Changes in expression of murine leukemia virus antigens and production of xenotropic virus in the late preleukemic period in AKR mice.

Abstract

We recently reported that thymocytes from 6-month-old preleukemic AKR mice express higher levels of murine leukemia virus (MuLV)related antigens than thymocytes from 2-month-old mice. We have now found that the level of xenotropic MuLV (defined operationally as MuLV able'to infect mink cell cultures) is also-markedly increased in thymus of 6-month-old AKR mice and that-this increase in virus correlates closely with increased MuLV-antigen expression. There is no increase of MuLV antigen or xenotropic virus in spleen or lymph nodes. Production of ecotropic MuLV remains unchanged with age in thymus, lymph nodes, and spleen. Thymic grafts from 6-month-old AKR mice, but not from 2-month-old mice, induce both amplified MuLV-antigen expression and xenotropic virus production in the thymus of young AKR recipients. Experiments with lethally irradiated AKR mice reconstituted with syngeneic bone marrow cells indicate that age-related changes in the thymus rather than in bone marrow precursor cells are responsible for MuLV-antigen amplification.The critical role of the thymus in murine leukemogenesis is well known (1). In many strains of mice with a high incidence of spontaneous leukemia, the thymus is the first site of recognizable disease, and thymectomy early in life prevents its development (2). The great majority of such leukemias have T-cell markers (3), indicating that these cells have undergone some phase of their differentiation in the thymic environment. The etiology of mouse leukemia is complex, with murine leukemia virus (MuLV) (4, 5), genetic factors that limit or facilitate virus or leukemia cell replication and spread (5, 6), and humoral factors presumably elaborated by thymic stromal cells (1, 7) each playing a role.Before the onset of leukemia, characteristic changes occur in the thymus of mice from the high-leukemia AKR strain: (a) the thymic cortex is reduced in size, and structures resembling lymphoid follicles and germinal centers may appear in the medulla (1); (b) the level of adenylate cyclase in the thymus increases (8); and (c) the thymocyte undergoes a marked change in the expression of certain cell surface antigens (9, 10). We have reported recently that starting at about 4-5 months, MuLVrelated antigens (GIx, GCSA, p3O, and gp7O) and H-2 alloantigens on thymocytes show a progressive increase, whereas the differentiation alloantigen Thy-i is reduced (9).The present study is a further analysis of the preleukemic changes occurring in AKR mice, with the following questions Abbreviations: MuLV, murine leukemia virus; anti-NTD, (W/Fu X BN)F1 anti-W/Fu leukemia (C58NT)D antiserum. t Present address:

A new class of murine leukemia virus associated with development of spontaneous lymphomas.

“…As expected from the large number of AKR thymic cells producing ecotropic virus (2), some of the mink cell lines yielded small amounts of XC-positive ecotropic virus, which had entered the mink cells as phenotypically mixed particles. This did not correlate with presence or absence of the CPE-type changes, and, once the mink-infectious viruses were established by cell-free passage, ecotropic virus was no longer detected.…”

“…The vacuolar membranes stain brilliantly for MuLV 789 Abbreviations: MuLV, murine leukemia virus; FA, fluorescent antibody; CPE, cytopathic effects; ME, mouse embryo; MCF, mink cell focus-inducing. (2). LN = lymph nodes, generally pooled axillary and mesenteric.…”

“…companied by any detectable change in the already high expression of ecotropic MuLV, but they correlate closely with emergence in thymus of MuLVs that have the capacity to infect mink cell cultures (2). Because this capacity is the hallmark of the xenotropic class of MuLV (3)(4)(5), we initially assumed that these isolates were xenotropic strains.…”

“…Because this capacity is the hallmark of the xenotropic class of MuLV (3)(4)(5), we initially assumed that these isolates were xenotropic strains. On further characterization, however, it became clear that many of the isolates are highly unique viruses in many respects and may represent recombinants between endogenous ecotropic and xenotropic MuLVs. MATERIALS AND METHODS As described in detail previously (2), MuLV strains capable of infecting heterotypic cells were tested for by plating mitomycin C-treated lymphoid cells as infectious centers on a mink lung cell line (ATCC no. CCL-64) (5).…”

“…The mink cell cultures so inoculated were maintained as cell lines and, at each passage, were tested for MuLV infection by the fluorescent antibody (FA) procedure. Culture conditions and details of the FA procedure were as described previously (2). Generally, if a line gave no FA staining after one or two transfers, it was discontinued.…”