Mutational analysis of the murine AIDS-defective viral genome reveals a high reversion rate in vivo and a requirement for an intact Pr60gag protein for efficient induction of disease

Huang, Ming; Hanna, Zaher; Jolicoeur, Paul

doi:10.1128/jvi.69.1.60-68.1995

Cited by 11 publications

(7 citation statements)

References 27 publications

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“…Currently proposed models suggest that lymphoproliferation associated with MAIDS locally involves the presence of: (1) the Pr60 gag protein encoded by the defective retrovirus genome; (2) B lymphocytes; and (3) CD4 + T cells [5,26,27]. Since the detection of the provirus renders likely the presence of the retroviral protein in the PP of infected mice, our results minimally suggest that either the PP microenvironment or the differentiation stage of PP lymphocytes locally modulates the lymphoproliferative process which is observed in the other lymphoid organs.…”

Section: Discussionmentioning

confidence: 99%

Peyer's Patches in Murine AIDS: Dissociation Between Lymphoproliferation and Anergy

Colombi¹,

Moutschen

Leval³

et al. 1997

Scand J Immunol

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RadLV-Rs infection induces a murine immunodeficiency syndrome associated with a dramatic enlargement of spleen and lymph nodes. Surprisingly, the lymphoproliferation excludes thymus and Peyer's patches (PP). To understand the cellular interactions underlying lymphoproliferation further, the authors investigated the fate of PP in RadLV-Rs infected mice. The atrophy of PP was mostly due to the depletion of B cells, while the proportion of CD4 + and CD8 + T cells was increased. Nevertheless, B cell phenotype was modified with the emergence of lymphocytes with a low expression of B220 in infected PP. T cells characterized by a memory/ activated phenotype in control PP did not undergo phenotypical changes after viral infection (i.e. regarding Thy-1 and CD44 expression). Despite the absence of lymphoproliferation, PP T and B cells displayed altered responses to mitogens in vitro. Finally, alterations of the expression of adhesion molecules and vascular addressins could not explain the atrophy of PP by a reduced homing to this lymphoid site. B cells and T cells from normal PP are clearly different from lymph nodes (LN) lymphocytes. The authors propose that the particular functional state which characterizes PP lymphocytes influences the B cell/T cell crosstalk necessary for RadLV-Rs-induced lymphoproliferation.

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Section: Discussionmentioning

confidence: 99%

Peyer's Patches in Murine AIDS: Dissociation Between Lymphoproliferation and Anergy

Colombi¹,

Moutschen

Leval³

et al. 1997

Scand J Immunol

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“…If the MAIDS defective virus does not encode a classical SAG, how does it induce the severe immune defects seen in inoculated mice? The Pr60 gag fusion protein appears to be the only gene product encoded by the defective viral genome (1,23). Moreover, mutational analysis has shown that this protein is essential for the pathogenicity of the virus (23,25,38,47).…”

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confidence: 99%

“…A third mechanism to explain the immune disorders seen in MAIDS has been proposed previously. This model postulates that the immune deficiency syndrome arises as a paraneoplasic phenomenon, as a consequence of the proliferation and reprogramming of the infected B cells (23,25,28,30,31,49). These infected B cells could produce a new factor responsible for triggering the immune defects.…”

Section: Downloaded Frommentioning

confidence: 99%

“…The defective virus encodes an uncleaved Gag precursor protein, Pr60 gag , which is myristylated and phosphorylated (6,24). This viral protein diverges from other MuLV Gag proteins mostly in its p12 region (1) and has been found to play an essential role in the pathogenesis of the syndrome, as deletion, point mutations, or myristylation-negative mutations of this protein were found to abolish the pathogenicity of the virus (23,25,47).…”

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Evidence that the murine AIDS defective virus does not encode a superantigen

Doyon

Simard

Sékaly

et al. 1996

J Virol

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The T-cell receptor repertoire was analyzed in C57BL/6 mice upon infection with helper-free stocks of the pathogenic murine AIDS (MAIDS) defective virus in order to demonstrate if, as previously reported, this virus encodes a superantigen. A polyclonal T-cell stimulation involving T cells expressing multiple V␤ subsets occurred within the first week of infection, while late in the disease we could note only a 50% deletion of V␤5 CD8 ؉ cells. Transfection of the MAIDS virus genomic DNA into fibroblasts and B cells expressing major histocompatibility complex class II molecules failed to show any stimulation of cells expressing the specific V␤ (V␤5) previously reported to respond to MAIDS virus-infected cells. In addition, mice lacking V␤5 cells did not show any significant decrease in susceptibility to the disease compared with mice expressing V␤5 and bred on the same genetic background. Our in vivo and in vitro results fail to demonstrate a role for a superantigen encoded by the MAIDS defective viral genome in the pathogenesis of MAIDS.

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“…The defective viral genome does not harbor an oncogene and appears to encode a single protein, the Pr60 gag precursor (2,10,25). This protein and its location on cell membranes seem necessary and suffi-cient for the virus to induce rapid expansion of infected target cells (24,26,51). Initially, this proliferation is polyclonal, but it is clonal or oligoclonal in late stages of the disease (29).…”

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confidence: 99%

The murine AIDS defective provirus acts as an insertional mutagen in its infected target B cells

Huang

Takác

Kozak

et al. 1995

J Virol

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In susceptible mice, the murine AIDS (MAIDS) defective virus can induce marked expansion of its target cells, the majority of which belong to the B-cell lineage. This expansion, which appears to be critical for the development of the immunodeficiency syndrome, is initially polyclonal but becomes oligoclonal late in the disease, suggesting the involvement of a secondary genetic event(s) during this proliferation. To determine whether integration of the MAIDS defective provirus into particular regions of the cellular genome contributes to this oligoclonal expansion, we searched for common provirus integration sites in enlarged lymphoid organs of MAIDS mice. We identified two common proviral integration sites, Dis-1 and Dis-2, which were occupied by a defective provirus at frequencies of 20 and 13%, respectively. Our analysis revealed that the Dis-1 region corresponds to the Sfpi1 (Spi-1, PU.1) locus, which maps on chromosome 2, and encodes a transcription factor. Insertion of the MAIDS defective provirus into this region led to a two-to threefold increase in the expression of Sfpi1 RNA. The Dis-2 locus was found to map to mouse chromosome 11, between Hox2 and Scya. It appears to be a novel locus probably harboring a gene involved in B-cell proliferation. The present study indicates that the MAIDS defective provirus can act as an insertional mutagen, thus contributing to the oligoclonal expansion of infected cells. The detection of two common proviral integration sites, each of which targetted at a low frequency in diseased organs, suggests that the deregulation of a unique gene through provirus insertion is essential for neither proliferation of infected B cells nor development of the immunodeficiency syndrome.

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Mutational analysis of the murine AIDS-defective viral genome reveals a high reversion rate in vivo and a requirement for an intact Pr60gag protein for efficient induction of disease

Cited by 11 publications

References 27 publications

Peyer's Patches in Murine AIDS: Dissociation Between Lymphoproliferation and Anergy

Peyer's Patches in Murine AIDS: Dissociation Between Lymphoproliferation and Anergy

Evidence that the murine AIDS defective virus does not encode a superantigen

The murine AIDS defective provirus acts as an insertional mutagen in its infected target B cells

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