukemia virus bearing an arginine at CA residue 110 (N-MLV), resulting in decreased accumulation of viral cDNA. The cellular factors accounting for Ref1 activity are unknown. As(2)O(3) increases N-MLV titer in Ref1-positive cells, possibly by counteracting Ref1. Restriction factor saturation experiments suggest that Ref1 may also target human immunodeficiency virus type 1 (HIV-1), but only if its CA is not bound to the cellular protein cyclophilin A (CypA). As a step towards understanding the genetic determinants of Ref1, we subjected Ref1-positive TE671 cells to three sequential rounds of selection with N-MLV reporter viruses. We isolated a subclone, 17H1, that was permissive for N-MLV infection and therefore deficient in Ref1 activity. Stimulation of N-MLV replication by As(2)O(3) was attenuated in 17H1, confirming that the drug acts by overcoming Ref1 activity. HIV-1 infection of 17H1 cells was resistant to disruption of the CA-CypA interaction, demonstrating that Ref1 restricts CypA-free HIV-1. Our results suggest that interaction with CypA evolved to protect HIV-1 from this human antiviral activity.

Large-scale identification of disease genes involved in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a heterogeneous group of diseases in which chromosomal aberrations, small insertions or deletions, or point mutations in certain genes have profound consequences for prognosis. However, the majority of AML patients present without currently known genetic defects. Retroviral insertion mutagenesis in mice has become a powerful tool for identifying new disease genes involved in the pathogenesis of leukemia and lymphoma. Here we have used the Graffi-1.4 strain of murine leukemia virus, which causes predominantly AML, in a screen to identify novel genes involved in the pathogenesis of this disease. We report 79 candidate disease genes in common integration sites (CISs) and 15 genes whose family members previously were found to be affected in other studies. The majority of the identified sequences (60%) were not found in lymphomas and monocytic leukemias in previous screens, suggesting a specific involvement in AML. Although most of the virus integrations occurred in or near the 5' or 3' ends of the genes, suggesting deregulation of gene expression as a consequence of virus integration, 18 CISs were located exclusively within the genes, conceivably causing gene disruption.

Possible retroviral origin of prion disease: could prion disease be reconsidered as a preleukemia syndrome?

A retroviral etiology might explain why amyloid plaque and/or spongiosis are or are not associated with neuronal death in prion diseases. While retroviral genes themselves may be responsible for neuronal death, a retrovirus may also cause mutations in cellular genes. Hence, the prion gene may be altered by a retrovirus in the same way as a cellular proto-oncogene is altered to produce an oncogene, either by transduction or by integration of the provirus in its vicinity. In both cases, the resulting abnormal prion protein, acting as a catalyst, may induce the formation of amyloid plaques. In addition, a wild type retrovirus may recombine to the vesicular stomatitis virus (VSV) to give rise to a pseudotyped retrovirus able to induce spongiosis. It is reported here that in scrapie, a blood monocytoid cell proliferates in vitro. If confirmed in other species, this raises the question of the potential link between prion disease and leukemia. Indeed neurovirulent strains of murine leukemia virus, a slow acting retrovirus, are known to induce spongiform encephalopathies. A preliminary attempt to purify reverse transcriptase by chromatography, using the classical protocol, failed because of the presence of a prion-like protein secreted by the blood mononuclear cells which stuck to the phosphocellulose column. Therefore, if a retrovirus is present in prion diseases, it would be evidenced only in animals developing the disease in the absence of prion protein. From this point of view, mice obtained in 1997 by the group of D. Dormont in France, offer a unique opportunity to test the retroviral hypothesis.

Entry of amphotropic and 10A1 pseudotyped murine retroviruses is restricted in hematopoietic stem cell lines.

