Proc. Natl. Acad. Sci. USA Vol. 76, No. 1, pp. 425-429, January 1979 Genetics

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)

BRUCE CHESEBRO AND KATHY WEHRLY Rocky Mountain Laboratory, National Institute of Allergy and Infectious Diseases, Hamilton, Montana 59840

Communicated by Hugh 0. McDevitt, October 26,1978

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.

ABSTRACT 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

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 3- to 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+L- cells 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

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Abbreviations: FV, Friend virus complex; LLV, lymphatic leukemia virus; SFFV, spleen focus-forming virus; FFU, focus-forming unit(s).

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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.

RESULTS Recovery from FV Viremia in the Presence of Leukemia in H-2a/l Mice. A/WySn mice were found to have a high incidence of viremia (82%) and leukemia (91%) 30-50 days after FV inoculation (Table 1). However, at this same time after virus inoculation (B1O.A X A/WySn)Fl mice had a low incidence of viremia (12%), even in the presence of ongoing leukemia (92%). Because it appeared that genes derived from the B1O.A parent of this F1 influenced the recovery from FV viremia, a backcross population, (BIO.A X A/WySn)Fl X A/WySn, was studied to determine how many genes were involved. Eightyeight percent of the backcross mice had enlarged spleens indicative of persistent leukemia 35 days after FV inoculation. This was expected because, due to their H-2a/a genotype, both of the parents of the backcross had a high incidence of leukemia. However, only 109 of 219 mice (50%) were still viremic at this time; 110 mice had recovered from viremia. The data strongly suggested that a single non-H-2 gene controlled the trait of recovery from FV viremia in this backcross. B1O.A mice appeared to have the allele associated with recovery from viremia, and in the F1 this B1O.A allele was dominant over the A/WySn allele which was associated with lack of recovery from viremia.

Recovery from FV Viremia in H-2b/b Mice. In H-2b/b mice, similar results on recovery from FV viremia 30-50 days after FV inoculation were seen (Table 1). A.BY mice had a high incidence of viremia (82%) and (C57BL/10 X A.BY)F1 mice had a low incidence of viremia (15%). C57BL/10-derived non-H-2 genes appeared to influence recovery from FV viremia in this F1 hybrid also. Therefore, this F1 was backcrossed to A.BY to determine the number of C57BL/10 genes involved: 73 of 169 (43%) of (C57BL/10 X A.BY)F1 X A.BY backcross mice were viremic 30-50 days after FV inoculation. These data indicated that in the H-2b/b backcross a single non-H-2 gene controlled recovery from FV viremia. Because the original H-2a/a and H_2b/b mice used in these experiments were conTable 1. Incidence of leukemia and viremia 30-50 days after FV inoculation Mouse strain* Leukemic/totalt Viremic/totalt In H-2a/a mice

A/WySn

10/11 (91%)

9/11(82%)

(B10.A X A/WySn)Fl 47/52 (92%) 6/52 (12%) (B1O.A X A/WySn)Fl X A/WySn 192/219 (88%) 109/219 (50%)§ In H-2b/b mice

A.BY

(C57BL/10 X A.BY)F1 (C57BL/10 x A.BY)F1 X A.BY *

49/57 (86%) 47/57 (82%) 16/59 (27%) 9/59 (15%) 102/169 (60%) 73/169 (43%)l

genic pairs differing only for genes at or near the H-2 locus (C57BL/10 and BLO.A; A.BY and A/WySn), the single non-H-2 genes that influenced recovery from viremia in H-24/a and

