Precise Identification of Endogenous Proviruses of NFS/N Mice Participating in Recombination with Moloney Ecotropic Murine Leukemia Virus (MuLV) To Generate Polytropic MuLVs

Abstract

Polytropic murine leukemia viruses (MuLVs) are generated by recombination of ecotropic MuLVs with env genes of a family of endogenous proviruses in mice, resulting in viruses with an expanded host range and greater virulence. Inbred mouse strains contain numerous endogenous proviruses that are potential donors of the env gene sequences of polytropic MuLVs; however, the precise identification of those proviruses that participate in recombination has been elusive. Three different structural groups of proviruses in NFS/N mice have been described and different ecotropic MuLVs preferentially recombine with different groups of proviruses. In contrast to other ecotropic MuLVs such as Friend MuLV or Akv that recombine predominantly with a single group of proviruses, Moloney MuLV (M-MuLV) recombines with at least two distinct groups. In this study, we determined that only three endogenous proviruses, two of one group and one of another group, are major participants in recombination with M-MuLV. Furthermore, the distinction between the polytropic MuLVs generated by M-MuLV and other ecotropic MuLVs is the result of recombination with a single endogenous provirus. This provirus exhibits a frameshift mutation in the 3 region of the surface glycoproteinencoding sequences that is excluded in recombinants with M-MuLV. The sites of recombination between the env genes of M-MuLV and endogenous proviruses were confined to a short region exhibiting maximum homology between the ecotropic and polytropic env sequences and maximum stability of predicted RNA secondary structure. These observations suggest a possible mechanism for the specificity of recombination observed for different ecotropic MuLVs.

In Vivo Interactions of Ecotropic and Polytropic Murine Leukemia Viruses in Mixed Retrovirus Infections

“…Furthermore, our studies indicated that interactions of the ecotropic and polytropic MuLVs, including pseudotyping and viral interference, might facilitate the induction of leukemia (29). Infection of mice by ecotropic MuLVs results in the generation of multiple recombinant viruses which may exhibit distinct infectious properties (2,29) and whose interactions in the host are likely to be quite complex. In this study, we have examined mixed infections that were initiated by coinoculation of an ecotropic MuLV with recombinant polytropic MuLVs.…”

“…Previous studies from this laboratory indicated that the interaction of polytropic and ecotropic MuLVs in a mixed infection may play a major role in a stepwise process of leukemogenesis in mice (29). There are multiple recombinant viruses generated in infected mice (2), and although they utilize the same cell-surface receptor for infection, different polytropic MuLVs may exhibit striking quantitative differences in their abilities to infect different cells. Thus, some polytropic MuLVs infect mink cells 3 to 4 orders of magnitude more efficiently than mouse cells, while others infect both cell types with nearly equal efficiently (19).…”

Endogenous retroviruses

“…3) [34]. Of the three groups of ERVs, only X-MuLV and E-MuLV have infectious members, although infectious P-MuLVs are generated following recombination with E-MuLVs [64, 65]. Some wild mouse populations carry infectious amphotropic MuLVs (A-MuLVs) or a novel E-MuLV (HoMuLV) in the absence of germline ERVs [66, 67].…”

Profound Amplification of Pathogenic Murine Polytropic Retrovirus Release from Coinfected Cells

“…Ecotropic MuLVs infect only cells of murine origin, whereas recombinant polytropic MuLVs infect murine cells as well as cells of numerous other species (16). Although some endogenous polytropic proviruses carry intact retroviral genes, replication-competent endogenous polytropic viruses have not been described (2,39). The generation of recombinant polytropic MuLVs is thought to be instrumental in proliferative diseases resulting from ecotropic MuLV infection (7,25,35,40,(42)(43)(44)(45).…”