Although transduction with amphotropic murine leukemia virus (MLV) vectors has been optimized successfully for hematopoietic differentiated progenitors, gene transfer to early hematopoietic cells (stem cells) is still highly restricted. A similar restriction to gene transfer was observed in the mouse stem cell line FDC-Pmix compared with transfer in the more mature myeloid precursor cell line FDC-P1 and the human erythroleukemia cell line K562. Gene transfer was not improved when the vector was pseudotyped with gp70SU of the 10A1 strain of MLV, which uses the receptor of the gibbon ape leukemia virus (Pit1), in addition to the amphotropic receptor (Pit2). Although 10A1 and amphotropic gp70SU bound to FDC-P1, K562, and fibroblasts, no binding to FDC-Pmix cells was detected. This indicates that FDC-Pmix cells lack functional Pit2 and Pit1 receptors. Pseudotyping with the vesicular stomatitis virus G protein improved transduction efficiency in FDC-Pmix stem cells by 2 orders of magnitude, to fibroblast levels, confirming a block to retroviral infection at the receptor level.

Efficient retroviral infection of human cells utilising an adenoviral vector expressing the ecotropic receptor.

Murine leukemia viruses (MLV) are a vector of choice for gene delivery in current human clinical trials. The first step in retroviral infection is the binding of the viral particle to a receptor on the target cell1. Thus, the presence of the appropriate viral receptors on the surface of target cells is the major determinant of the susceptibility of mammalian cells to MLV. The phosphate transporter shared by primates, mice, and rats that acts as the viral receptor for amphotropic MLV2,3 is present on many different human cell types but is not ubiquitous or plentiful, placing a grave restriction on the infection efficiency of this retrovirus. In this study, we utilized an adenoviral vector to express transiently the receptor for the ecotropic murine leukemia virus in a panel of human cell lines. Ecotropic strains of MLV, such as Moloney, Rauscher, and Friend, attach to cells utilizing a common cationic amino acid transporter that is confined to mice and rats4. The cationic amino acid transporter was expressed in human cells by means of a recombinant adenovirus constructed with murine cDNA. Expression of the receptor made cells from human mesothelium, kidney, lung, and cervical epithelium highly permissive to infection with recombinant ecotropic retrovirus. This strategy offers a means of obtaining high levels of stable gene transfer in a wide range of human cells. The use of a dual vector system may overcome some of the present limitations to gene transfer.

Single Amino Acid Changes in the Murine Leukemia Virus Capsid Protein Gene Define the Target ofFv1Resistance

The mouseFv1genetic locus controls resistance to subgroups of ecotropic, MCF, and amphotropic murine leukemia viruses (MuLVs). In addition to the four previously defined alleles ofFv1(Fv1n, Fv1b, Fv1nr, Fv10), we present evidence that the novel restriction pattern characteristic of DBA/2J mice maps to theFv1locus and therefore represents a novel allele, here designatedFv1d.Previous studies had demonstrated that theFv1-mediated viral tropism is determined within the capsid protein gene, and that N- and B-tropic virus capsids differ only in two adjacent amino acids. We introduced various amino acid substitutions at these two sites in the N-tropic AKV MLV capsid gene, and typed resulting viruses for host range on cells carrying all fiveFv1alleles as well as on cells from additional wild mouse species withFv1-like differences in virus susceptibility. Results indicate that alteration of the first of the two amino acids does not alter tropism, but alteration of the second alone is sufficient to convert the N-tropic AKV MLV to a B-tropic virus. Substitution of leucine for arginine at this site produced a virus with an unusual tropism not characteristic of any of the naturally occurring or laboratory strains of MuLV.

Efficiency of in vivo gene transfer using murine retroviral vectors is strain-dependent in mice.

Retroviral vectors can be used to transduce cultured cells at high frequencies, but efficient transduction of target cells in vivo has proved difficult and little is known about the factors that influence the efficiency of retroviral infection. Many commonly used mouse strains harbor endogenous C-type proviruses, some of which are expressed and have circulating antibodies against the viral envelope glycoproteins that cross-react with the Moloney strain of murine leukemia virus (MoMLV), from which most current retroviral vectors are derived. We have investigated the relative efficiency of retroviral-mediated gene transfer into regenerating skeletal muscle of a variety of mouse strains using a MoMLV-based vector. Humoral immune competence and interference between endogenous MLVs and exogenous recombinant MoMLV were observed to affect the efficiency of retroviral-mediated transfection in vivo. Our results indicate that the mouse genetic background and immune status need to be considered when choosing a preclinical model for in vivo retroviral-mediated gene transfer.

