scholarly journals A Mouse Model That Mimics AIDS-Related Cytomegalovirus Retinitis: Insights into Pathogenesis

Pathogens ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 850
Author(s):  
Jay J. Oh ◽  
Jessica J. Carter ◽  
Richard D. Dix
Keyword(s):  
Mouse Model ◽  
Mouse Models ◽  
Vision Loss ◽  
Opportunistic Infections ◽  
Retinal Disease ◽  
Cytomegalovirus Retinitis ◽  
Murine Cytomegalovirus ◽  
Virus Infections ◽  
Tissue Destruction ◽  
Immunodeficiency Syndrome

With the appearance of the worldwide AIDS pandemic four decades ago came a number of debilitating opportunistic infections in patients immunosuppressed by the pathogenic human retrovirus HIV. Among these was a severe sight-threatening retinal disease caused by human cytomegalovirus (HCMV) that remains today a significant cause of vision loss and blindness in untreated AIDS patients without access or sufficient response to combination antiretroviral therapy. Early investigations of AIDS-related HCMV retinitis quickly characterized its hallmark clinical features and unique histopathologic presentation but did not begin to identify the precise virologic and immunologic events that allow the onset and development of this retinal disease during HIV-induced immunosuppression. Toward this end, several mouse models of experimental cytomegalovirus retinitis have been developed to provide new insights into the pathophysiology of HCMV retinitis during AIDS. Herein, we provide a summary and comparison of these mouse models of AIDS-related HCMV retinitis with particular emphasis on one mouse model developed in our laboratory in which mice with a murine acquired immunodeficiency syndrome (MAIDS) of murine retrovirus origin develops a reproducible and well characterized retinitis following intraocular infection with murine cytomegalovirus (MCMV). The MAIDS model of MCMV retinitis has advanced the discovery of many clinically relevant virologic and immunologic mechanisms of virus-induced retinal tissue destruction that are discussed and summarized in this review. These findings may extend to the pathogenesis of AIDS-related HCMV retinitis and other AIDS-related opportunistic virus infections.

Mechanisms of AIDS-related cytomegalovirus retinitis

2019 ◽  
Vol 14 (8) ◽  
pp. 545-560 ◽  
Author(s):  
Jessica Carter ◽  
Christine I Alston ◽  
Jay Oh ◽  
Lauren-Ashley Duncan ◽  
Judee Grace Esquibel Nemeno ◽  
...  
Keyword(s):  
Mouse Model ◽  
Human Cytomegalovirus ◽  
Human Disease ◽  
Cytomegalovirus Retinitis ◽  
Murine Cytomegalovirus ◽  
Opportunistic Pathogens ◽  
Aids Patients ◽  
Clinical Burden ◽  
Antiretroviral Therapies ◽  
Murine Aids

Human cytomegalovirus (HCMV) generates a significant clinical burden worldwide, particularly among the immune compromised. In approximately 30% of untreated HIV/AIDS patients without access or sufficient response to antiretroviral therapies, for example, HCMV causes a sight-threatening retinitis. To study the mechanisms of AIDS-related HCMV retinitis, our lab has for many years used a mouse model in which a mixture of mouse retroviruses induces murine AIDS after approximately 10 weeks, rendering otherwise resistant mice susceptible to opportunistic pathogens. This immunodeficiency combined with subretinal inoculation of murine cytomegalovirus yields a reproducible model of the human disease, facilitating the discovery of many clinically relevant virologic and immunologic mechanisms of retinal destruction which we summarize in this review.

scholarly journals Suppressor of Cytokine Signaling 1 (SOCS1) and SOCS3 Are Stimulated within the Eye during Experimental Murine Cytomegalovirus Retinitis in Mice with Retrovirus-Induced Immunosuppression

2018 ◽  
Vol 92 (18) ◽  
Author(s):  
Hsin Chien ◽  
Christine I. Alston ◽  
Richard D. Dix
Keyword(s):  
Cytomegalovirus Infection ◽  
Retinal Disease ◽  
Cytomegalovirus Retinitis ◽  
Murine Cytomegalovirus ◽  
Cytokine Signaling ◽  
Host Proteins ◽  
Suppressor Of Cytokine Signaling ◽  
Mcmv Infection ◽  
Socs Proteins ◽  
Socs3 Mrna

