Retrovirus-induced immunodeficiency in the mouse

Morse, Herbert C.; Chattopadhyay, Sisir K.; Makino, Masahiko; Fredrickson, T. N.; Hügin, Ambros W.; Hartley, Janet W.

doi:10.1097/00002030-199207000-00001

Cited by 210 publications

(142 citation statements)

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“…Because of several similar disease manifestations in HIV-induced AIDS and this MAIDS model (22)(23)(24), the recent finding that cryptic MHC class I-restricted epitopes have also been identified in HIV-1 ARFs (25) is especially relevant to our present study. Yet, despite evidence that nontraditional CTL epitopes are generated from frame shifting of HIV translational sequences, a possible in vivo protective role against AIDS for CTL directed against ARF-derived epitopes could not be directly addressed.…”

mentioning

confidence: 86%

Cytolytic CD8+ T Cells Directed against a Cryptic Epitope Derived from a Retroviral Alternative Reading Frame Confer Disease Protection

Green

2006

The Journal of Immunology

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Cytolytic CD8+ T cells (CTL) are key to the immune response that controls virus infections and mediates disease protection. The ability of CTL to induce apoptosis of infected cells and/or limit viral replication is determined by recognition of processed viral peptide epitopes on the surface of the target cell. An understudied source of MHC class I-presented peptides is the aptly named “cryptic epitopes,” defined by their nontraditional methods of generation, including derivation from alternative reading frames (ARFs). Although ARF-encoded epitopes have now been documented in a few systems, their potential functional relevance in vivo has been debated. In this study, we demonstrate the physiological significance of an ARF-derived CTL epitope in a retrovirus-induced disease model. We show that disease-susceptible CD8-deficient mice reconstituted with CTL specific for the retroviral ARF-derived SYNTGRFPPL epitope controlled an infection by the LP-BM5 retrovirus isolate, evidently at the level of viral clearance, resulting in protection of these mice from disease. These data indicate that ARF-derived epitopes are indeed relevant inducers of the immune system and demonstrate the importance of atypically generated peptides as functional Ag with a physiologic role in disease protection.

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confidence: 86%

Cytolytic CD8+ T Cells Directed against a Cryptic Epitope Derived from a Retroviral Alternative Reading Frame Confer Disease Protection

Green

2006

The Journal of Immunology

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“…Immunodeficiency of increasing severity is a second prominent feature of MAIDS (38,39). At 4, 8, and 12 wk p.i., spleen cells were prepared from wild-type and KO mice and stimulated for 48 h with LPS, Con A, and PMA/ionomycin.…”

Section: Immunodeficiency In Cr2-and Cd22-deficient Mice But Not In Cmentioning

confidence: 99%

CD19 Signaling Pathways Play a Major Role for Murine AIDS Induction and Progression

Knoetig

Torrey

Naghashfar

et al. 2002

The Journal of Immunology

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Infection of genetically susceptible mice with the LP-BM5 mixture of murine leukemia viruses including an etiologic defective virus (BM5def) causes an immunodeficiency syndrome called murine AIDS (MAIDS). The disease is characterized by interactions between B cells and CD4+ T cells resulting in polyclonal activation of both cell types. It is known that BM5def is expressed at highest levels in B cells and that B cells serve as viral APC. The CD19-CD21 complex and CD22 on the surface of B cells play critical roles as regulators of B cell responses to a variety of stimuli, influencing cell activation, differentiation, and survival. CD19 integrates positive signals induced by B cell receptor ligation by interacting with the protooncogene Vav, which leads to subsequent tyrosine phosphorylation of this molecule. In contrast, CD22 negatively regulates Vav phosphorylation. To analyze the role of CD19, CD21, Vav, and CD22 in MAIDS, we infected mice deficient in CD19, CD21 (CR2), Vav-1, or CD22 with LP-BM5 murine leukemia viruses. Infected CR2−/− mice developed MAIDS with a time course and severity indistinguishable from that of wild-type mice. In contrast, CD19 as well as Vav-1 deficiency restricted viral replication and suppressed the development of typical signs of MAIDS including splenomegaly, lymphadenopathy, and hypergammaglobulinemia. Finally, CD22 deficiency was found to accelerate MAIDS development. These results provide novel insights into the B cell signaling pathways required for normal induction and progression of MAIDS.

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“…The HIV Gag protein p6 gag , the C-terminal polypeptide of the precursor Pr55 gag , contains a P-X-X-P sequence which is required for e cient virus particle production (Huang et al, 1995) and may function by binding to an SH3 domain-containing protein. Another example of Gag protein participation in pathogenesis is that of the murine acquired de®ciency syndrome (MAIDS) virus, whose causative agent is a defective MuLV encoding a truncated Gag protein p60 gag (Aziz et al, 1989;Morse et al, 1992), which is similar to p58 gag . In one hypothesis proposed to explain the pathogenic e ects of MAIDS, p60 gag is assumed to interact with one or more cellular signal transduction pathways to induce an oncogenic type response (Aziz et al, 1989).…”

Section: Discussionmentioning

confidence: 99%

c-Src association with and phosphorylation of p58gag, a membrane- and microfilament-associated retroviral Gag-like protein in a xenotransplantable rat mammary tumor

Huang

Zhang

et al. 1999

Oncogene

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The retroviral Gag-like protein p58 gag expressed in a highly metastatic ascites rat mammary adenocarcinoma has been implicated in cell surface changes contributing to xenotransplantability. p58 gag is present in the cells in a plasma membrane-and micro®lament-associated signal transduction particle containing Src and is phosphorylated on tyrosine. Overlay analyses and a nity chromatography with glutathione S-transferase (GST) fusion proteins of Src homology-3 (SH3) domains showed direct binding of the Src but not the Crk SH3 domain to p58 gag . This association was con®rmed by coimmunoprecipitation of partially puri®ed p58 gag from ascites cell lysates with platelet Src. Further, a GSTp58 gag fusion protein bound full length c-Src from either platelets or c-Src-expressing insect cells. The GST-p58 gag fusion protein, but not GST, was phosphorylated by platelet or insect cell-expressed c-Src, but not by a kinase negative c-Src variant. The binding of GST-p58 gag to c-Src was almost completely abolished by a 50-fold excess of the GST-SH3 domain of Src, and a parallel decrease in tyrosine phosphorylation of p58 gag was observed. These results demonstrate that p58 gag is tyrosine-phosphorylated as a consequence of its speci®c association with c-Src via its SH3 domain. These observations suggest a mechanism by which Gag proteins may contribute to retroviral maturation or pathogenesis through binding and relocalization of SH3 domaincontaining proteins such as Src-like tyrosine kinases to sites of association of micro®laments with the plasma membrane.

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Retrovirus-induced immunodeficiency in the mouse

Cited by 210 publications

References 0 publications

Cytolytic CD8+ T Cells Directed against a Cryptic Epitope Derived from a Retroviral Alternative Reading Frame Confer Disease Protection

Cytolytic CD8+ T Cells Directed against a Cryptic Epitope Derived from a Retroviral Alternative Reading Frame Confer Disease Protection

CD19 Signaling Pathways Play a Major Role for Murine AIDS Induction and Progression

c-Src association with and phosphorylation of p58gag, a membrane- and microfilament-associated retroviral Gag-like protein in a xenotransplantable rat mammary tumor

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