Persistence and pathogenicity of defective Friend spleen focus-forming virus. Decreased transplantability of hemopoietic cells as a marker for preleukemic change.

Abstract

A latent form of persistent infection can be established in susceptible adult mice inoculated with a preparation of defective Friend spleen focus-forming virus (SFFV) purified free from standard leukemia-inducing helper virus (LLV-F). SFFV persistence was initially observed using an in vivo rescue technique in which SFFV could be directly rescued to form splenic foci of malignant erythropoiesis in mice. At approximately 30 d after virus inoculation however, SFFV could not be rescued after inoculation of LLV-F indicating that persistently infected (i.e., SFFV+) mice were either immume to exogenous helper virus or able to express SFFV-associated defective-interfering (DI) function(s). Persistent infection by SFFV was further documented using an in vitro rescue technique and ultimately resulted in the induction by SFFV of erythroleukemia in the absence of polycythemia or overt virus production. However, SFFV rescued by LLV-F from persistently infected normal and transformed hemopoietic cells was able to induce polycythemia in adult mice suggesting that this is a helper controlled property of the Friend virus complex. Transplantable SFFV-induced erythroleukemic cells could be retrieved from persistently infected yet histologically normal mice. The duration of SFFV persistence in normal spleen tissue suggests that the SFFV provirus resides in either a long-lived or pluripotent hemopoietic cell. Further, certain changes occurred, presumably in the membranes of persistently infected cells, which preceded the overt development of Friend leukemia and facilitated the definition of an SFFV preleukemic phase. Cell surface alterations were revealed using cell transfer techniques. Hemopoietic cells harboring a rescuable SFFV failed to proliferate when inoculated into lethally irradiated, syngeneic adult mice. In contrast, the transformed progeny of preleukemic cell populations and spleen cells transformed by FV complex (i.e., cells replicating both SFFV and LLV-F) were not rejected. This result suggests that histologically normal SFFV+ preleukemic cells express an antigen recognition site which is not present on overtly transformed cells and which may be a pertinent surveillance target for host anti-leukemogenic reactions.

Natural killer cell suppression of Friend virus-induced preleukemic hemopoietic stem cells

“…We have previously shown SFFVp-induced alterations of hemopoietic stem cell frequency and function (10)(11)(12). Mice reconstituted with serially transplanted stem cells can survive for .8 months free of disease.…”

“…Thomsen et al (45) have demonstrated that NK cell activation following lymphocytic choriomeningitis virus infection is associated with the acquired ability of mice to inhibit the growth of syngeneic pluripotent hemopoietic spleen colony-forming stem cells (CFUs). The decreased transplantability of syngeneic CFUs latently infected with replication-defective Friend polycythemia-inducing spleen focus-forming virus (SFFVp) is a hallmark of preleukemic change (10). Multistage Friend disease can be induced by helper-free SFFVp in leukemiasensitive (Fv-2ss) B6.C hosts (C57BL/6-H-7b [47N] congenic with C57BL/6 at Fv-2 [4,10,50]) and is characterized by early effects upon erythroid progenitor cells (30) followed * Corresponding author.…”

“…The decreased transplantability of syngeneic CFUs latently infected with replication-defective Friend polycythemia-inducing spleen focus-forming virus (SFFVp) is a hallmark of preleukemic change (10). Multistage Friend disease can be induced by helper-free SFFVp in leukemiasensitive (Fv-2ss) B6.C hosts (C57BL/6-H-7b [47N] congenic with C57BL/6 at Fv-2 [4,10,50]) and is characterized by early effects upon erythroid progenitor cells (30) followed * Corresponding author. weeks later by the evolution of transplantable and often culturable FV-induced tumors (10,34,49,50).…”

“…Multistage Friend disease can be induced by helper-free SFFVp in leukemiasensitive (Fv-2ss) B6.C hosts (C57BL/6-H-7b [47N] congenic with C57BL/6 at Fv-2 [4,10,50]) and is characterized by early effects upon erythroid progenitor cells (30) followed * Corresponding author. weeks later by the evolution of transplantable and often culturable FV-induced tumors (10,34,49,50). The NK cell deficiency in 89Sr-treated C57BL/6 (+/+) mice (17) and the partial abrogation of potent Fv-2-determined (31,37) leukemia resistance suggest that NK cell effectors are responsible for the rejection of SFFVp-induced preleukemic stem cells.…”

Integration of spleen focus-forming virus proviruses in Friend tumor cells

“…Biological and molecular studies have demonstrated that spleen focus-forming virus (SFFV) is directly responsible for the enhanced proliferation of the erythroid cells in the first step of Friend leukemia (6,9,11). Whether the SFFV genome is also implicated in late malignant erythroid cell transformation has been suggested only by previous studies (4,24). In addition, in this late transformation process an eventual role played by the ecotropic F-MuLV cannot be excluded, even though F-MuLV alone provokes (in certain cases only) late erythroid leukemias after a latency exceeding 3 to 4 months (2, 15).…”