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FEMS Microbiology Reviews Sep 2019Approximately 4.4% of the human genome is comprised of endogenous retroviral sequences, a record of an evolutionary battle between man and retroviruses. Much of what we... (Review)
Review
Approximately 4.4% of the human genome is comprised of endogenous retroviral sequences, a record of an evolutionary battle between man and retroviruses. Much of what we know about viral immunity comes from studies using mouse models. Experiments using the Friend virus (FV) model have been particularly informative in defining highly complex anti-retroviral mechanisms of the intrinsic, innate and adaptive arms of immunity. FV studies have unraveled fundamental principles about how the immune system controls both acute and chronic viral infections. They led to a more complete understanding of retroviral immunity that begins with cellular sensing, production of type I interferons, and the induction of intrinsic restriction factors. Novel mechanisms have been revealed, which demonstrate that these earliest responses affect not only virus replication, but also subsequent innate and adaptive immunity. This review on FV immunity not only surveys the complex host responses to a retroviral infection from acute infection to chronicity, but also highlights the many feedback mechanisms that regulate and counter-regulate the various arms of the immune system. In addition, the discovery of molecular mechanisms of immunity in this model have led to therapeutic interventions with implications for HIV cure and vaccine development.
Topics: Adaptive Immunity; Animals; Anti-Retroviral Agents; Friend murine leukemia virus; Host Microbial Interactions; Humans; Immunity, Innate; Immunotherapy; Mice; Retroviridae Infections
PubMed: 31087035
DOI: 10.1093/femsre/fuz012 -
Retrovirology Dec 2022Friend virus (FV) is a complex of the Friend murine leukemia virus (F-MuLV) and the replication-defective, pathogenic spleen focus forming virus (SFFV). In the past, we...
A detailed analysis of F-MuLV- and SFFV-infected cells in Friend virus-infected mice reveals the contribution of both F-MuLV- and SFFV-infected cells to the interleukin-10 host response.
BACKGROUND
Friend virus (FV) is a complex of the Friend murine leukemia virus (F-MuLV) and the replication-defective, pathogenic spleen focus forming virus (SFFV). In the past, we used a fluorescently labeled F-MuLV to analyze FV target cells. To build on these findings, we have now created a double-labeled FV that contains a Katushka-labeled F-MuLV and an mTagBFP-labeled SFFV, which we have used to study the infection by the two individual viruses in the FV infection of highly susceptible BALB/c mice.
RESULTS
Our data show that the target cells of SFFV largely mirror those of F-MuLV, with the highest virus loads in erythroblasts, B cells and myeloid cells. The early phase of infection was dominated by cells infected by either SFFV or F-MuLV, whereas double-infected cells became dominant later in the course of infection with increasing viral loads. In the late phase of infection, the frequency of double-infected cells was similarly high as the frequencies of SFFV or F-MuLV single-infected cells, and single- and double-infected cells outnumbered the uninfected cells in the most highly infected cell populations such as erythroblasts. FV and retroviruses in general have been shown to induce interleukin 10 (IL-10) as a means of suppressing immune responses. Interestingly, we found in infected IL-10-eGFP reporter mice that SFFV-infected cells contributed to the IL-10-producing cell pool much more significantly than F-MuLV-infected cells, suggesting that the truncated SFFV envelope protein gp55 might play a role in IL-10 induction. Even though BALB/c mice mount notoriously weak immune responses against FV, infection of mice with an ablation of IL-10 expression in T cells showed transiently lower viral loads and stronger T cell activation, suggesting that IL-10 induction by FV and by SFFV in particular may contribute to a suppressed immune response in BALB/c mice.
CONCLUSION
Our data provide detailed information about both F-MuLV- and SFFV-infected cells during the course of FV infection in highly susceptible mice and imply that the pathogenic SFFV contributes to immune suppression.
