Friend Murine Leukemia Virus Complex Research Articles

Cross-species infectivity and pathogenesis of the Friend murine leukemia virus complex in Syrian hamsters

To investigate cross-species infectivity and pathogenesis of Friend murine leukemia virus (MuLV) in hamsters, we infected newborn Syrian hamsters with ecotropic Friend MuLV that was passaged in BALB/c mice for approximately 30 years. During acute infection, 39.5% of newborn Syrian hamsters developed severe growth interruption and weight loss, spleen atrophy, severe lymphocyte depletion, and massive viral antigen loads in the spleen. The lymph nodes and thymuses were observed in all diseased hamsters. Ecotropic Friend MuLV was rescued from the sera and spleen and heart extracts of the diseased hamsters, and the same disease was confirmed by induction of erythroleukemia in BALB/c mice. Our results demonstrate that an ecotropic MuLV after extended passage in vivo to infect hamster cells that are resistant to infection by wild type MuLV, causing pathologic lesions and a wasting syndrome in newborn hamsters in vivo. This may occur with variants of Friend MuLV that have lower infectivity in hamster cells and are not cleared by the immune system of newborn hamsters. These findings suggest the potential danger of the interspecies transmission and pathogenesis of heterologous retroviruses in humans.

Passive immunotherapy for retroviral disease: influence of major histocompatibility complex type and T-cell responsiveness.

Administration of virus-specific antibodies is known to be an effective early treatment for some viral infections. Such immunotherapy probably acts by antibody-mediated neutralization of viral infectivity and is often thought to function independently of T-cell-mediated immune responses. In the present experiments, we studied passive antibody therapy using Friend murine leukemia virus complex as a model for an immunosuppressive retroviral disease in adult mice. The results showed that antibody therapy could induce recovery from a well-established retroviral infection. However, the success of therapy was dependent on the presence of both CD4+ and CD8+ T lymphocytes. Thus, cell-mediated responses were required for recovery from infection even in the presence of therapeutic levels of antibody. The major histocompatibility type of the mice was also an important factor determining the relative success of antibody therapy in this system, but it was less critical for low-dose than for high-dose infections. Our results imply that limited T-cell responsiveness as dictated by major histocompatibility genes and/or stage of disease may have contributed to previous immunotherapy failures in AIDS patients. Possible strategies to improve the efficacy of future therapies are discussed.

Characterization of monoclonal antibodies recognizing neurotropic Friend murine leukemia virus

We isolated a replication-competent, neurotropic retrovirus (FrC6 virus) and its molecular clone A8 from the NB-tropic Friend murine leukemia virus (FLV) complex. For detection and characterization of the FrC6 and A8 viruses, monoclonal antibodies (MAbs) against the FLV complex were established. Thirty MAbs, each of which reacted with the FLV-producing cell line, were tested for potential neutralizing activities; only two MAbs inhibited the proliferation of the A8 virus. These two MAbs were ineffective or had very weak neutralizing activities toward the non-neurotropic FLV strain clone 57 virus. Further characterization of MAbs by immunoprecipitation revealed that 4 MAbs recognized the envelope protein of the A8 virus. Two of these 4 MAbs recognized the surface glycoprotein gp70, requiring the conformational epitope of the virus for this recognition, while the other two MAbs, which were reactive with the transmembrane protein p15E, were conformation-independent Both of the MAbs against gp70 distinguished neuropathogenic and non-neuropathogenic viruses to some extent, through neutralizing activity or binding activity detected by immunoprecipitation, whereas the two MAbs against p15E reacted with the viruses in a similar manner. Furthermore, one of the MAbs distinguished the viral antigen in the wall of the vacuolation that composes the spongiotic lesion induced by FrC6 viral infection of the brain.

Influence of the murine MHC (H-2) on Friend leukemia virus-induced immunosuppression.

