A population of murine hematopoietic progenitors expresses an endogenous retroviral gp70 linked to the Rmcf gene and associated with resistance to erythroleukemia

Abstract

Multiple copies of retroviral sequences are stably integrated in the genomes of many higher organisms, and are thus transmitted vertically to offspring via the germline (1). Most of these heritable viral genes are not expressed, and expression, when observed, is commonly limited to envelope (env) genes as demonstrated by the presence of cell surface and serum envelope glycoprotein (gp70) in mice. Studies of the mouse have shown that certain tissues such as the reproductive tract and lymphoid organs are common sites for the expression of endogenous env genes, suggesting that the transcription of at least some endogenous sequences is tissue specific. The transcription of endogenous viral genes is regulated by both cis and trans mechanisms (2-5) and their expression can be temporally linked to differentiation and development (6-8). The consequences to the host of endogenous retroviral genes are varied. At one extreme, expression of endogenous virus can result in the development of leukemia and death. Another potentially detrimental effect is that of insertional mutagenesis, seen when the integration of retroviral sequences interrupts the functioning of a cellular gene (9, 10). However, it is now clear that expression of endogenous retroviral genes may also have a beneficial effect for the host: namely, mediating resistance to retroviral leukemias as has been demonstrated for the Fv-4 gene in mice (11) and some ea loci in chickens (12). This form of resistance is due to the blockage of cellular viral receptors by the expression of envelope glycoprotein on the cell surface. The Rmcf locus of the mouse is another resistance gene that may exert its effect by the expression of an endogenous env gene. A summary of our current state of knowledge concerning the Rmcf gene is shown in Table I. The Rmcf gene was originally described when it was observed that fibroblast cell cultures derived from certain strains of mice restricted the replication of recombinant mink cell focus-forming(MCF)1 viruses (13). As detailed in Table I, DBA/2 mice are the prototypic strain exhibiting the Rmcf resistance (Rmcf(r)) phenotype. Cell cultures from other strains, such as C57BL/6 and IRW, are permissive for MCF viral replication and are termed Rmcf sensitive (Rmcf(s)). Previously, we described two allelic forms of an endogenous env gene, whose expression is linked to the Rmcf gene (14). Cell cultures from Rmcf(r) mice express gp70 related to that of MCF viruses, whereas cultures derived from Rmcf(s) mice either express no gp70 (IRW) or express an endogenous xenotropic gp70 (C57BL/6). These two gp70 alleles are detectable by type-specific mAbs.

Human Endogenous Retroviral Sequences: Possible Roles in Reproductive Physiopathology1

“…Expression of gp 70 was undetectable in mature myeloid or lymphoid cells of adult mice, but it was elicited in spleen by the treatment with an hemolytic agent, thus inducing a request for enhanced hemopoiesis. The thymus of weanlings also showed a small (5-10%) gp 70ϩ subpopulation composed by large cells with increased mitotic rate, which were identified as lymphoid progenitors [106]. In fact, the thymus of young mice is a preferential expression site for IAPs [15]; it should be also noted that some of the cells populating the fetal thymus originate in the liver.…”

“…The gp 70ϩ subpopulation included almost all erythropoietic and myeloid precursors, whereas positivity was almost undetectable in smaller, more mature cells. The basal pool of the most primitive, multipotent cells showed heterogeneity of expression, segregating into gp 70Ϫ (81%) and gp 70ϩ (19%) subpopulations [106]. It might be noteworthy that the ERV-locus examined (Rmcf) is close to the W v gene locus, which is responsible for a defective hemopoietic stem cell compartment.…”

Endogenous Retroviral Envelope Antigens Recognized by B Lymphocytes during Graft-Versus-Host Reaction.

“…Interestingly, in adult mice we were unable to find cells expressing these proteins within hematopoietic organs (i.e., spleen and bone marrow), although high levels of xenotropic gp70, reactive with other GVHR-derived monoclonal antibodies, were found within these tissues (Buller et al 1989). Upon stimulation of erythropoiesis by treating adult D2 or B6 mice with the hemolytic agent phenylhydrazine, a small population of cells expressing respectively the 514 and 18-6-reactive gp70's were detected in the spleen (Buller et al 1989). This illustrates the power of discrimination of the monoclonal antibodies used in these studies, allowing the detection of several endogenous envelope proteins expressed within the same organ.…”

“…This illustrates the power of discrimination of the monoclonal antibodies used in these studies, allowing the detection of several endogenous envelope proteins expressed within the same organ. On analysis of the lineage distribution of the 514/18-6-reactive gp70 proteins (Buller et al 1989) it was found that these proteins did not just mark erythroid cells, but were expressed by cells of the myeloid, granulocyte/macrophage and lymphoid lineages as well. Expression of these proteins was detected from primitive stem cells (CFU/S) through more mature progenitors such as CFU/GM, CFU/E and BFU/E.…”

Physiology and Pathology of Host Immune Responses to Exogenous and Endogenous Murine Retroviruses. From Gene Fragments to Epitopes.

“…In mice prone to spontaneous leukemia and/or lymphoma, expression of infectious recombinant polytropic viruses is closely associated with the leukemogenesis. Of course, endogenous polytropic or xenotropic viral env genes are physiologically expressed as differentiation antigens in subsets of hematopoietic cells (Buller et al 1989). Therefore, the immune system must be tolerant to the products of some, if not all, endogenous polytropic viruses.…”