Topics: Mice; Animals; Friend murine leukemia virus; Spleen Focus-Forming Viruses; Interleukin-10; Leukemia, Experimental; Spleen; Mice, Inbred BALB C; Immunity
PubMed: 36527061
DOI: 10.1186/s12977-022-00613-4 -
Virologica Sinica Jun 2023Erythroleukemia belongs to acute myeloid leukemia (AML) type 6 (M6), and treatment remains difficult due to the poor prognosis of the disease. Friend virus (FV) is a...
Erythroleukemia belongs to acute myeloid leukemia (AML) type 6 (M6), and treatment remains difficult due to the poor prognosis of the disease. Friend virus (FV) is a complex of two viruses: Friend murine leukemia virus (F-MuLV) strain along with a defective spleen focus-forming virus (SFFV), which can induce acute erythroleukemia in mice. We have previously reported that activation of vagal α7 nicotinic acetylcholine receptor (nAChR) signaling promotes HIV-1 transcription. Whether vagal muscarinic signaling mediates FV-induced erythroleukemia and the underlying mechanisms remain unclear. In this study, sham and vagotomized mice were intraperitoneally injected with FV. FV infection caused anemia in sham mice, and vagotomy reversed this change. FV infection increased erythroblasts ProE, EryA, and EryB cells in the spleen, and these changes were blocked by vagotomy. In bone marrow, FV infection reduced EryC cells in sham mice, an effect that was counteracted by vagotomy. FV infection increased choline acetyltransferase (ChAT) expression in splenic CD4 and CD8 T cells, and this change was reversed by vagotomy. Furthermore, the increase of EryA and EryB cells in spleen of FV-infected wild-type mice was reversed after deletion of ChAT in CD4 T cells. In bone marrow, FV infection reduced EryB and EryC cells in sham mice, whereas lack of ChAT in CD4 T cells did not affect this change. Activation of muscarinic acetylcholine receptor 4 (mAChR4) by clozapine N-oxide (CNO) significantly increased EryB in the spleen but decreased the EryC cell population in the bone marrow of FV-infected mice. Thus, vagal-mAChR4 signaling in the spleen and bone marrow synergistically promotes the pathogenesis of acute erythroleukemia. We uncover an unrecognized mechanism of neuromodulation in erythroleukemia.
Topics: Mice; Animals; Leukemia, Erythroblastic, Acute; Friend murine leukemia virus; CD8-Positive T-Lymphocytes; Signal Transduction; Leukemia, Experimental
PubMed: 37172825
DOI: 10.1016/j.virs.2023.05.005 -
Journal of Virology Oct 1977Defective Friend spleen focus-forming virus (SFFV) is able to interfere with the ability of its naturally occurring leukemia-inducing helper virus (LLV-F) to induce XC...
Defective Friend spleen focus-forming virus (SFFV) is able to interfere with the ability of its naturally occurring leukemia-inducing helper virus (LLV-F) to induce XC plaque formation in several different strains of mouse embryo cells. This interference has been observed by using two different SFFV preparations, one contained in an NB-tropic stock of Friend virus (FV) complex, and the second present in a C57BL-adapted strain of FV complex containing an associated B-tropic LLV-F helper. The LLV-F in NB-tropic FV complex effectively induced XC plaques in C57BL/6 (Fv-1(bb); Fv-2(rr)) mouse embryo fibroblasts (MEF) only in the absence of coinfecting SFFV, indicating that Fv-2-associated resistance to SFFV-induced focus formation in vivo does not necessarily extend to the restriction of SFFV function(s) in vitro (i.e., in Fv-2(rr) C57BL MEF). SFFV interference appears to be an intracellular event since LLV-F can adsorb onto, penetrate, and rescue defective murine sarcoma virus (MSV) from transformed 3T3FL S(+)L(-) cells with equal efficiency in the presence and absence of SFFV. However, significantly fewer LLV-infected S(+)L(-) cells released LLV-F progeny if SFFV was present. These observations suggest that Friend SFFV may be classified as a defective, interfering (DI) particle. Further support for this conclusion has come from studies designed to investigate two physical properties of defective SFFV particles. SFFV layered onto a 0 to 20% sucrose sedimentation gradient was recovered as a symmetrical band of virus that sedimented more slowly than standard LLV-F particles. Pooled SFFV-containing gradient samples contained visualizable type C virus particles and occasionally small amounts of detectable LLV-F. In an attempt to determine the buoyant density of sedimentation gradient-purified SFFV, pooled SFFV samples were layered onto a 25 to 50% sucrose equilibrium density gradient and were centrifuged to equilibrium. Greater than 50% of the infectious SFFV originally layered onto this gradient was recovered and seen as a narrow symmetrical band with peak SFFV infectivity at a sucrose density of 1.14 g/ml. The observed difference between SFFV and LLV-F buoyant densities appears to be related to an inherent physical property of each virus. Mixtures of these two viruses express the buoyant density of that virus population which is in excess in fabricated FV complexes probably due to the formation of SFFV-LLV aggregates. Finally, gradient-purified SFFV failed to induce XC plaques in MEF and did not function to rescue MSV as expected since SFFV itself is replication defective.
