Germ line integration and Mendelian transmission of the exogenous Moloney leukemia virus.

Abstract

Mice were infected with the exogenous Moloney leukemia virus (M-MuLV) at two different stages of development. Either newborn mice (which can be considered as essentially fully differentiated animals) or preimplantation mouse embryos (at the 4-8 cell stage) were infected with M-MuLV. In both cases, animals that had developed an MMuLV-induced leukemia were obtained. Two lines of evidence indicate that infection of preimplantation embryos, in contrast to infection of newborns, can lead to integration of the virus into the germ line.1. Viremic males of the first backcross generation (N-i generation) transmitted the virus to 50% of their offspring (N-2 generation) when mated with uninfected females. Likewise, a 50% transmission was observed from viremic N-2 and N-3 males to the next generations.2. Molecular hybridization experiments revealed that viremic N-1 and N-2 animals carried one copy of M-MuLV per diploid mouse genome equivalent in all "non-target" organs tested.Together, both experiments indicate that the exogenous M-MuLV can be converted to an endogenous virus after infection of preimplantation embryos. The available evidence suggests that M-MuLV integrated into the germ line at one out of two possible integration sites. Thus, viremic backcross animals are heterozygous for a single Mendelian locus carrying the M-MuL V gene. During leukemogenesis an amplification of the M-MuLV from one copy to a maximum of four copies per diploid mouse genome equivalent takes place in, the tumor tissues.The genetic information of endogenous C-type viruses is present in all somatic and germ cells of all individuals of many species, and these virus-related genes are transmitted genetically according to Mendelian expectations (1-5). In contrast, exogenously infecting C-type viruses are not transmitted genetically and thus are not part of the normal genetic complement of an animal (6, 7). Whereas it is reasonable to assume that exogenous viruses evolved from endogenous viruses (7-9), the converse event, namely the conversion of exogenous viruses into endogenous viruses, seems to be very rare. However, recent evidence suggests that the transfer of an exogenous virus into the germ line of another species can occur during evolution (1, 10).Prior to this study, the conversion of an exogenous into an endogenous virus had not been observed under defined laboratory conditions. Thus, leukemic mice infected in utero or after birth with leukemia virus never transmitted the virus genetically, i.e., from the leukemic father to the offspring (11,12). In this instance, it is important to distinguish genetic transmission from the congenital transmission (13) which occurs from leukemic mothers to the majority of their offspring by infection through the placenta or the milk. The apparent resistance of the germ line to virus infection may be explained by the "organtropism" of murine leukemia viruses, i.e., the observation that only certain "target" tissues, such as spleen or thymus cells, are susceptible to infection with leukemia viruses,...

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