Endogenous MMTV Proviruses Induce Susceptibility to Both Viral and Bacterial Pathogens

Bhadra, Sanchita; Lozano, Mary M.; Payne, Shelley M.; Dudley, Jaquelin P.

doi:10.1371/journal.ppat.0020128

Cited by 21 publications

(21 citation statements)

References 57 publications

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“…Other mechanisms of resistance to lymphocyte infection and virus spread include a hyperimmune antibody response that occurs in I/LnJ mice and increased viral clearance by T cells in YBr/Ei mice (8,9,33). The lymphoid tissues of mice lacking endogenous copies of the MMTV provirus are also resistant to MMTV infection, although the mechanism for this resistance is not known (5,6). Here, we examined 19 different inbred mouse strains and found that there are two alleles of the mA3 gene with regard to exon 5 and the surrounding introns.…”

Section: Discussionmentioning

confidence: 99%

Expression of Murine APOBEC3 Alleles in Different Mouse Strains and Their Effect on Mouse Mammary Tumor Virus Infection

Okeoma

Petersen

Ross

2009

J Virol

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Recent work has shown that mouse APOBEC3 restricts infection by mouse mammary tumor virus (MMTV) and murine leukemia virus (MLV) and that there are polymorphic APOBEC3 alleles found in different inbred mouse strains. For example, C57BL/6 mice, which are resistant to Friend MLV (F-MLV), encode a APOBEC3 gene different from that encoded by F-MLV-susceptible BALB/c mice; the predominant RNA produced in C57BL/6 mice lacks exon 5 (mA3 ؊5 ) and encodes a protein with 15 polymorphic amino acids. It has also been reported that BALB/c mice produce only a variant RNA that lacks exon 2 (mA3 ؊2 ). In this study, we examined the effect of these polymorphic APOBEC3 proteins on MMTV infection. We found that the major RNA made in C57BL/6 and B10.BR mice lacks exon 5 but that BALB/c and C3H/HeN mice predominantly express an RNA that contains all nine exons. In addition to producing the splice variant, C57BL/6 and B10.BR cells and tissues had levels of mA3 RNA fivefold higher than those from BALB/c and C3H/HeN mice. A cloned C57BL/6-derived mA3 protein lacking exon 5 inhibited MMTV infection better than a cloned full-length protein derived from 129/Ola RNA when packaged into MMTV virions. We also tested dendritic cells derived from different inbred mouse strains for their abilities to be infected by MMTV and showed that susceptibility to infection correlated with the presence of the exon 5-encoding allele. In vivo susceptibility to infection cosegregated with the inherited mA3 allele in a C57BL/6 ؋ BALB/c backcross analysis. Moreover, virus produced in vivo in the mammary tissue of mA3 knockout and BALB/c mice was more infectious than that produced in the tissue of C57BL/6 mice. These data indicate that mA3 plays a role in the genetics of susceptibility and resistance to MMTV infection.

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Section: Discussionmentioning

confidence: 99%

Expression of Murine APOBEC3 Alleles in Different Mouse Strains and Their Effect on Mouse Mammary Tumor Virus Infection

Okeoma

Petersen

Ross

2009

J Virol

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“…Sag is a transmembrane glycoprotein that is involved in the lymphocyte-mediated transmission of MMTV from maternal milk in the gut to susceptible epithelial cells in the mammary gland (5,6). The Sag protein expressed by endogenous (germline) MMTV proviruses has been reported to provide susceptibility to infection by exogenous MMTVs or the bacterial pathogen, Vibrio cholerae (7). These results suggest a role for MMTV Sag in the host innate immune response.…”

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confidence: 99%

Mapping of the Functional Boundaries and Secondary Structure of the Mouse Mammary Tumor Virus Rem-responsive Element