Topics: Animals; Cell Line; Centrifugation, Density Gradient; Defective Viruses; Female; Friend murine leukemia virus; Helper Viruses; Male; Mice; Mice, Inbred Strains; Viral Interference
PubMed: 904028
DOI: 10.1128/JVI.24.1.383-396.1977 -
Proceedings of the National Academy of... Sep 1979The nature and distribution of sequences related to the murine erythroleukemia virus, Friend spleen focus-forming virus (SFFV), have been analyzed by using a radioactive...
The nature and distribution of sequences related to the murine erythroleukemia virus, Friend spleen focus-forming virus (SFFV), have been analyzed by using a radioactive cDNA probe specific for the SFFV genome (cDNA(sff)). From the proportion of high molecular weight viral [(32)P]RNA which hybridized to cDNA(sff), it was estimated that these sequences represent about 50% of the SFFV genome, indicating a genetic complexity of about 3300 nucleotides. cDNA(sff) hybridized extensively (80-95%) to SFFV virion RNA and to cellular RNA from murine and rat cells productively or nonproductively infected with SFFV. Only background homology was detected between cDNA(sff) and viral RNA from a number of murine [Friend murine leukemia virus (MuLV), Moloney-MuLV, and Kirsten sarcoma virus] and nonmurine (Rous sarcoma virus, feline leukemia virus, baboon endogenous virus, and Mason-Pfizer mammary tumor virus) retroviruses. Limited homology was also detected to a number of murine xenotropic and mink cell focus-inducing viruses (20-35%) as well as Rauscher leukemia virus (50%). Nucleotide sequences homologous to cDNA(sff) were also detected in the DNA of normal cells of several mouse strains as single or a few copies per cell. Thermal denaturation analysis indicated that duplexes formed between cDNA(sff) and normal DBA/2J cellular DNA have a reduction in melting temperature of 2 degrees C when compared with the dissociation of hybrids between cDNA(sff) and homologous sequences in SFFV-infected mouse spleen cell DNA. Examination of cellular RNA from uninfected mouse cells indicated that SFFV-related RNA sequences were also expressed in varying degrees in different tissues of adult DBA/2J mice. The highest amounts were observed in cells from bone marrow and spleen, whereas considerably lower amounts were found in cells from the thymus and kidney. No SFFV-related sequences could be detected in RNA extracted from liver, muscle, or fibroblasts. The presence of these SFFV-related sequences in normal, uninfected mouse cell DNA and their differential expression in hematopoietic tissues suggest that these sequences may be an integral part of the program of both normal and leukemic hematopoietic cell differentiation.
