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Expression of defective virus and cytokine genes in murine AIDS
S C Cheung1, S K Chattopadhyay, H C Morse
1Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Abstract:
A syndrome characterized by severe immunodeficiency and lymphoproliferation develops in susceptible strains of mice infected with a mixture of murine leukemia viruses (MuLVs) designated LP-BM5 MuLV. The etiologic agent in this mixture has been shown to be a replication-defective virus (BM5d) with a 4.8-kb genome that required replication-competent helper viruses, primarily ecotropic (BM5e), for cell-to-cell spread in the host. In the present study, we studied the expression of BM5d and BM5e in tissues of infected mice at various times after inoculation in relation to the expression of cytokine genes that may contribute to the pathogenesis of this disorder. Northern (RNA) analysis of total RNA showed that BM5d was expressed at significant levels in lymphoid tissues within 1 week of infection and that the levels of expression increased with time after inoculation. By 16 weeks postinfection, BM5d was expressed in all tissues examined. Expression of BM5e was relatively more restricted to lymphoid tissues and was detected at lower levels than expression of BM5d at early times after infection, but this virus was expressed in all tissues by 16 weeks. Infection with the virus mixture was associated with constitutive expression of tumor necrosis factor in all tissues examined and of interleukin-1 (IL-1) in lymphoid tissues within 1 week of infection, and at later times with widespread expression of these cytokines and gamma interferon. Also, the levels of interferon regulatory factor 1 mRNA were significantly increased in all infected tissues during the infection. In contrast, expression of IL-3, IL-4, IL-5, and IL-6 was not detectable by Northern analysis of the respective mRNAs in any infected tissue at early or late times postinfection.
Insights
Murine leukemia viruses (MuLVs) cause immunodeficiency and lymphoproliferation in mice. This study tracks viral and cytokine gene expression, revealing widespread viral spread and altered cytokine profiles during infection.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- LP-BM5 MuLV infection in mice causes severe immunodeficiency and lymphoproliferation.
- The LP-BM5 MuLV mixture contains a replication-defective virus (BM5d) dependent on helper viruses (BM5e).
Purpose of the Study:
- To investigate the expression patterns of BM5d and BM5e viruses.
- To correlate viral expression with cytokine gene expression in infected mouse tissues.
- To understand the molecular mechanisms underlying MuLV-induced immunodeficiency.
Main Methods:
- Northern (RNA) analysis was used to quantify viral RNA and cytokine mRNA levels.
- Total RNA was extracted from various tissues of infected mice at different time points.
- Expression levels of BM5d, BM5e, and key cytokine genes (TNF, IL-1, IFN-gamma, IRF1, IL-3, IL-4, IL-5, IL-6) were assessed.
Main Results:
- BM5d expression was detected early in lymphoid tissues and increased over time, becoming widespread by 16 weeks.
- BM5e expression was initially restricted to lymphoid tissues but also became widespread by 16 weeks.
- Constitutive expression of tumor necrosis factor and interleukin-1 was observed early, followed by widespread gamma interferon and increased interferon regulatory factor 1 mRNA levels.
Conclusions:
- Both BM5d and BM5e viruses show increasing and widespread tissue distribution post-infection.
- MuLV infection induces significant alterations in cytokine gene expression, including TNF, IL-1, IFN-gamma, and IRF1.
- The observed viral and cytokine expression patterns contribute to the pathogenesis of MuLV-induced immunodeficiency and lymphoproliferation.