Autoantibodies against peptide-defined epitopes of T-cell receptors in retrovirally infected humans and mice.

Autoantibodies directed against peptide-defined epitopes of T-cell receptors occur in the serum of healthy humans with the levels and isotypic expression dependent upon physiological changes (aging, pregnancy) or upon the development of autoimmune disease. We carried out investigations of autoantibodies against Tcr peptide-defined epitopes in retroviral infections of humans (HIV-1) and mice (LP-BM5 strain of murine leukemia virus) to determine whether infection with these agents disrupted the regulation of the production of these antibodies. Retroviral infection in humans resulted in increased levels of autoantibody production against putative immunoregulatory regions of the Tcr beta chain (V beta CDR1 and Fr3), a result reflecting a disruption of regulation. In addition, antigenic mimicry was observed with a cross-reaction shared between the common portion of the V3 neutralizing loop of the HIV-1 gp120 molecule and the joining segment of T-cell receptors (J beta). Infection of mice with the defective retrovirus resulted in the induction of antibodies directed particularly against V beta CDR1 peptide-defined determinants. Analysis of the virally induced response to a set of 8 CDR1 peptide epitopes indicated a selectivity to the process. It was possible to partially reverse aberrant cytokine changes correlated with the onset of murine MAIDS by administration of T-cell receptor peptides in saline. These results show that retroviral infection in humans and mice has a profound dysfunctional effect on the regulation of autoantibodies to T-cell receptors. The function of these autoantibodies in the immunopathogenesis of acquired immunodeficiency remains to be determined.

Viral load and its relationship to quinolinic acid, TNF alpha, and IL-6 levels in the CNS of retroviral infected mice.

Mouse models of infection of the central nervous system (CNS) have been used to study retroviral-induced neurologic disease. Ecotropic-neurotropic murine leukemia virus (MuLV) infection of susceptible neonatal mice causes a neurologic disease characterized by progressive hindlimb paralysis. The lesions consist of chronic noninflammatory spongiform change predominantly involving brainstem and spinal cord. Two molecularly cloned strains of MuLV, ts-1, a temperature-sensitive mutant of Moloney MuLV, and pNE-8, derived from a feral mouse isolate Cas-Br-E, were used in this study. Infected mice were sacrificed at regular intervals postinoculation throughout the time-course of disease. The neuropathology was evaluated using standard histological and immunohistopathological techniques. Tissue concentrations of viral proteins and potentially cytotoxic factors were compared with the histopathology in select regions of the CNS. Areas of extensive vacuolation with neuronal and oligodendroglial infection were observed in spinal cord, brainstem, and cerebellum. High titers of infectious virus were observed within CNS lesions, whereas low titers were observed in morphologically uninvolved areas. Western blot analysis revealed abundant production of viral envelope proteins, which correlated well with infectious virus titers. Serum quinolinic acid (QUIN) concentrations in both groups of noninfected and infected mice were similar. However, CNS tissue concentrations of QUIN, TNF alpha, and IL-6 in ts-1 infected mice were significantly higher than in pNE-8 infected or noninfected mice. The difference in concentration of these factors may be the result of greater activation of macrophages/microglia in ts-1 infected mice. During murine retroviral encephalitis, CNS damage may be mediated by direct infection of CNS cells and may be enhanced by indirect effects of neurotoxic factors possibly secreted by infected/activated macrophages.

Different abilities of Friend murine leukemia virus (MuLV) and Moloney MuLV to induce promonocytic leukemia are due to determinants in both psi-gag-PR and env regions.

