Neurodegenerative disease induced by the wild mouse ecotropic retrovirus is markedly accelerated by long terminal repeat and gag-pol sequences from nondefective Friend murine leukemia virus

Abstract

The wild mouse ecotropic retrovirus (WM-E) induces a spongiform neurodegenerative disease in mice after a variable incubation period of 2 months to as long as 1 year. We isolated a molecular clone of WM-E (15-1) which was weakly neurovirulent (incidence, 8%) but was highly leukemogenic (incidence, 45%). Both lymphoid and granulocytic leukemias were observed, and these leukemias were often neuroinvasive. A chimeric virus was constructed containing the env and 3' pol sequences of 15-1 and long terminal repeat (LTR), gag, and 5' pol sequences from a clone of Friend murine leukemia virus (FB29). FB29 has been shown previously to replicate to high levels in the central nervous system (CNS) but is not itself neurovirulent. This fnding was confirmed at the DNA level in the current study. Surprisingly, intraperitoneal inoculation of neonatal IRW mice with the chimeric virus (FrCasE) caused an accelerated neurodegenerative disease with an incubation period of only 16 days and was uniformly fatal by 23 days postinoculation. Introduction of the LTR of 15-1 into the FrCasE genome yielded a virus (FrCasEL) with a degree of neurovirulence intermediate between those of 15-1 and FrCasE. No differences were found in the levels of viremia or the relative levels of viral DNA in the spleens of mice inoculated with 15-1, FrCasE, or FrCasEL. However, the levels of viral DNA in the CNS correlated with the relative degrees of neurovirulence of the respective viruses (FrCasE > FrCasEL > 15-1). Thus, the env and 3' pol sequences of WM-E (15-1) were required for neurovirulence, but elements within the LTR and gag-pol regions of FB29 had a profound influence on the level of CNS infection and the rate of development of neurodegeneration.

Long-Lasting Protective Antiviral Immunity Induced by Passive Immunotherapies Requires both Neutralizing and Effector Functions of the Administered Monoclonal Antibody

“…Virus stocks, cell lines, and monoclonal antibody production. Culture supernatants of Mus dunni embryo fibroblasts transfected with the FrCas E proviral clone (58) were used as viral stocks (56). The anti-murine leukemia virus Env mouse 667 MAb (IgG2a/) (44) was purified from hybridoma supernatant and assayed as previously described (16).…”

“…FrCas E is a simple chimeric mouse retrovirus in which the env gene of the leukemogenic Friend murine leukemia virus (F-MuLV) was replaced by that of the neurodegenerationinducing CasBr retrovirus (58). When 5 ϫ 10 4 infectious particles are inoculated into newborn mice under the age of 5 to 6 days, FrCas E can enter the central nervous system (CNS) and induces a neurodegeneration fatal within 1 to 2 months with 100% incidence (15,23,41,58). However, upon infection at a later time, FrCas E can no longer enter the CNS.…”

Antiviral Monoclonal Antibodies: Can They Be More Than Simple Neutralizing Agents?

“…FrCasE infection of newborn mice is reminiscent of perinatal infection by HIV, in that viral expansion occurs in an organism with developing immunity. It provides one of the rare models of chronic viral infection, in an immunocompetent animal, for which neutralizing mAbs of the same species (mouse) are available [33]. It was the first experimental system to permit the unambiguous demonstration of the possibility of inducing vaccine-like effects by mAb-based immunotherapy [34][35][36][37].…”

A Crucial Role for Infected-Cell/Antibody Immune Complexes in the Enhancement of Endogenous Antiviral Immunity by Short Passive Immunotherapy

“…Establishing whether, and how, mAb-based treatments can orientate antiviral immune responses towards long-term protective immunity lasting long after the mAb has disappeared is, however, important as this might influence the design of mAb immunotherapies of severe chronic life-threatening viral infections. To address this issue, we have resorted to the infection of immunocompetent mice by the FrCas E retrovirus, as it is one of the rare model systems permitting extensive analysis of the endogenous immune response after passive mAb-based immunotherapy under conditions of both chronic infection and pathological development [15][16][17].…”

“…FrCas E is an ecotropic retrovirus derived from the Friend murine leukemia virus (MuLV) [15]. Upon inoculation to newborn mice under the age of 5 days, it first propagates in lymphoid organs before penetrating into the central nervous system (CNS), which leads to a fatal neurodegeneration within 1-2 months [17][18][19].…”