Friend murine leukemia virus complex (FV)-induced immunosuppression was studied by assaying splenic anti-SRBC PFC responses and plasma antibody titers in mice at various times after FV inoculation. Genes located within the H-2 complex were found to influence resistance to FV-induced immunosuppression. Near normal responses were observed in mice having the H-2a/b or H-2b/b genotype, whereas mice having the H-2a/a genotype were suppressed. This H-2 effect was observed not only in mice having heterozygous C57BL/10 X A background genes, including Rfv-3r/s, but also was apparent in mice having homozygous A-strain background genes, including Rfv-3s/s. Therefore, the Rfv-3 gene did not appear to convey resistance to FV-induced immunosuppression. The suppression in susceptible H-2a/a mice was characterized by a partial suppression of the IgM response and a profound suppression of both the primary and secondary IgG responses. Neither splenomegaly nor viremia alone appeared to be sufficient for the induction or maintenance of the immunosuppression. The mechanism of suppression was unclear, but both B lymphocyte and T lymphocyte functions appeared to be altered.

Spontaneous regression of friend virus-induced erythroleukemia—VIII. Humoral immune reactivity in regressed and leukemic mice

Mice infected with the RFV strain of the Friend murine leukemia virus complex (FV) develop an erythroleukemia that spontaneously regresses. Sera from regressed mice contain virus neutralizing activity and cytolytic activity for leukemic spleen cells and RFV-induced erythroleukemia cell lines. The virus neutralizing antibody in regressed sera is directed against antigens on viral gp70 and/or p15(E), while the cytolytic antibody is directed against antigens contained on gp70. p12 and possibly p15(E). Sera from 24% of regressed mice contain only neutralizing activity, 17% contain only cytolytic activity, 26% contain both and 33% contain neither activity. The failure to detect anti-RFV or cytotoxic antibody in one third of regressed mice suggests that humoral immunity does not play an important role in causing regression. Additionally, there was no correlation between the presence of cytolytic reactivity in the sera of viremic, leukemic mice and subsequent regression of the disease. However, neutralizing activity in regressed mice was associated with the absence of leukemia recurrence. Regressed mice with neutralizing titers of 1:80 or greater rarely redevelop leukemia, either spontaneously, or following reinoculation with RFV.

Spontaneous Regression of Friend Murine Leukemia Virus-Induced Erythroleukemia. IV. Effects of Radiation and Athymia on Leukemia Regression in Mice<xref ref-type="fn" rid="FN2">2</xref>

The spontaneous regression of the erythroleukemia induced by the regressing Friend murine leukemia virus (F-MuLV) complex was inhibited by irradiation of the animals prior to F-MuLV inoculation. This inhibition was proportional to the dose of radiation used. Treatment of the mice with the bone-seeking isotope 89Sr also inhibited erythroleukemia regression, which implicates the same effector mechanisms involved in the resistance to F-MuLV or F-MuLV-induced immunosuprression. Erythroleukemias induced in athymic nude mice by the regressing F-MuLV complex exhibited higher rates of lethality than did the leukemias in heterozygous or homozygous thymus gland-containing controls. These data suggested the involvement of the immune system in erythroleukemia regression and the specific participation of thymus cells and an 89Sr-susceptible function, perhaps marrow-dependent cells, in the process of regression.

Enhancement of Erythroid Target Cells for Friend Murine Leukemia Virus by Intravenous Pyran Treatment<xref ref-type="fn" rid="FN2">2</xref>

Male BALB/c mice that received prophylactic iv treatment with pyran had significantly enhanced splenomegaly, an increased number of splenic foci induced by the spleen focus forming virus (SFFV) in the Friend murine leukemia virus (F-MuLV) complex, and a slightly decreased mean survival time as compared with untreated controls infected with F-MuLV. A corresponding increase in the lymphatic leukemia virus component of the F-MuLV complex was not observed, which suggests that the enhancement of the disease was due primarily to a selective increase in the SFFV component of the F-MuLV complex. That the enhancement was related to an increased number of target cells for SFFV was substantiated by data concerning erythropoiesis in iv pyran-treated animals. Increases in splenic hematocrits and in uptake of 59Fe in the spleens of animals treated iv with pyran provided quantitative evidence for the histologic finding of increased erythroid precursors in the spleens.