Moloney murine leukemia virus (M-MuLV) is capable of inducing promonocytic leukemia in 50% of adult BALB/c mice that have received peritoneal injections of pristane, but Friend MuLV strain 57 (F-MuLV) is nonleukemogenic under similar conditions. It was shown earlier that these differences could not be mapped to the U3 region of the virus long terminal repeat, indicating the probable influence of structural genes and/or R-U5 sequences. In this study, reciprocal chimeras containing exchanged structural genes and R-U5 sequences from these two closely related viruses were analyzed for differences in ability to induce disease. Results showed that two regions of F-MuLV, psi-gag-PR and env, when substituted for those of M-MuLV were dramatically disease attenuating. The 5'-most region, which is widely distributed, overlaps with the 5' end of the env intron and includes the RNA packaging region, psi, the entire gag coding region, and the viral protease coding region (PR) of pol. It was also found that reciprocal constructs having substitutions of both of these regions of M-MuLV in an F-MuLV background allowed full reestablishment of promonocytic leukemia. These leukemias were positive for c-myb rearrangements which are characteristic of M-MuLV-induced promonocytic leukemias. Neither region alone, however, was sufficient to produce disease with a greater incidence than 13%. Further studies demonstrated that the inability of viruses with psi, gag, PR, or env sequences from F-MuLV to induce leukemia in this model system was not due to their inability to replicate in hematopoietic tissue, to integrate into the c-myb locus early on after infection in vivo, or to express gag-myb mRNA characteristic of M-MuLV-induced preleukemic cells and acute leukemia.

Genetic control of retroviral disease in aging wild mice.

Different populations of wild mice (Mus musculus domesticus) in Los Angeles and Ventura Counties were observed over their lifespan in captivity for expression of infectious murine leukemia virus (MuLV) and murine mammary tumor virus (MMTV) and for the occurrence of cancer and other diseases. In most populations of feral mice these indigenous retroviruses were infrequently expressed and cancer seldom occurred until later in life (> 2 years old). MMTV was found in the milk of about 50% of wild mice, but was associated with only a low incidence (> 1%) of breast cancer after one year of age. By contrast, in several populations, most notably at a squab farm near Lake Casitas (LC), infectious MuLV acquired at birth via milk was highly prevalent, and the infected mice were prone to leukemia and a lower motor neuron paralytic disease after one year of age. These two diseases were both caused by the same infectious (ecotropic) strain of MuLV and were the principal cause of premature death in these aging LC mice. A dominant gene called FV-4R restricting the infection with ecotropic MuLV was found segregating in LC mice. Mice inheriting this FV-4R allele were resistant to the ecotropic MuLV associated lymphoma and paralysis. The FV-4R allele represents a defective endogenous MuLV provirus DNA segment that expresses an ecotropic MuLV envelope-related glycoprotein (gp70) on the cell surface. This FV-4R encoded gp70 presumably occupies the receptor for ecotropic MuLV and blocks entry of the virus. The FV-4R gene was probably acquired by the naturally occurring crossbreeding of LC feral mice with another species of feral mice (Mus castaneus) from Southeast Asia. The FV-4R gp70 does not block entry of the amphotropic MuLV that uses a separate cell surface receptor. Therefore LC mice continued to be susceptible to the highly prevalent but weakly lymphogenic and nonparalytogenic amphotropic strain of MuLV. The study points out the potential of feral populations to reveal genes associated with specific disease resistance.

Presence of transplantable T-lymphoid cells in C57BL/6 mice infected with murine AIDS virus.

The Duplan strain of murine leukemia virus induces murine AIDS in C57BL/6 mice. When spleen cells from C57BL/6 mice infected with the virus were transplanted into nude mice, subcutaneous solid tumors at the transplanted sites were formed and splenomegaly and lymphadenopathy were induced. These transplantable cells were Thy-1- CD4+ alpha-beta T-cell receptor-positive T cells and integrated with the pathogenic defective viral genome. These results indicate that neoplastic cells of T-cell lineage were induced by infecting C57BL/6 mice with murine AIDS virus.