H-2b/b backcross populations probably were identical. Correlation of Recovery from FV Viremia and Leukemia in H_2b/b Mice. We previously showed (9) that the C57BL/10 allele of a single non-H-2 gene was necessary for H-2b/b-associated recovery from FV leukemia in the (C57BL/10 X A.BY)F1 A.BY (H_2b/b) backcross population. We wanted to determine whether recovery from FV viremia and recovery from FV leukemia were controlled by the same non-H-2 gene in this backcross. The A.BY parents of the backcross had a high incidence of leukemia (86%), and the (C57BL/10 X A.BY)F1 parents of the backcross had a low incidence of leukemia (27%) (Table 1). Because all mice had splenic leukemia cell colonies 9 days after FV inoculation (8), absence of leukemia at 30-50 days after virus inoculation represented recovery from leukemia rather than decreased susceptibility to leukemogenesis. In agreement with previous results (9), 102 of 169 (60%) H_2b/b backcross mice were still leukemic 30-50 days after FV inoculation. There was an excellent correlation between viremia and leukemia in this population (Table 2): 68 of 73 (93%) viremic mice had persistent leukemia. This group was similar to the A.BY parent of the backcross (high percentages of viremia and leukemia): 34 of 96 (35%) nonviremic mice had persistent leukemia. This group of mice appeared to behave in a manner similar to the (C57BL/10 X A.BY)F1 parent of the backcross which had a low incidence of viremia (15%) with a significantly higher incidence of leukemia (27%). The strong correlation between recovery from viremia and recovery from leukemia seen in the H-2b/b backcross indicated that this same non-H-2 gene was involved in facilitating both these recovery effects. Therefore, we have tentatively named this gene Rfv-3 (recovery from Friend virus, no. 3) because it X

is the third gene described which influences recovery from

FV-induced leukemia (13). Progeny Testing of Second and Third Backcrosses to ABY. In order to substantiate further the fact that a single non-H-2 gene (Rfv-3) was responsible for the effects on recovery from viremia and leukemia observed in the backcross populations, mice from the first backcross to A.BY were further analyzed for Rfv-S genotype by progeny testing of the offspring obtained when these mice were backcrossed a second time to A.BY mice. If these first backcross mice had the Rfv-38/ genotype, all the progeny from the second backcross to A.BY (Rfv-38s) should be leukemic and viremic (Rfv-3'8). If the first backcross mice had the Rfv-32/r' genotype, progeny from the second backcross to A.BY should be 50% Rfv-3818 (leukemic and viremic) and 50% Rfv-3/r (nonleukemic and nonviremic). Litters were obtained from nine female first-backcross mice. These mice Table 2. Correlation of viremia and leukemia in (C57BL/10 X A.BY)F1 X A.BY (H-2bl/b) backcross mice 30-50 days after FV inoculation Viremic* Not viremic

Mice were inoculated intravenously with 150 FFU of FV.

Not leukemic Leukemict

5 68t

levels were usually very high (>104 PFU/ml) or very low (103 PFU/ml plasma). Plasma LLV

102-104 PFU/ml.

§ Seventeen of the 219 backcross mice died from leukemia earlier than 30 days after FV inoculation and were scored as viremic. I Nineteen backcross mice died from leukemia earlier than 30 days after FV inoculation and were scored as viremic.

62 34 96

* LLV viremia 2103 PFU/ml plasma.

t Dead mice and mice with splenomegaly were scored as leukemic.

Nineteen mice died from leukemia earlier than 30 days after FV inoculation and were scored as viremic.

Genetics: Chesebro and Wehrly Table 3. Segregation of recovery from FV leukemia and viremia in progeny of second A.BY backcross generation First A.BY backcross mothers Progeny from second (C57BL/10 X A.BY)F1 X A.BY backcross to A.BY Rfv-3 genotype by Leukemic/ Viremic/ Mouse progeny test* totalt total$ 3031 Ws/s 3/3 (100%) ND 3032 s/s 12/13 (92%) 4/5 (80%) 2759 r/s 2/9 (22%) 0/3 (0%) 2764 r/s 6/10 (60%) 4/10 (40%) 2769 r/s 10/21 (48%) 6/14 (43%) 3030 rls 6/10 (60%) 1/2 (50%) 3033 r/s 12/22 (55%) 6/14 (43%) 3034 r/s 0/4 (0%) ND 3094 rls 4/13 (31%) 3/6 (50%) * Observed incidence of leukemia and viremia in each group was compared by the x2 test to the expected incidence for the Rfv-3s/s genotype and the Rfv-3r/s genotype. Mother of progeny that could not be definitively typed on a statistical basis is indicated by a question mark before the suspected genotype. I Dead mice and mice with splenomegaly were scored as leukemic at 50-60 days after FV inoculation. Mice were bled at 50-60 days after FV inoculation, and plasma was tested for LLV viremia (2103 PFU/ml). ND, not done.

