Antibody Alone Does Not Prevent Experimental Cytomegalovirus Retinitis in Mice with Retrovirus-lnduced Immunodeficiency (MAIDS)

Dix, Richard D.; Cray, Carolyn; Cousins, Scott W.

doi:10.1159/000268039

Cited by 17 publications

(26 citation statements)

References 10 publications

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“…These eyes harbored high titers of infectious virus consistent with the presence of productive infection during retinitis. These findings support an earlier observation that development of retinitis correlates with high titers of intraocular virus (10,11) and suggest that PKO mice but not gld mice are unable to clear infectious MCMV from ocular tissues when compared at day 8 after subretinal MCMV inoculation.…”

Section: Resultssupporting

confidence: 89%

“…A hematoxylin and eosin stain was used; original magnification, ϫ200. normal mice (10,12) (Fig. 1A).…”

Section: Resultsmentioning

confidence: 97%

“…Results are shown in Table 1. None (0%) of the MCMV-infected eyes of gld mice (zero of eight) or normal mice (zero of eight) developed retinal necrosis, although retinal folding was apparent in some histopathologic sections as noted previously in virus-infected eyes of (10,12). A hematoxylin and eosin stain was used; original magnification, ϫ200.…”

Section: Resultsmentioning

confidence: 99%

“…The presence of MCMV-induced intranuclear inclusions within the cells of both the neurosensory retina and retinal pigment epithelium supports the existence of productive virus infection during the pathogenesis of experimental MCMV retinitis. It has been shown previously that development of retinitis in MCMV-infected eyes of mice with MAIDS correlates with the recovery of large amounts of infectious virus from whole eyes (10,11). To determine if this correlation extended to MCMV-infected eyes of PKO mice that are susceptible to retinitis, groups of PKO mice, gld mice, MAIDS mice, and normal mice were inoculated subretinally with MCMV.…”

Section: Resultsmentioning

confidence: 99%

“…Previous in vitro studies have shown that exogenous interleukin-2 (IL-2), a Th1 regulatory cytokine of T-cell origin with potent effects on T cells, B cells, and NK cells (47), enhances the depressed NK cell activity and HCMV-specific cytotoxic T-cell activity of peripheral blood mononuclear cells recovered from patients with AIDS (43). Moreover, it has been shown previously that systemic cytokine immunotherapy with IL-2 during MAIDS will restore resistance to MCMV retinitis at a level seen in normal, healthy mice following subretinal MCMV inoculation (12). Experiments are presently in progress to determine if protection provided by IL-2 immunotherapy during MAIDS correlates with an upregulation of perforin mRNA levels.…”

Section: Discussionmentioning

confidence: 99%

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Loss of the Perforin Cytotoxic Pathway Predisposes Mice to Experimental Cytomegalovirus Retinitis

Dix

Podack²,

Cousins

2003

J Virol

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AIDS-related human cytomegalovirus (HCMV) retinitis continues to be a chronic ophthalmologic problem among human immunodeficiency virus type 1 (HIV-1)-infected patients who do not respond to highly active antiretroviral therapy. Although HCMV retinitis occurs during HIV-1-induced immunosuppression, the precise effector mechanism(s) that fails during the immunopathogenesis of AIDS to allow onset and progression of HCMV retinal disease remains unclear. We therefore performed a series of experiments to explore the relative roles of distinct pathways of lymphocyte-mediated cytotoxicity in either resistance or susceptibility to experimental murine cytomegalovirus (MCMV) retinitis in mice. Whereas mutant C57BL/6 mice deficient in the Fas/FasL cytotoxic pathway (gld mice) were identical to normal C57BL/6 mice and exhibited absolute resistance to retinal necrosis following subretinal MCMV inoculation, knockout C57BL/6 mice deficient in the perforin cytotoxic pathway (PKO mice) were susceptible to MCMV retinitis. Susceptibility of PKO mice to MCMV retinitis correlated with increased ocular MCMV titers when compared with ocular MCMV titers of gld and normal mice. Since mice with retrovirus-induced immunodeficiency syndrome (MAIDS) exhibited a frequency and severity of MCMV retinitis that were equivalent to those observed in PKO mice, we hypothesized that susceptibility to MCMV retinitis during MAIDS correlates with a decrease in the perforin cytotoxic pathway. To test this hypothesis, we developed a quantitative competitive reverse transcription-PCR assay to measure mouse perforin mRNA levels in the splenic T lymphocytes and MCMV-inoculated eyes of normal mice or mice with MAIDS. Perforin mRNA levels in splenic T lymphocytes were significantly decreased during MAIDS, by ϳ100-fold, from perforin mRNA levels in normal mice. Moreover, MCMV-inoculated eyes destined to develop retinitis during MAIDS also showed a significant decrease in perforin mRNA levels from the perforin mRNA levels of MCMV-inoculated eyes of normal mice destined to be resistant to retinitis. As expected, perforin mRNA could not be detected in unmanipulated and uninfected eyes of normal mice. These results provide the first evidence that the perforin cytotoxic pathway is more important than the Fas/FasL cytotoxic pathway in providing resistance to experimental MCMV retinitis and that loss of the perforin cytotoxic pathway predisposes to MCMV retinitis.

