Virus Disease MMTV

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Mouse mammary tumor virus has both exogenous and endogenous forms. The endogenous viruses are passed vertically, are incorporated into the mouse genome in Mendelian fashion, and become specific characteristics of different mouse strains. The exogenous mouse mammary tumor virus has also been identified in wild mice, both in milk and in mammary tumor lesions. In infected wild mice, the incidence of tumor formation is generally low.

The exogenous form of mouse mammary tumor virus is transmitted to pups through the dam’s milk and saliva. As implied in the name of the virus, infection with exogenous mouse mammary tumor virus can result in the formation of mammary tumors, but infection can result in other tumors as well (notably T-cell lymphoma). While the exogenous mouse mammary tumor virus has been essentially eliminated from contemporary laboratory mouse strains (unless purposefully maintained for research purposes), the endogenous provirus is present in the genomes of all laboratory mice. Some mouse strains have up to 50 provirus copies of the endogenous mouse mammary tumor virus. The genomic distribution of these loci is a signature feature of the particular strain. Many of these proviruses are transcriptionally inactive or do not encode infectious virus. However, certain mouse strains encode endogenous proviruses that produce infectious virus. The replication competence of the endogenous mouse mammary tumor virus is, therefore, somewhat unique.

The endogenous mouse mammary tumor virus can induce mammary neoplasia by insertional mutagenesis. Virus-associated spontaneous mammary neoplasia is diverse, ranging from precancerous glandular hyperplasia to adenomas and various carcinomas. Affected glands are generally enlarged, firm, and often circumscribed (Fig. 14.8). Lesions can occur anywhere in the mammary chain from the axilla to the inguinal region. Interestingly, specific tumor morphology is often predictive of the activation of particular oncogenes.

Mouse mammary tumor viruses encode a superantigen protein (Sag). This virus-derived protein is presented on murine MHC II molecules on antigen-presenting cells, conferring broad clonal reactivity of responding T cells. These T cells, in turn, activate multiple clones of B cells, resulting in B cell hyperplasia, fostering virus integration and replication, as well as trafficking of infected B cells to the mammary gland. The LTR of mouse mammary tumor virus is an important determinant of mammary tissue tropism.

In MMTV there is an additional gene (sag) whose product functions as a superantigen, which is located at the 3′-end of the genome, overlapping U3. This gene is absent from other members of the genus. The tRNA primer is tRNALys-3 for MMTV and tRNALys-1,2 for other members of the genus. The LTR of MMTV is about 1300 nt long primarily due to the sag encoding U3 region of 1200 nt. The R sequence (15 nt) and the U5 region (95-120 nt) are of similar length in all members of the genus.

Viruses assigned to this genus include exogenous, (milk-transmitted) and endogenous viruses of mice, as well as exogenous, horizontally transmitted and endogenous viruses of new and old-world primates and sheep. Murine viruses are associated with mammary carcinoma and T-lymphomas, while the exogenous primate viruses are associated with immuno-deficiency diseases; Jaagsiekte sheep virus is associated with pulmonary cancer of sheep. No oncogene-containing member is known.

LIST OF SPECIES DEMARCATION CRITERIA IN THE GENUS

The list of species demarcation criteria is:–

Differences in the genome sequence,–

Differences in gene product sequences,–

Differences in natural host range,–

Different oncogenes that may be incorporated.

Several primate retroviruses have been described that appear to be divergent members of a single virus that arose from a recombination event in which the env gene of a primate gammaretrovirus was captured. The most divergent of these are the endogenous Squirrel monkey retrovirus (SMRV) and Langur virus (LNGV), which are unable to infect cells from the primate species of origin. Several serologically distinct strains exist within the Mason-Pfizer monkey virus species. The most divergent of these are the endogenous SMRV and LNGV, nevertheless, the most closely related isolates Mason-Pfizer monkey virus, Simian retrovirus-1, and Simian retrovirus-2 are serologically distinct. Mouse mammary tumor virus is assigned to a separate species because of the unique sag coding region and a widely divergent and distinct env gene. Jaagsiekte sheep retrovirus is also assigned to a separate species on the degree of nt sequence divergence. Related endogenous proviruses have been identified in other mammalian species (rodents, primates).

