Inbred mouse strains harbor a family of closely related endogenous retroviral sequences. Upon infection of these mice by retroviruses such as the ecotropic Friend murine leukemia virus (F-MuLV) or Moloney lymphocytic leukemia virus (M-MuLV),the inoculated viruses undergo recombination with the endogenous retroviral genes to generate new retroviruses. The recombinant viruses, termed polytropic MuLVs, exhibit an altered infectious host range and utilize a cell surface receptor distinct from the receptor utilized by ecotropic MuLVs. In several instances polytropic MuLVs have been directly implicated in pathogenesis, including the induction of proliferative, immunological, and neurological disorders. The generation of variants after infection of the host by retroviruses results in mixed retrovirus infections. Prime examples of this are variants that arise by point mutation in HIV-infected individuals and the polytropic variants in mice that arise by recombination. Mixed infections by retroviruses with different properties can result in virus interactions that could potentially influence their spread and pathogenicity. A primary goal of this project is to elucidate the effect of mixed retrovirus infections on the induction of disease. Recently our studies of mixed retrovirus infection have focused on mice co-inoculated with mixtures of ecotropic and polytropic MuLVs. We have observed profound effects on the infectious spread of the polytropic virus in co-inoculated mice, concomitant with a very rapid induction of neurological disease not observed after inoculation with either virus alone. The initial results were observed after co-inoculation of NFS/N mice with an ecotropic MuLV and a polytropic MuLV known to be neuropathogenic in IRW but not NFS/N mice. These studies have been extended to demonstrate the induction of neurological disease in NFS/N and IRW mice by other polytropic viruses that had not been previously observed to be neuropathogenic. A common effect of mixed infections resulting in neurological disease is a greatly enhanced spread of the polytropic virus in tissues peripheral to the central nervous system (CNS). This phenomenon is mediated by pseudotyping of polytropic viral genomes within ecotropic virus particles. Polytropic MuLVs initially detected in the CNS are also pseudotyped, however a subsequent rapid spread of the virus in the CNS appears to proceed by polytropic virions that are not pseudotyped. This rapid spread is nearly coincident with the onset of neurological symptoms. Polytropic viruses that do not exhibit enhanced peripheral replication in mixed infections exhibit a lesser degree of CNS infection and have not been observed to induce neurological disease. C57Bl/6 mice co-inoculated with ecotropic and polytropic MuLVs do not exhibit neurological disease, yet an enhanced peripheral replication of the polytropic MuLV is observed. In contrast to the findings in NFS/N and IRW mice, polytropic MuLVs detected in the CNS of co-infected C57Bl/6 mice are pseudotyped throughout the course of infection and do not exhibit a rapid spread in the CNS. Overall, these studies suggest that neuropathogenicity may be a general property of polytropic MuLVs; that a threshold of peripheral replication is required for invasion of the CNS, and that spread of the polytropic virus through interaction of the polytropic receptor-binding protein with receptors on CNS cells may be a requirement for the induction of neuropathology.