were inoculated with FV at 12 weeks of age and were followed for recovery from splenomegaly and FV viremia (Table 3). The litters from two individual mothers (mice 3031 and 3032) were nearly 100% leukemic by palpation. Thus, these mothers had the Rfv-3s/s genotype. Progeny from seven other mothers ranged from 0-60% leukemic and 0-50% viremic 50 days after FV inoculation. These values were not significantly different from the expected value of 50% for progeny of mothers with the Rfv-3'/r genotype. A third backcross to A.BY was also studied, and similar results were obtained (Table 4). Second-backcross females were randomly selected as mothers from the litters of first-backcross mice shown to have the Rfv-3 /s genotype by progeny testing (Table 3). Third-backcross litters were obtained from eight

mice. Progeny testing indicated that one second-backcross mother had the Rfv-3s/s genotype (mouse 3296), two mothers were not conclusively typed (mice 3294 and 3438), and the remaining five were Rfv-3/rs. Linkage Data for Rfv-3 Gene. So far we have no information linking the Rfv-3 gene to any known genetic markers in the mouse. Rfv-3 was not observed to be linked to sex, coat color

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traits (albino, black, agouti), or the Ig-1 locus (14, 15) segregating in the backcrosses studied (data not shown). Because the H-2 types of mice in each backcross were identical, we could not look for linkage to H-2. However, it is doubtful that close linkage to H-2 exists because both congenic pairs of mouse strains differing at H-2 did not differ for Rfv-3 (i.e., C57BL/10 vs. B10.A and A.BY vs. A/WySn). We have also attempted to clarify the possible role of the Fv-2 gene (6, 7) in recovery from FV viremia and leukemia. The mice in our experiments had either the Fv-2818 genotype (A/WySn and A.BY) or the Fv-2s/r genotype [(B10.A X A/ WySn)Fl and (C57BL/10 X A.BY)Ff]. Thus, in the backcross populations one would expect an equal distribution of Fv-281/ and Fv-2s/r genotypes. Fv-2s/s is not known to be different from Fv-2s/?, because the Fv-28 allele is dominant for suscep-

tibility to FV-induced spleen foci and splenomegaly. Nonetheless, it is possible that these two genotypes might differ with regard to their influence on other aspects of FV leukemia, such as recovery from viremia.

In order to check for possible linkage or identity between the Fv-2 and Rfv-3 genes, we determined the Fv-2 genotype of Rfv-3r/s mice from the second backcross to A.BY (Table 3) by crossing these mice with C57BL/10 mice (Fv-2r/r, Rfv-3r/r). If the Rfv-3s/r parent had the Fv-2s/r genotype (i.e., identity