Active immunotherapy of friend virus-induced erythroleukemia and its spontaneous regression

We have tested the effects of specific and nonspecific immunostimulation on the spontaneous regression and recurrence of erythroleukemia induced by a strain of the Friend murine leukemia virus complex, RFV. Subcutaneous inoculation of mice with UV-irradiated allogeneic leukemic spleen cells (LSC) protected against subsequent virus challenge. RFV-leukemic mice injected with LSC into subcutaneous BCG-primed sites had a significantly increased incidence of leukemia regression. When leukemic mice received BCG or LSC alone or normal allogeneic spleen cells (NSC) in place of LSC the incidence of regression was not different from that recorded in untreated controls. A single treatment of recently regressed mice with LSC given into BCG-primed sites prolonged the disease-free period, while LSC alone, BCG alone, or NSC had no such effect. Our data support an immunological basis for spontaneous regression of erythroleukemia and for maintenance of the regressed state. This system provides a model for testing the efficacy of immunotherapeutic protocols for maintenance of leukemia remission and tumor dormancy.

Mechanism of Genetic Resistance to Friend Virus Leukemia in Mice. V. Relevance of <italic>Fv-3</italic> Gene in the Regulation of in Vivo Immunosuppression<xref ref-type="fn" rid="FN1">2</xref>

Infection with the Friend murine leukemia virus complex (F-MuLV) suppressed humoral antibody synthesis in vivo and lymphocyte mitogenesis in vitro. Both these effects of F-MuLV were under host genetic control. In vitro suppression of lymphocyte mitogenesis was regulated by a single autosomal gene called Fv-3 that is dominant for susceptibility. Genetic analyses, with the use of the susceptible DBA/2 and resistant B10.D2/n parents, their F1, intercross, and backcross progeny, indicated that a single autosomal gene dominant for susceptibility regulated the in vivo susceptibility to immunosuppression by F-MuLV. Individual [(DBA/2xB10.D2)F1xB10.D2] mice were typed both for susceptibility to F-MuLV-induced suppression of lymphocyte mitogenesis in vitro (an Fv-3 function) and susceptibility to immunosuppression by F-MuLV in vivo. Such an analysis indicated that the same mice that were susceptible or resistant to immunosuppression in vivo were susceptible or resistant to suppression of lymphocyte mitogenesis in vitro. Spearman's rank analysis of the data also indicated that the in vivo and in vitro immunosuppressive effects of F-MuLV were correlated with and not independent of each other. Thus Fv-3, which regulates the effect of F-MuLV on lymphocytes in vitro, also appears to regulate the effect of F-MuLV on antibody-forming cells in vivo.

Effects of Thymectomy and Antithymocyte Serum on Spontaneous Regression of Friend Virus-Induced Erythroleukemia 2

To evaluate the role of immune response in regression of leukemia, we studied the effect of immunosuppression on the spontaneous regression of a leukemia induced by a specific strain of Friend murine leukemia virus complex (RFV). Thymectomy of newborn but not adult outbred Swiss mice markedly inhibited regression. The effect of antithymocyte serum (ATS) on regression depended on the timing of ATS treatment. Regression was markedly inhibited in leukemic mice given ATS just before the start of regression. During leukemia development, ATS treatment but not thymectomy potentiated splenomegaly and delayed the start of regression. Both ATS treatment and neonatal thymectomy increased mortality as a function of the decrease in disease regression. Treatment with normal rabbit serum also inhibited regression but, when given during leukemia development, affected neither the splenomegalic response to RFV nor the number of deaths. The data demonstrated that an intact immune system was required for leukemia regression and suggested that some thymus-dependent parameter of immune response was a major factor in regression.