Topics: Animals; Base Sequence; Cell Line; DNA, Neoplasm; DNA, Viral; Friend murine leukemia virus; Genes, Viral; Leukemia, Experimental; Mice; Nucleic Acid Hybridization; RNA, Neoplasm; RNA, Viral
PubMed: 291976
DOI: 10.1073/pnas.76.9.4455 -
Blood Dec 2000
Review
Topics: Animals; Friend murine leukemia virus; Leukemia, Erythroblastic, Acute; Mice; Multigene Family; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-met; Receptors, Erythropoietin; Retroviridae Infections; Signal Transduction; Tumor Virus Infections; Viral Envelope Proteins
PubMed: 11090047
DOI: No ID Found -
Journal of Virology Jul 1976The factors that control oncornavirus formation were analyzed in Friend leukemia cells that undergo hematopoiesis when treated with dimethyl sulfoxide. Suspension...
The factors that control oncornavirus formation were analyzed in Friend leukemia cells that undergo hematopoiesis when treated with dimethyl sulfoxide. Suspension cultures of Ostertag FSD-1 cell line were found to enter a G or resting state at the end of their proliferative phase and to simultaneously cease producing helper and dependent components of Friend virus. Whereas the decline in virus production is at least 100-fold, rates of cellular RNA and protein synthesis are only slightly lower in resting than in growing cells. Both resting and growing cells contain similarly large concentrations of the viral proteins P(30) and P(12). Dimethyl sulfoxide induces hemoglobin synthesis in growing cells, but its effects on virus production appear to be indirect results of its action to inhibit cell growth and thus to delay entry of cells into the G resting state. Furthermore, variant cell lines were obtained with differing abilities to synthesize virus or hemoglobin. Some lines no longer produce infectious virus, although they all harbor murine leukemia virus genes which are expressed to varying extents. The major internal protein of these oncornaviruses, P(30), is synthesized in large amounts by all of the cell lines. These results suggest that Friend virus production is not coinduced with erythroid differentiation, as had been proposed, but rather is controlled by a cellular growth cycle.
Topics: Cell Division; Cell Line; DNA, Neoplasm; Dimethyl Sulfoxide; Friend murine leukemia virus; Genetic Variation; Helper Viruses; Hemoglobins; Leukemia, Erythroblastic, Acute; Viral Proteins; Virus Replication
PubMed: 1065778
DOI: 10.1128/JVI.19.1.118-125.1976 -
Journal of Virology Nov 1994The FIS variant is a weakly leukemogenic, relatively strong immunosuppressive murine retrovirus which was isolated from the T helper cells of adult NMRI mice infected...
The FIS variant is a weakly leukemogenic, relatively strong immunosuppressive murine retrovirus which was isolated from the T helper cells of adult NMRI mice infected with Friend murine leukemia virus (F-MuLV) complex (FV). Unlike FV, it does not induce acute erythroleukemia but retains the immunosuppressive property of FV and induces suppression of the primary antibody response rapidly and persistently in adult mice. A previous study showed that the FIS variant contains two viral components, a replication-competent virus and a defective virus. In this study, we have biologically purified the FIS variant by end point dilution and we show that the replication-competent virus FIS-2 alone can induce immunosuppression as the parental FIS variant. Most newborn mice infected with FIS-2 developed erythroleukemia, but with an increased latency period compared with that of F-MuLV clone 57. In contrast, FIS-2 induced suppression of the primary antibody response and disease more rapidly than F-MuLV clone 57 in immunocompetent, adult mice. FIS-2 was further molecularly cloned and characterized. Restriction mapping and nucleotide sequence analysis of FIS-2 showed a high degree of homology between FIS-2 and F-MuLV clone 57, suggesting that FIS-2 is a variant of F-MuLV. The striking difference is the deletion of one of the tandem repeats in the FIS-2 long terminal repeat and the single point mutation in the binding sites for core-binding protein and FVa compared with the long terminal repeat of F-MuLV clone 57. Two single point mutations led to the appearance of two extra potential N glycosylation sites in the FIS-2 gag-encoded glycoprotein. Together, the results suggest that FIS-2 represents an interesting murine model to study retrovirus-induced immunosuppression on the basis of its unique combined property of low leukemogenicity and relatively strong and persistent immunosuppressive activity in adult mice.