Mertz

Chadee

Byun

et al. 2009

Journal of Biological Chemistry

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Mouse mammary tumor virus (MMTV) is a complex retrovirus that encodes at least three regulatory and accessory proteins, including Rem. Rem is required for nuclear export of unspliced viral RNA and efficient expression of viral proteins. Our previous data indicated that sequences at the envelope-3 long terminal repeat junction are required for proper export of viral RNA. To further map the Rem-responsive element (RmRE), reporter vectors containing various portions of the viral envelope gene and the 3 long terminal repeat were tested in the presence and absence of Rem in transient transfection assays. A 476-bp fragment that spans the envelope-long terminal repeat junction had activity equivalent to the entire 3-end of the mouse mammary tumor virus genome, but further deletions at the 5-or 3-ends reduced Rem responsiveness. RNase structure mapping of the full-length RmRE and a 3-truncation suggested multiple domains with local base pairing and intervening single-stranded segments. A secondary structure model constrained by these data is reminiscent of the RNA response elements of other complex retroviruses, with numerous local stem-loops and long-range base pairs near the 5-and 3-boundaries, and differs substantially from an earlier model generated without experimental constraints. Covariation analysis provides limited support for basic features of our model. Reporter assays in human and mouse cell lines revealed similar boundaries, suggesting that the RmRE does not require cell typespecific proteins to form a functional structure. Mouse mammary tumor virus (MMTV)3 has multiple regulatory and accessory genes (1, 2). The known accessory genes specify a dUTPase (3), which is believed to be involved in retroviral replication in non-dividing cells (4), as well as superantigen (Sag). Sag is a transmembrane glycoprotein that is involved in the lymphocyte-mediated transmission of MMTV from maternal milk in the gut to susceptible epithelial cells in the mammary gland (5, 6). The Sag protein expressed by endogenous (germline) MMTV proviruses has been reported to provide susceptibility to infection by exogenous MMTVs or the bacterial pathogen, Vibrio cholerae (7). These results suggest a role for MMTV Sag in the host innate immune response.MMTV recently was shown to be a complex retrovirus (1). Complex retroviruses encode RNA-binding proteins that facilitate nuclear export of unspliced viral RNA by using a leucinerich nuclear export sequence (8), which binds to chromosome region maintenance 1 (Crm1)(9), whereas simple retroviruses have a cis-acting constitutive transport element that directly interacts with components of the Tap/NXF1 pathway (10). Similar to other complex retroviruses, MMTV encodes a Revlike protein, regulator of export/expression of MMTV mRNA (Rem) (1). Rem is translated from a doubly spliced mRNA into a 33-kDa protein that contains nuclear and nucleolar localization signals as well as a predicted RNA-binding motif and leucine-rich nuclear export sequence (1, 2). Our previous experiments indicated that Rem ...

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“…A recent study has shown that endogenous MMTV SAg expression can increase susceptibility to infection by a range of bacterial and viral pathogens through an unidentified mechanism (45). Potentially, HERV-K18 SAg may exert similar properties.…”

Section: Herv-k and Melanomamentioning

confidence: 99%

Human RNA “Rumor” Viruses: the Search for Novel Human Retroviruses in Chronic Disease

Voisset

Weiss

Griffiths

2008

Microbiol Mol Biol Rev

145

156

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SUMMARY Retroviruses are an important group of pathogens that cause a variety of diseases in humans and animals. Four human retroviruses are currently known, including human immunodeficiency virus type 1, which causes AIDS, and human T-lymphotropic virus type 1, which causes cancer and inflammatory disease. For many years, there have been sporadic reports of additional human retroviral infections, particularly in cancer and other chronic diseases. Unfortunately, many of these putative viruses remain unproven and controversial, and some retrovirologists have dismissed them as merely “human rumor viruses.” Work in this field was last reviewed in depth in 1984, and since then, the molecular techniques available for identifying and characterizing retroviruses have improved enormously in sensitivity. The advent of PCR in particular has dramatically enhanced our ability to detect novel viral sequences in human tissues. However, DNA amplification techniques have also increased the potential for false-positive detection due to contamination. In addition, the presence of many families of human endogenous retroviruses (HERVs) within our DNA can obstruct attempts to identify and validate novel human retroviruses. Here, we aim to bring together the data on “novel” retroviral infections in humans by critically examining the evidence for those putative viruses that have been linked with disease and the likelihood that they represent genuine human infections. We provide a background to the field and a discussion of potential confounding factors along with some technical guidelines. In addition, some of the difficulties associated with obtaining formal proof of causation for common or ubiquitous agents such as HERVs are discussed.

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Endogenous MMTV Proviruses Induce Susceptibility to Both Viral and Bacterial Pathogens

Cited by 21 publications

References 57 publications

Expression of Murine APOBEC3 Alleles in Different Mouse Strains and Their Effect on Mouse Mammary Tumor Virus Infection

Expression of Murine APOBEC3 Alleles in Different Mouse Strains and Their Effect on Mouse Mammary Tumor Virus Infection

Mapping of the Functional Boundaries and Secondary Structure of the Mouse Mammary Tumor Virus Rem-responsive Element

Human RNA “Rumor” Viruses: the Search for Novel Human Retroviruses in Chronic Disease

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