ABSTRACTAIDS-related human cytomegalovirus retinitis remains the leading cause of blindness among untreated HIV/AIDS patients worldwide. To study mechanisms of this disease, we used a clinically relevant animal model of murine cytomegalovirus (MCMV) retinitis with retrovirus-induced murine AIDS (MAIDS) that mimics the progression of AIDS in humans. We found in this model that MCMV infection significantly stimulates ocular suppressor of cytokine signaling 1 (SOCS1) and SOCS3, host proteins which hinder immune-related signaling by cytokines, including antiviral type I and type II interferons. The present study demonstrates that in the absence of retinal disease, systemic MCMV infection of mice without MAIDS, but not in mice with MAIDS, leads to mild stimulation of splenic SOCS1 mRNA. In sharp contrast, when MCMV is directly inoculated into the eyes of retinitis-susceptible MAIDS mice, high levels of intraocular SOCS1 and SOCS3 mRNA and protein are produced which are associated with significant intraocular upregulation of gamma interferon (IFN-γ) and interleukin-6 (IL-6) mRNA expression. We also show that infiltrating macrophages, granulocytes, and resident retinal cells are sources of intraocular SOCS1 and SOCS3 protein production during development of MAIDS-related MCMV retinitis, and SOCS1 and SOCS3 mRNA transcripts are detected in retinal areas histologically characteristic of MCMV retinitis. Furthermore, SOCS1 and SOCS3 are found in both MCMV-infected cells and uninfected cells, suggesting that these SOCS proteins are stimulated via a bystander mechanism during MCMV retinitis. Taken together, our findings suggest a role for MCMV-related stimulation of SOCS1 and SOCS3 in the progression of retinal disease during ocular, but not systemic, MCMV infection.IMPORTANCECytomegalovirus infection frequently causes blindness in untreated HIV/AIDS patients. This virus manipulates host cells to dysregulate immune functions and drive disease. Here, we use an animal model of this disease to demonstrate that cytomegalovirus infection within eyes during retinitis causes massive upregulation of immunosuppressive host proteins called SOCS. As viral overexpression of SOCS proteins exacerbates infection with other viruses, they may also enhance cytomegalovirus infection. Alternatively, the immunosuppressive effect of SOCS proteins may be protective against immunopathology during cytomegalovirus retinitis, and in such a case SOCS mimetics or overexpression treatment strategies might be used to combat this disease. The results of this work therefore provide crucial basic knowledge that contributes to our understanding of the mechanisms of AIDS-related cytomegalovirus retinitis and, together with future studies, may contribute to the development of novel therapeutic targets that could improve the treatment or management of this sight-threatening disease.

scholarly journals Long Term Therapy of Cytomegalovirus Retinitis with Ganciclovir in a Child with Acquired Immunodeficiency Syndrome

1993 ◽  
Vol 4 (1) ◽  
pp. 15-20
Author(s):  
Scott A Halperin ◽  
G Robert La Roche
Keyword(s):  
Drug Toxicity ◽  
Retinal Disease ◽  
Immune Deficiency Syndrome ◽  
Deficiency Syndrome ◽  
Cytomegalovirus Retinitis ◽  
Term Therapy ◽  
Laboratory Findings ◽  
Acquired Immunodeficiency ◽  
Immunodeficiency Syndrome ◽  
Long Term Therapy

Cytomegalovirus retinitis is the most severe ophthalmological complication of patients with acquired immune deficiency syndrome (aids). Ganciclovir must be given continuously to control progression of the disease or relapse typically occurs. Data in children are limited; this report describes a nine-year-old boy with transfusion-acquiredaidswho was treated with ganciclovir for 23 months for control of cytomegalovirus retinitis. The retinal disease was exacerbated when ganciclovir was temporarily withheld because of presumed drug toxicity, and improved with re-institution of therapy. When ganciclovir was finally discontinued because of complete loss of vision, the patient rapidly deteriorated and died; widespread cytomegalovirus infection was found at autopsy. Subcapsular cataracts appearing during therapy were thought to be a toxic effect of ganciclovir. Ganciclovir can be effective in controlling cytomegalovirus retinitis in children; however, similarities in laboratory findings may lead to confusion between systemic drug toxicity and disease progression.

scholarly journals Acquired immunodeficiency syndrome and opportunistic infections

Medicina ◽  
2009 ◽  
Vol 45 (11) ◽  
pp. 929
Author(s):  
Lina Dvaranauskaitė ◽  
Daiva Vėlyvytė ◽  
Virginija Kurklietytė ◽  
Antanas Gumbelevičius ◽  
Evaldas Keleras ◽  
...  
Keyword(s):  
Acquired Immunodeficiency Syndrome ◽  
Clinical Case ◽  
Opportunistic Infections ◽  
Cytomegalovirus Retinitis ◽  
Late Diagnosis ◽  
Cerebral Toxoplasmosis ◽  
Hiv Status ◽  
Clinical Diagnostic ◽  
Acquired Immunodeficiency ◽  
Immunodeficiency Syndrome

This article presents a clinical case of late diagnosis of cerebral toxoplasmosis and cytomegalovirus retinitis of right eye in a 32-year-old patient who was unaware of her HIV status. In addition, this article reviews the literature reflecting clinical, diagnostic, and treatment issues of some opportunistic infections in AIDS.