LIST OF SPECIES IN THE GENUS

Species names are in green italic script; strain names and synonyms are in black roman script; tentative species names are in blue roman script. Sequence accession numbers [ ], and assigned abbreviations ( ) are also listed.

Distinguishing features

Virions of mouse mammary tumor virus (MMTV) exhibit a “B-type” morphology with prominent surface spikes and an eccentric condensed core. Other members of the genus have a “D-type” morphology with fewer dense surface spikes and a cylindrical core. Capsid assembly occurs within the cytoplasm (to yield structures previously termed “A-type” particles) prior to transport to and budding from, the plasma membrane. Approximate protein sizes are: MA 10 kDa; p21 21 kDa; p8/p12 8 12 kDa; CA 27 kDa; NC 14 kDa; DU 30 kDa; PR 15 kDa; RT 50 kDa; IN 36 kDa; SU 52 kDa; and TM 36 kDa. The genome is 8–10 kb in size (one monomer); its organization in MMTV is illustrated in Figure 3.

In MMTV there are two additional genes: sag, whose product functions as a superantigen, is located at the 3′ end of the genome, overlapping U3 and rem, which encodes an RNA export protein and is translated from a doubly spliced mRNA overlapping the env gene. The sag gene is absent from other members of the genus, but several other viruses encode activities analogous to Rem. The tRNA primer is tRNALys-3 for MMTV and tRNALys-1,2 for other members of the genus. The LTR of MMTV is about 1300 nt long, primarily due to the sag-encoding U3 region of 1200 nt. The R sequence (15 nt) and the U5 region (95–120 nt) are of similar length in all members of the genus.

Viruses assigned to this genus include exogenous (milk-transmitted) and endogenous viruses of mice, as well as exogenous, horizontally transmitted and endogenous viruses of New and Old World primates and sheep. Murine viruses are associated with mammary carcinoma and T-lymphomas, whereas the exogenous primate viruses are associated with immunodeficiency diseases; Jaagsiekte sheep retrovirus is associated with pulmonary cancer of sheep. No oncogene-containing member is known. View chapter purchase book

Mouse Mammary Tumor Virus

Mouse mammary tumor virus (MMTV) is a retrovirus that is transmitted vertically from infected mothers to their pups via milk. Specifically, lymphocytes containing MMTV provirus in the milk are ingested by the pups where the virus can access intestinal Peyer’s patches and initiate infection. A previous study revealed that MMTV persistence subsequent to the ingestion of MMTV-laden milk requires the LPS receptor TLR4 and the anti-inflammatory cytokine IL-10 (Jude et al., 2003). Based on these observations, Kane et al., (2011) tested the hypothesis that MMTV avoids immune-driven elimination by associating with bacterial LPS and inducing a tolerogenic immune response. Supporting this idea, the Abx treatment of infected mothers prevented MMTV transmission to their offspring (Kane et al., 2011). Furthermore, germ-free infected mothers failed to transmit the virus while their reconstitution with a defined gut flora fully restored transmission (Kane et al., 2011). Similar to poliovirus, MMTV appears to directly bind LPS: MMTV isolated from the stomachs of pups ingesting infected milk was associated with LPS, and LPS cofractionated with MMTV in ultracentrifugation density gradients. MMTV associated with LPS induced IL-10 secretion when inoculated onto splenocytes in culture whereas LPS-free MMTV isolated from germ-free animals failed to induce IL-10 secretion. Overall, these data support a model whereby an orally transmitted retrovirus avoids immune-driven elimination by binding commensal bacterial LPS that is recognized by TLR4 and ultimately induces IL-10 secretion and a tolerogenic immune environment (Fig. 5.2.1D). These results are in accordance with a well-established immune phenomenon referred to as bystander suppression (Miller et al., 1991).

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