or close linkage between Rfv-3 and Fv-2), the progeny from the cross with C57BL/10 (Fv-2r/r) would be 50% susceptible to spleen foci (Fv-2s/T) and 50% resistant (Fv-2r/r). On the other hand, if the Rfv3sl/r parent had the Fv-2818 genotype (i.e., lack of close linkage or identity between Rfv-3 and Fv-2), the progeny from the cross with C57BL/10 would be 100% susceptible to FV spleen foci (Fv-2s/r). Progeny were obtained from seven Rfv-3l/s mice mated to C57BL/10. The offspring from six of these parents had a 100% incidence of spleen foci 9 days after FV inoculation (data not shown). Thus, these six Rfv-3-/s mice had the Fv-2/sl genotype, and Rfv-3 and Fv-2 appeared to be distinct unlinked genes. We also studied C X B recombinant-inbred mice (10, 11) with the Fv-2/sl genotype. The results indicated that two of the Fv-2s/s C X B strains (C X BE and C X BK) recovered from FV viremia as did the comparable Fv-28/r hybrid (C57BL/10 X BALB.B)F1 (Table 5). Thus, because Fv-2 did not appear to be important in influencing recovery from viremia in the C X B mice, it is unlikely that Fv-2 is the gene responsible for segregation of the recovery from viremia seen in the (C57BL/10 X A.BY)F1 X A.BY or (B10.A X A/WySn)Fl X A/WySn backcross populations.

Table 4. Segregation of recovery from FV leukemia and viremia in progeny of the third A.BY backcross generation First A.BY backcross Second A.BY backcross Progeny from third backcross mother mother to A.BY Mouse Rfv-3 genotype* Mouse Rfv-3 genotype* Leukemic/totalt Viremic/totalt 2759 ?s/s r/s 3294 11/14 (79%) 10/14 (71%) 2759 r/s 3296 s/s 9/11 (82%) 11/11 (100%) 2769 r/s 3434 r/s 7/13 (54%) 7/13 (54%) 2769 r/s 406 r/s 1/6 (17%) 1/6 (17%) 3030 r/s 3438 Ws/s 6/8 (75%) 5/8 (62%) 3030 r/s 3440 r/s 8/14 (57%) 7/14 (50%) 3030 r/s 3441 r/s 1/8 (12%) 1/8 (12%) 3094 r/s 409 r/s 2/4 (50%) 0/4 (0%) * Observed incidence of leukemia and viremia in each group was compared by the x2 test to the expected incidence for the Rfv-33/S genotype and the Rfv-3r/s genotype. Mothers of progeny that could not be definitively typed on a statistical basis are indicated by a question mark before the suspected genotype. t Dead mice and mice with splenomegaly were scored as leukemic at 50-60 days after FV inoculation. Mice were bled at 50-60 days after FV inoculation, and plasma was tested for LLV viremia (2103 PFU/ml).

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Table 5. Incidence of leukemia and viremia 30-50 days after FV inoculation in four C X B mouse strains

Leukemic/

Mouse strain*

H-2t Fv-2t

Viremic/ totalt 22/22 (100%) 10/10 (100%) totalt

BALB.B b/b s/s (C57BL/10 X BALB.B)F1 b/b sir 14/20 (70%) 2/10 (2096) C X BE b/b s/s 4/19 (21%) 0/12 (0%) C X BG b/b s/s 18/21 (86%) 9/11 (82%) C X BJ b/b s/s 10/10 (100%) 2/2 (100%) C X BK b/b s/s 13/17 (76%) 2/10 (2096) * Mice were inoculated intravenously with 15 FFU of FV. t H-2 and Fv-2 genotypes of C X B strains were obtained from D. Bailey (Jackson Laboratory). Mice were scored for leukemia (splenomegaly or death) and viremia (2103 PFU/ml LLV) at 50-70 days after FV inoculation.