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

2003 ◽  
Vol 77 (6) ◽  
pp. 3402-3408 ◽  
Author(s):  
Richard D. Dix ◽  
Eckhard R. Podack ◽  
Scott W. Cousins
Keyword(s):  
T Lymphocytes ◽  
Highly Active Antiretroviral Therapy ◽  
Retinal Disease ◽  
Murine Cytomegalovirus ◽  
Mrna Levels ◽  
Reverse Transcription Pcr ◽  
Highly Active ◽  
Series Of Experiments ◽  
Immunodeficiency Syndrome ◽  
Hiv 1

ABSTRACT 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 ∼100-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.

Effects of Plant-Derived Polysaccharides on Murine Cytomegalovirus and Encephalomyocarditis Virus Infections in Mice

1995 ◽  
Vol 6 (6) ◽  
pp. 385-390 ◽  
Author(s):  
D. F. Smee ◽  
A. J. Verbiscar
Keyword(s):  
Body Weight ◽  
Antiviral Activity ◽  
Mouse Models ◽  
Encephalomyocarditis Virus ◽  
Murine Cytomegalovirus ◽  
Virus Infections ◽  
Virus Inoculation ◽  
Antiviral Effects ◽  
Sterculia Urens

Polysaccharides from three plant species, Astragalus brachycentrus (AV222), Astragalus echidnaeformis (AV224) and Sterculia urens (AV223), which are devoid of in vitro antiviral activity, were evaluated in mouse models of murine cytomegalovirus and encephalomyocarditis virus infections. AV223 and AV224 were very potent agents, protecting mice from mortality at intraperitoneal doses between 3.2 and 100 mgkg−1 day−1 treatments. Treatment with compounds needed to be started one day prior to virus inoculation for maximum protective benefit. Treatments starting after virus inoculation were ineffective. No detectable toxicity was apparent in mice treated with up to 100 mg of each polysaccharide per kg of body weight. Interferon was not detected in mouse sera from polysaccharide-treated mice, suggesting a different mode of immuno-enhancement may be responsible for the antiviral effects observed.

Dengue and Zika Virus Infections Are Enhanced by Live Attenuated Dengue Vaccine but Not by Recombinant DSV4 Vaccine Candidate in Mouse Models

2020 ◽  
Author(s):  
Rahul Shukla ◽  
Julia A. Brown ◽  
Hemalatha Beesetti ◽  
Richa Ahuja ◽  
Viswanathan Ramasamy ◽  
...  
Keyword(s):  
Mouse Models ◽  
Zika Virus ◽  
Vaccine Candidate ◽  
Virus Infections ◽  
Dengue Vaccine

scholarly journals Intranasal oxytocin administration ameliorates social behavioral deficits in a POGZWT/Q1038R mouse model of autism spectrum disorder

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Kohei Kitagawa ◽  
Kensuke Matsumura ◽  
Masayuki Baba ◽  
Momoka Kondo ◽  
Tomoya Takemoto ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Social Behavior ◽  
Mouse Model ◽  
Mouse Models ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
De Novo Mutation ◽  
Behavioral Deficits

AbstractAutism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZWT/Q1038R mice), showed ASD-like social behavioral deficits. Here, we have explored whether oxytocin (OXT) administration improves impaired social behavior in POGZWT/Q1038R mice and found that intranasal oxytocin administration effectively restored the impaired social behavior in POGZWT/Q1038R mice. We also found that the expression level of the oxytocin receptor gene (OXTR) was low in POGZWT/Q1038R mice. However, we did not detect significant changes in the number of OXT-expressing neurons between the paraventricular nucleus of POGZWT/Q1038R mice and that of WT mice. A chromatin immunoprecipitation assay revealed that POGZ binds to the promoter region of OXTR and is involved in the transcriptional regulation of OXTR. In summary, our study demonstrate that the pathogenic mutation in the POGZ, a high-confidence ASD gene, impairs the oxytocin system and social behavior in mice, providing insights into the development of oxytocin-based therapeutics for ASD.

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