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Human retinal and brain cell lines: A model of HCMV retinitis and encephalitis
1Department of Pathology, Morehouse School of Medicine, Atlanta, Georgia 30310, USA. duttk@msn.edu
Insights
Human cytomegalovirus (HCMV) infects human brain and retinal cells, accelerating AIDS progression. This study introduces new cell models to investigate HIV-HCMV interactions and test antiviral therapies for neurological complications.
Area of Science:
- Virology
- Neuroscience
- Immunology
Background:
- Human immunodeficiency virus (HIV) causes AIDS, but co-infections like human cytomegalovirus (HCMV) can accelerate disease progression.
- HCMV frequently infects the central nervous system (CNS) in AIDS patients, leading to encephalitis and retinitis.
- Lack of suitable animal models hinders the study of human HCMV pathogenesis and HIV-HCMV interactions.
Purpose of the Study:
- To develop and validate human cell line models for studying HCMV infectibility and pathogenesis in neural tissues.
- To investigate the interaction between HIV and HCMV at the cellular level.
- To assess the potential of these models for testing antiviral therapies.
Main Methods:
- Development of immortalized human brain (mixed glial/neuronal) and retinal precursor cell lines.
- Infection of cell lines with HCMV (AD 169, Towne strains) and monitoring infectibility via phenotypic analysis, antigen expression (immunohistochemistry, Western blot), and viral particle detection (TEM).
- Assessment of HIV-HCMV interaction using indicator plasmids (HIV-LTR-CAT) and evaluation of HIV production enhancement by HCMV immediate-early (IE) genes.
Main Results:
- Both human brain and retinal cell lines were permissive to HCMV infection, showing viral antigen expression and formation of multinucleate giant cells and syncytia.
- Productive viral infection was confirmed by the ability of infected cell supernatant to induce pathogenicity in fresh cultures.
- Evidence of cellular interaction between HIV and HCMV was demonstrated, with HCMV IE genes enhancing HIV production in infected neural cells.
Conclusions:
- The developed human brain and retinal cell lines serve as optimal models for studying HCMV infectibility and pathogenesis in neural tissues.
- These models are suitable for investigating HIV-HCMV interactions and the molecular mechanisms underlying their interplay.
- The models offer a valuable platform for evaluating the efficacy of antiviral therapies against HCMV and HIV co-infections in the CNS.
Abstract:
Although HIV is accepted as the etiologic agent in AIDS, other factors have been implicated in accelerating the disease. Human cytomegalovirus (HCMV) in particular has been implicated as a cofactor in the progression from AIDS-related complex (ARC) to AIDS. HCMV infection of the central nervous system (CNS) (brain, retina) has been reported in at least 50% of AIDS patients, and has been implicated in producing encephalitis and sight-threatening retinitis. HCMV exhibits strict species specificity and animal models for human HCMV are conspicuous by their absence. We have developed a human brain cell line (mixed glial/neuronal) and a multipotential human retinal precursor cell line (neuronal in nature). We have tested the suitability of these cell lines as models for the study of HCMV infectibility. In this study, we report that these cell lines are optimal for the study of HCMV infectibility and pathogenesis in tissues of neural origin and appropriate to study HIV-HCMV interaction. Immortalized human brain and retinal cell lines were infected with a laboratory strain of HCMV (AD 169, Towne) at a multiplicity of infection moi (1-5) and viral infectibility and cell specificity monitored by: (a) phenotypic analysis (multinucleate cells, syncytium formation, etc.), (b) antigen expression (IE, E, late) by immunohistochemistry, Western blot analysis, (c) presence of viral particles by TEM, and (d) expression of indicator plasmids (HIV-LTR-CAT). We report that both human retinal and brain cell lines are permissive for HCMV infectibility. Cell specificity was not seen; both cells expressing glial/neuronal cell markers were positive for the presence of HCMV early/late antigens. Formation of multinucleate giant cells with nuclear inclusion bodies and syncytia were seen. Productive viral infection was confirmed by the ability of cell-free supernatant from the third passage of infected cells to produce pathogenicity and express viral particles, when added to fresh cultures. Using indicator plasmids, HIV-LTR, and CAT, we have shown that HIV and HCMV interact at the cellular level. We have also shown that HIV production in retinal and brain cell lines transfected with cloned HIV was enhanced by HCMV-IE genes. We did not see any differences in HCMV. AD 169, Towne isolate, and data from both strains is presented in this paper. This model could prove extremely useful for the study of cell specificity/cellular and molecular interaction between HIV/HCMV and to test antiviral therapies.