DISCUSSION The present results demonstrate the influence of a new gene, Rfv-3, on recovery from FV-induced viremia and leukemia. C57BL/10 and B10.A mice have the Rfv-3r/? genotype, and A/WySn, A.BY, and BALB.B mice have the Rfv-3s/s genotype. F1 or backcross mice with the Rfv-3r/s genotype have a high incidence of recovery from FV viremia 30-40 days after virus inoculation compared to Rfv 3S/S mice. Recovery from viremia is independent of H-2 genotype. In H-2a/a mice, recovery from viremia frequently occurs in the presence of persistent leukemia. However, in H-2b/b mice, recovery from viremia is strongly associated with recovery from leukemia. Thus, the Rfv-3r/s genotype is necessary for expression of H-2b/b-associated recovery from FV leukemia (4, 5, 9, 13). The data indicate that mechanisms controlled by the Rfv-3 gene are sufficient for control of FV viremia regardless of H-2 genotype and that these mechanisms are necessary but not sufficient for control of FV leukemia. Recovery from leukemia appears to be a more complex phenomenon influenced by at least two separate genes (Rfv-3 and H-2) in the F1 hybrids we have studied. Nongenetic factors also appear to be of major importance because, after inoculation of high FV doses, a significant number (10-30%) of mice fail to recover from FV leukemia even in the (C57BL/10 X A.BY)F1 population in which no genes are segregating. Thus, it was not surprising to observe 35% persistent leukemia among the nonviremic H-2b/b backcross mice because nonviremic mice with persistent leukemia were also seen in the H-2b/b F1 population. Non-H-2 genetic influences on H-2-associated resistance to leukemia have been demonstrated in two other systems. Tennant and Snell (16, 17), studying B/T-L virus leukemia, noted a marked difference in incidence of leukemia between two H-2b/b strains (A.BY and C57BL/10). A.BY mice had a high incidence of leukemia (75%) and C57BL/10 had a low incidence (39%). It seems highly likely that this difference might be due at least in part to the Rfv-3 gene, because the same mouse strains were used in our experiments and also B/T-L virus was the helper virus used to produce our FV stock (18). In the radiation leukemia virus system, Meruelo et al. (19, 20) have shown that H-2-associated resistance to leukemia is influenced by a non-H-2 gene which they called Srlv-1. In this model, susceptibility was a dominant trait because the Srlv-1 r/r genotype was required for demonstration of H-2-associated resistance. Because resistance is dominant for the Rfv-3 gene, it is unlikely that Srlv-1 and Rfv-3 are identical. However, experiments comparing the effects of both FV and radiation leukemia virus on the same mouse populations will have to be done to answer this question conclusively.

Proc. Natl. Acad. Sci. USA 76 (1979)

All the inbred mouse strains that have the Rfv-3 /r genotype are also known to have the Fv-2r/l genotype which causes resistance to FV-induced splenomegaly and spleen focus formation (3, 15, 16). Nevertheless, several lines of evidence indicate that Fv-2 and Rfv-3 are different genes. First, susceptibility (Fv-28) is the dominant allele for Fv-2. Fv-28/1 and Fv-2s/r mice do not differ in susceptibility to spleen focus formation or induction of leukemic splenomegaly (3, 15, 16). In the case of Rfv-3, the resistant allele (recovery from viremia) appears to be dominant. Second, using Bailey's C X B mice, we have found two Fv-2s/s strains, C X BE and C X BK, that have a high incidence of recovery from FV viremia similar to Fv-281r mice such as (C57BL/10 X BALB.B)Fj. Therefore, the Fv-28lr genotype is not necessary for control of FV viremia in the BALB system. Unless C X B mice have some unique genetic mechanisms involved in control of viremia compared to (BlO.A X A/WySn)Fl, (B1O.A X A.BY)F1, and (C57BL/10 X A.BY)F1 mice, it is unlikely that Fv-2 is involved in the effects on viremia at 30-40 days in these F1 hybrids either. Third, mating of Rfv-3r/s mice with Rfv-3r/r, Fv-21/1 mice (C57BL/10) indicated that Rfv-3 and Fv-2 were separate unlinked genes. At this time we have no conclusive evidence concerning the mechanism of action of the Rfv-3 gene. Rfv-3 theoretically could influence susceptibility to FV-induced immunosuppression (21, 22) as has been demonstrated for the Fv-3 gene (23). However, Rfv-3 and Fv-3 do not appear to be identical genes because susceptibility to FV-induced immunosuppression is dominant with the Fv-3 gene, whereas recovery from FV viremia is dominant with the Rfv-3 gene. The F1 and backcross mice used in this study should be susceptible to FV-induced immunosuppression (Fv-3 f/s or Fv-3/8s); nevertheless, nearly 90% of F1 mice and 50-57% of backcross mice were still able to recover from FV viremia. These results suggest that Fv-3controlled susceptibility to FV immunosuppression is not involved in the phenomenon of recovery from FV viremia described here. The Rfv-3 gene could also act by influencing the rate of virus growth via effects on interferon (24), defective interfering particles (25), virus-specific cell surface receptors (26), or the antiviral immune response (8, 27). The initial observation of a dissociation between recovery from FV viremia and leukemia in certain F1 hybrid mice indicated that recovery from viremia was correlated with the presence of neutralizing anti-FV antibodies in the blood (8). Although the cause and effect relationship was not proven, it seemed likely that antiviral antibodies were important in elimination of viremia. The Rfv-3 gene may have affected FV viremia by influencing the quality of the specific antiviral immune response in a manner similar to the immune response genes (28). If immunocompetent cell populations from Rfv-3l/s mice are capable of altering the host response to FV infection in Rfv-3s/s mice, this would provide strong support for the idea that the Rfv-3 gene acts in immunocompetent organs, perhaps by influencing the antiviral humoral immune response. We thank Dr. R. Riblet for Ig-1 typing of backcross mice, Ms. Jane Nishio for technical assistance, Mrs. Helen Blahnik for preparation of the manuscript, and Mr. Ray Holt for assistance with the mouse colony. 1. Friend, C. (1957) J. Exp. Med. 105,307-318. 2. Metcalf, D., Furth, J. & Buffett, R. F. (1959) Cancer Res. 19,