Topics: 3T3 Cells; Amino Acid Sequence; Animals; Base Sequence; Cloning, Molecular; Female; Friend murine leukemia virus; Gene Products, gag; Immune Tolerance; Leukemia, Experimental; Mice; Molecular Sequence Data; Repetitive Sequences, Nucleic Acid; Retroviridae Infections; Tumor Virus Infections; Viral Envelope Proteins; Virus Replication
PubMed: 7933079
DOI: 10.1128/JVI.68.11.6976-6984.1994 -
Journal of Virology Nov 2008Several members of the apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like complex 3 (APOBEC3) family in primates act as potent inhibitors of retroviral...
Several members of the apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like complex 3 (APOBEC3) family in primates act as potent inhibitors of retroviral replication. However, lentiviruses have evolved mechanisms to specifically evade host APOBEC3. Likewise, murine leukemia viruses (MuLV) exclude mouse APOBEC3 from the virions and cleave virion-incorporated APOBEC3. Although the betaretrovirus mouse mammary tumor virus has been shown to be susceptible to mouse APOBEC3, it is not known if APOBEC3 has a physiological role in restricting more widely distributed and long-coevolved mouse gammaretroviruses. The pathogenicity of Friend MuLV (F-MuLV) is influenced by several host genes: some directly restrict the cell entry or integration of the virus, while others influence the host immune responses. Among the latter, the Rfv3 gene has been mapped to chromosome 15 in the vicinity of the APOBEC3 locus. Here we have shown that polymorphisms at the mouse APOBEC3 locus indeed influence F-MuLV replication and pathogenesis: the APOBEC3 alleles of F-MuLV-resistant C57BL/6 and -susceptible BALB/c mice differ in their sequences and expression levels in the hematopoietic tissues and in their abilities to restrict F-MuLV replication both in vitro and in vivo. Furthermore, upon infection with the pathogenic Friend virus complex, (BALB/c x C57BL/6)F(1) mice displayed an exacerbated erythroid cell proliferation when the mice carried a targeted disruption of the C57BL/6-derived APOBEC3 allele. These results indicate, for the first time, that mouse APOBEC3 is a physiologically functioning restriction factor to mouse gammaretroviruses.
Topics: Amino Acid Sequence; Animals; Cell Line; Cytidine Deaminase; Disease Susceptibility; Female; Friend murine leukemia virus; Gene Expression Profiling; Leukemia, Experimental; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Molecular Sequence Data; Mutagenesis, Insertional; Polymorphism, Genetic; Retroviridae Infections; Sequence Alignment; Tumor Virus Infections; Virus Replication
PubMed: 18786991
DOI: 10.1128/JVI.01311-08 -
Immunologic Research Mar 2013Major conceptual roadblocks impede the development of an HIV-1 vaccine that can stimulate a potent neutralizing antibody response. Animal models that support HIV-1... (Review)
Review
Major conceptual roadblocks impede the development of an HIV-1 vaccine that can stimulate a potent neutralizing antibody response. Animal models that support HIV-1 replication and allow for host genetic manipulation would be an ideal platform for testing various immunological hypotheses, but progress on this research front has been slow and disappointing. In contrast, many valuable concepts emerged from more than 50 years of studying the Friend retrovirus model. This was recently exemplified by the identification of an innate restriction gene, Apobec3, that could promote the retrovirus-specific neutralizing antibody response. Here we review both classical and recent data on humoral immunity against Friend retrovirus infection, and highlight the potential of this model for unraveling novel aspects of the retrovirus-specific antibody response that may guide HIV-1 vaccine development efforts.
Topics: Animals; Disease Models, Animal; Friend murine leukemia virus; Humans; Immunity, Humoral; Retroviridae Infections
PubMed: 22961660
DOI: 10.1007/s12026-012-8370-y