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Section: Resultssupporting

confidence: 89%

“…A hematoxylin and eosin stain was used; original magnification, ϫ200. normal mice (10,12) (Fig. 1A).…”

Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Loss of the Perforin Cytotoxic Pathway Predisposes Mice to Experimental Cytomegalovirus Retinitis

Dix

Podack²,

Cousins

2003

J Virol

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A Mouse Model for Cytomegalovirus Infection

2001

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This unit describes procedures for infecting newborn and adult mice with murine cytomegalovirus (mCMV). Methods are included for propagating mCMV in cell cultures and for preparing a more virulent form of mCMV from salivary glands of infected mice. A plaque-forming cell (PFC) assay is provided for measuring mCMV titers of infected tissues or virus stocks. In addition, a method is described for preparing the murine embryonic fibroblasts used for propagating mCMV and for the PFC assay.

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Polyclonal cytomegalovirus-specific antibodies not only prevent virus dissemination from the portal of entry but also inhibit focal virus spread within target tissues

Wirtz

Schader

Holtappels

et al. 2008

Med Microbiol Immunol

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Therapy of cytomegalovirus (CMV) infection in recipients of hematopoietic stem cell transplantation (HSCT) by immune serum transfer did not fulfill the high clinical expectations, although immune sera or immunoglobulin-enriched preparations pooled from many CMV-immune donors are likely to contain virus neutralizing antibodies covering a broad range of virus variants. Likewise, the highest risk of CMV disease in HSCT recipients results from the reactivation of the latently infected recipient's own virus despite pre-transplantation humoral immunity. These findings suggest the conclusion that antiviral antibodies are inefficient in controlling CMV. Rather than B cells and antibodies, T cells, in particular CD8 T cells, are thought to play a major role in resolving established organ infection. In theory, antibodies, though being capable of neutralizing free virions, could fail to prevent cell-bound virus dissemination from the portal of entry to distant target tissues and also could fail in preventing cell-to-cell spread within tissue. Here we have used murine model systems, including B cell deficient C57BL/6 micro(- ) micro(-) (microMT) mutants, to revisit the role of antiviral antibodies in the control of CMV infection and to reevaluate the prospects of an antibody-based immunotherapy from a basic science point of view.

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Antibody Alone Does Not Prevent Experimental Cytomegalovirus Retinitis in Mice with Retrovirus-lnduced Immunodeficiency (MAIDS)

Cited by 17 publications

References 10 publications

Loss of the Perforin Cytotoxic Pathway Predisposes Mice to Experimental Cytomegalovirus Retinitis

Loss of the Perforin Cytotoxic Pathway Predisposes Mice to Experimental Cytomegalovirus Retinitis

A Mouse Model for Cytomegalovirus Infection

Polyclonal cytomegalovirus-specific antibodies not only prevent virus dissemination from the portal of entry but also inhibit focal virus spread within target tissues

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