52-58. 3. Lilly, F. & Pincus, T. (1973) Adv. Cancer Res. 17,231-277. 4. Lilly, F. (1968) J. Exp. Med. 127,465-473. 5. Chesebro, B., Wehrly, K. & Stimpfling, J. (1974) J. Exp. Med. 140, 1457-1467. 6. Odaka, T. & Yamamoto, T. (1962) Jpn. J. Exp. Med. 32,405413.

Genetics: Chesebro and Wehrly 7. Lilly, F. (1970) J. Natl. Cancer Inst. 45, 163-169. 8. Chesebro, B. & Wehrly, K. (1976) J. Exp. Med. 143,73-84. 9. Chesebro, B. & Wehrly, K. (1978) Advances Comparative Leukemia Research, eds. Bentvelzen, P., Hilgers, J. & Yohn, D. S. (Elsevier/North-Holland, Amsterdam), pp 69-73. 10. Bailey, D. (1971) Transplantation 11,325-327. 11. Bailey, D. W. (1975) Immunogenetics 2,249-256. 12. Chesebro, B., Wehrly, K., Chesebro, K. & Portis, J. (1976) J. Immunol. 117, 1267-1274. 13. Chesebro, B. & Wehrly, K. (1978) J. Immunol. 120, 10811085. 14. Herzenberg, L. A., McDevitt, H. 0. & Herzenberg, L. A. (1968) Annu. Rev. Genet. 2,209-244. 15. Riblet, R., Blomberg, B., Weigert, M., Lieberman, R., Taylor, B. A. & Potter, M. (1975) Eur. J. Immunol. 5,775-777. 16. Tennant, J. & Snell, G. (1966) Natl. Cancer Inst. Monog. 22, 61-72. 17. Tennant, J. R. & Snell, G. D. (1968) J. Natl. Cancer Inst. 41, 579-604.

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Identification of a non-H-2 gene (Rfv-3) influencing recovery from viremia and leukemia induced by Friend virus complex.

Proc. Natl. Acad. Sci. USA Vol. 76, No. 1, pp. 425-429, January 1979 Genetics Identification of a non-H-2 gene (Rfv-3) influencing recovery from vire...
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