The mouse H-2A region influences the envelope gene structure of tumor-associated murine leukemia viruses

Abstract

C57BL/10 (B10) strains congenic at the mouse major histocompatibility locus (H-2) were injected with a modified ecotropic SL3-3 murine leukemia virus (MuLV) to determine the effect of the H-2 genes on the envelope gene structure of recombinant MuLVs. All tested strains rapidly developed T-cell lymphomas, and recombinant proviruses were detected in the tumor DNAs by Southern blot. The B10.D2 (H-2d), B10.Br (H-2k), B10.Q (H-2q), and B10.RIII (H-2r) strains exhibited a TI phenotype in which almost all tumors contained type I recombinants. These recombinants characteristically acquire envelope gene sequences from the endogenous polytropic viruses but retain the 5' p15E (TM) gene sequences from the ecotropic virus. The parental B10 (H-2b) strain, however, had a novel phenotype that was designated NS for nonselective. Only 30% of the B10 tumors had detectable type I recombinants, whereas a proportion of the others appeared to contain type II recombinants that lacked the type I-specific ecotropic p15E gene sequences. Studies of other B10 congenic strains with hybrid H-2 loci and selected F1 animals revealed that the NS phenotype was regulated by a dominant gene(s) that mapped to the A region of H-2b. These results demonstrate that a host gene within the major histocompatibility complex can influence the genetic evolution of pathogenic retroviruses in vivo.

FIG. 1

Predicted amino acid sequences of p15E proteins of type I and type II recombinant MuLVs in relationship to known or suspected functional domains. Underlined residues may participate in the formation of a leucine zipper-like region.

FIG. 2

Strategy for Southern blot detection of type I viruses. The relevant restriction enzyme sites and relative position of the AKV5 probe within the different types of proviruses are shown. The AKV5 probe hybridizes to the ecotropic p15E gene sequences but not to the polytropic p15E gene sequences found in the type II recombinant and endogenous polytropic proviruses.

FIG. 3

Detection of type I recombinants in lymphomas from B10.D2 and B10 mice. Shown are autoradiographs of Southern blots of tumor DNAs from control and SL3-3NB-injected mice. Approximate band sizes in kilobases are shown at the left. (A) Lanes: +, positive control DNA from SL3-3NB-injected B10.Br mouse; −, negative control DNA from uninjected B10.D2 mouse; A to R, lymphoma DNAs from SL3-3NB-injected B10.D2 mice. (B) Lanes: +, positive control DNA from SL3-3NB-injected B10.Br mouse; −, negative control DNA from uninjected B10 mouse; A to R, lymphoma DNAs from SL3-3NB-injected B10 mice.

FIG. 4

Comparison of partial envelope gene sequence of the B10 recombinant provirus E9-TA9 with sequences of other endogenous and recombinant proviruses. The sequences are compared to those of the endogenous polytropic virus MX27 (POLY). The first base corresponds to position 863 of the MX27 sequence (28). ECO is the endogenous ecotropic virus AKV623, CWNT25 is a type II recombinant from a CWD mouse, and PTV-1 is a type I recombinant from an HRS/J mouse (34). Dots in the sequence indicate homology with the corresponding nucleotide of the POLY sequence; nucleotide substitutions are shown by placement of the appropriate symbol. The sequence of E9-TA9 beyond position 710 was not determined. The most 3′ extents of substitution by endogenous polytropic sequences in PTV-1 and E9-TA9 are shown. The overlined sequences indicate the relative position of the AKV5 probe (ECO sequences) that distinguishes type I from type II proviruses. Restriction enzyme sites for PstI (polytropic only), XbaI (ecotropic only), and BglII are underlined.