Identification of a non-H-2 gene (Rfv-3) influencing recovery from viremia and leukemia induced by Friend virus complex (murine leukemia virus/erythroleukemia/immune response genes/H-2 and non-H-2 gene interactions)

The dominant C57BL/10 allele of a single, autosomal, non-H-2 gene (Rfv-3) was found to be required for recovery from viremia and leukemia induced by Friend virus complex in H-2bI b mice. In H-2 a/ a mice, the Rfv-3 gene apparently influenced recovery from viremia in the presence of persistent leukemia because these mice lacked the appropriate H-2 genotype for recovery from leukemia. The Rfv-3 gene was distinct from the Fv-2 gene because recovery from viremia was seen in recombinant-inbred mice with the Fv-2s/s genotype. Furthermore, backcross studies indicated that Rfv-3 and Fv-2 were not linked. The Rfv-3 gene may act by influencing the specific anti-FV humoral antibody response. Friend virus complex (FV) induces the rapid onset of an erythroleukemia in the spleen, bone marrow, blood, and liver of both newborn and adult mice of many strains (1, 2). A number of host genes influence the course of the disease (3). In particular, genes of the major histocompatibility complex (H-2) play a major role in controlling the incidence of spontaneous recovery from established leukemia. The H-2b/b genotype is associated with a high recovery incidence compared to the H-2b/d genotype. This finding was originally demonstrated by Lilly (4) in a backcross population [(C57BL X BALB/c)F1 X C57BL]. Surprisingly, our initial attempts to observe recovery from FV leukemia in inbred strains with the H-2b/b genotype were unsuccessful. The A-BY and BALB.B strains (both H-2 b/b) failed to recover from FV-induced leukemia (5). The C57BL/10 strain (H-2b/b) could not be tested because the presence of the Fv-2r/r genotype in these mice prevented FV-induced splenomegaly (6,7). Only after A.BY or BALB.B mice were crossed with the C57BL/10 strain did we observe a high recovery incidence (5) similar to what had been reported originally by Lilly (4). We surmised that some essential non-H-2 genes from the C57BL/10 strain were present in both the backcross mice and the F1 hybrids and allowed the expression of the H-2b/b-associated recovery trait. Initial studies to look for evidence of these non-H-2 genes in (C57BL/10 X BALB.B)F1 X BALB.B backcross mice (all H2b/b) suggested that BALB.B mice lacked three or more nonH-2 genes present in C57BL/10 mice that were necessary for the H-2b/b recovery effect (8). However, in the H-2b/b backcross involving A.BY mice, (C57BL/10 X A.BY)F1 X A.BY, we found that the dominant C57BL/10 allele of a single, autosomal, non-H-2 gene was necessary for H-2b/b-associated recovery from FV leukemia (9). In our previous studies (8) of FV-induced leukemia, we also noted that several different F1 hybrid strains were able to recover from the viremia 30-40 days after FV inoculation (8). Nevertheless, many of these mice had progressive leukemia resulting ultimately in death. Recovery from FV viremia was independent of H-2 type and occurred only in F1 mice that had The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate this fact. 425 C57BL/10 or a C57BL/10 congenic strain (B1O.A or B1O.D2) as one of the parents; it did not occur in (BALB/c X A)F1 mice (8). This observation suggested that non-H-2 genes derived from the C57BL/10 mouse were involved in the phenomenon of recovery from FV viremia. In order to study recovery from FV viremia independently of the H-2 effect on recovery from leukemia, we have examined two congenic backcross populations in which genes other than H-2 were segregating. The results indicated that, in H-2a/a mice, a single non-H-2 gene aappeared to control the recovery from FV viremia in the presence of ongoing leukemia. In H2b/b mice, a single non-H-2 gene also appeared to control recovery from FV viremia, and furthermore there was a strong correlation between recovery from viremia and recovery from leukemia. Thus, the same non-H-2 gene appeared to be responsible for recovery from.both viremia and leukemia in the H-2b/b population and for recovery from viremia in the presence of leukemia in the H-2a/a population. MATERIALS AND METHODS Mice. A/WySn (H-2a/a, Fv2s/s), A.BY (H-2b/b, Fv25/S), C57BL/lOSn (H-2b/b, Fv-2r/r), B1O.A (H-2a/a, Fv 2r/r), and the C X B (10, 11) mouse strains were obtained from the Jackson Laboratory and from Jack Stimpfling (McLaughlin Research Institute, Great Falls, MT). F1 hybrids and backcross mice were bred at the Rocky Mountain Laboratory. BALB.B mice (H-2b/b, Fv-2s/s) were from our own colony and were originally obtained from Frank Lilly (Albert Einstein College of Medicine, Bronx, NY). Spleen Palpation. Mouse spleen size was determined by palpation during ether anesthesia as described (5). An increase in spleen size of 3to 4-fold (>0.4 g) could be detected reliably in this fashion. Mice with enlarged spleens were considered to be leukemic, and persistence of this condition invariably resulted in death. Virus. The B-tropic strain of FV was used in all experiments. Virus was propagated, assayed, and stored as described (5). Mice were bled from the tail or orbit into heparinized tubes, and plasma was assayed for the helper lymphatic leukemia virus (LLV) component of FV on S+Lcells as described (12). The spleen focus-forming virus (SFFV) component of FV was assayed by spleen palpation of BALB.B, BALB/c, or (B1O.D2 X BALB/c)F1 mice inoculated intravenously with 0.5 ml of a 1:70 dilution of plasma in phosphate-buffered balanced salt solution. Mice with normal spleen size at 50 or more days after inoculation were scored as negative. Preliminary experiments indicated that as few as 0.1 spleen focus-forming unit (FFU) of virus could be detected reliably by this method (data not shown). In all the mouse strains we studied there was a strong correlation Abbreviations: FV, Friend virus complex; LLV, lymphatic leukemia virus; SFFV, spleen focus-forming virus; FFU, focus-forming unit(s). 426 Genetics: Chesebro and Wehrly between plasma SFFV and plasma LLV. Of 248 mice tested for both viruses, 106 had detectable SFFV (>14 FFU/ml plasma) and plasma LLV greater than 103 PFU/ml. Of the 142 mice negative for plasma SFFV, 17 (12%) had plasma LLV greater than 103 PFU/ml. Therefore, we have reported only plasma LLV data in the results to follow.