Neuropathogenesis of influenza virus infection in mice

The neurovirulent WSN strain of influenza A virus, introduced into the olfactory bulb of C57BL/6 mice, selectively attacks several brain nuclei which are highly implicated in the pathogenesis of neuropsychiatric disturbances. The virus-infected neurons are eradicated through apoptotic neurodegeneration. On the other hand, activated microglia serve the neuroprotection against virus infection.     

Neuropathogenesis of HIV-1 infection. Outstanding questions

Significant progress in understanding and treating acquired immunodeficiency syndrome (AIDS) has been made over the last 5 years. Current multi drug therapies prolong patients' lives and reduce the incidence of neurobehavioural symptoms. However, the impact of therapy on human immunodeficiency virus type one (HIV-1), the causative agent of AIDS, in the brain, is unknown. Some patients develop dementia in spite of the multi drug therapies and others develop subtle neurobehavioural changes that diminish the quality of their prolonged lives. Thus, HIV-1 infection of the central nervous system remains an important clinical concern. Although much is known about neuropathology of HIV-1 infection, major questions about neuropathogenesis remain. How does HIV-1 reach the brain? Is it present in neurons and glial cells? What is the biological and therapeutic significance of neurotropism of HIV-1? What causes neuronal damage and loss? And, is CNS a resevoir of HIV-1? More research in vivo and in situ in humans and in animals, is needed to answer these outstanding questions. Specific experiments addressing these questions are proposed.     

Neuropathogenesis of Japanese Encephalitis in a Primate Model

Background

Japanese encephalitis (JE) is a major cause of mortality and morbidity for which there is no treatment. In addition to direct viral cytopathology, the inflammatory response is postulated to contribute to the pathogenesis. Our goal was to determine the contribution of bystander effects and inflammatory mediators to neuronal cell death.

Methodology/Principal Findings

Material from a macaque model was used to characterize the inflammatory response and cytopathic effects of JE virus (JEV). Intranasal JEV infection induced a non-suppurative encephalitis, dominated by perivascular, infiltrates of mostly T cells, alongside endothelial cell activation, vascular damage and blood brain barrier (BBB) leakage; in the adjacent parenchyma there was macrophage infiltration, astrocyte and microglia activation. JEV antigen was mostly in neurons, but there was no correlation between intensity of viral infection and degree of inflammatory response. Apoptotic cell death occurred in both infected and non-infected neurons. Interferon-α, which is a microglial activator, was also expressed by both. Tumour Necrosis Factor-α, inducible nitric oxide synthase and nitrotyrosine were expressed by microglial cells, astrocytes and macrophages. The same cells expressed matrix metalloproteinase (MMP)-2 whilst MMP-9 was expressed by neurons.

Conclusions/Significance

The results are consistent with JEV inducing neuronal apoptotic death and release of cytokines that initiate microglial activation and release of pro-inflammatory and apoptotic mediators with subsequent apoptotic death of both infected and uninfected neurons. Activation of astrocytes, microglial and endothelial cells likely contributes to inflammatory cell recruitment and BBB breakdown. It appears that neuronal apoptotic death and activation of microglial cells and astrocytes play a crucial role in the pathogenesis of JE.     

Neuropathogenesis of chimeric simian human immunodeficiency virus infection in rhesus macaques

Comparative studies were performed to determine the neuropathogenesis of infection in macaques with simian human immunodeficiency virus (SHIV)89.6P and SHIV(KU). Both viruses utilize the CD4 receptor and CXCR4 co-receptor. However, in addition, SHIV89.6P uses the CCR5 co-receptor. Both agents are dual tropic for CD4+ T cells and blood-derived macrophages of rhesus macaques. Following inoculation into macaques, both caused rapid elimination of CD4+ T cells but they varied greatly in mechanisms of neuropathogenesis. Two animals infected with SHIV89.6P developed typical lentiviral encephalitis in which multinucleated giant cell formation, nodular accumulations of microglial cells, activated macrophages and astrocytes, and perivascular accumulations of mononuclear cells were present in the brain. Many of the macrophages in these lesions contained viral RNA. Three macaques infected with SHIV(KU) and killed on days 6, 11 and 18, respectively, developed a slowly progressive infection in the CNS but macrophages were not productively infected and there were no pathological changes in the brain. Two other animals infected with this virus and killed several months later showed minimal infection in the brain even though one of the two developed encephalitis of unknown etiology. The basic difference in the mechanisms of neuropathogenesis by the two viruses may be related to co-receptor usage. SHIV89.6P, in utilizing the CCR5 co-receptor, caused neuropathogenic effects that are similar to other neurovirulent primate lentiviruses.     

Neuropathogenesis of chimeric simian human immunodeficiency virus infection in rhesus macaques

Comparative studies were performed to determine the neuropathogenesis of infection in macaques with simian human immunodeficiency virus (SHIV)89.6P and SHIV_KU. Both viruses utilize the CD4 receptor and CXCR4 co-receptor. However, in addition, SHIV89.6P uses the CCR5 co-receptor. Both agents are dual tropic for CD4⁺ T cells and blood-derived macrophages of rhesus macaques. Following inoculation into macaques, both caused rapid elimination of CD4⁺ T cells but they varied greatly in mechanisms of neuropathogenesis. Two animals infected with SHIV89.6P developed typical lentiviral encephalitis in which multinucleated giant cell formation, nodular accumulations of microglial cells, activated macrophages and astrocytes, and perivascular accumulations of mononuclear cells were present in the brain. Many of the macrophages in these lesions contained viral RNA. Three macaques infected with SHIV_KU and killed on days 6, 11 and 18, respectively, developed a slowly progressive infection in the CNS but macrophages were not productively infected and there were no pathological changes in the brain. Two other animals infected with this virus and killed several months later showed minimal infection in the brain even though one of the two developed encephalitis of unknown etiology. The basic difference in the mechanisms of neuropathogenesis by the two viruses may be related to co-receptor usage. SHIV89.6P, in utilizing the CCR5 co-receptor, caused neuropathogenic effects that are similar to other neurovirulent primate lentiviruses.     

Interferon-Induced Ifit2/ISG54 Protects Mice from Lethal VSV Neuropathogenesis

Interferon protects mice from vesicular stomatitis virus (VSV) infection and pathogenesis; however, it is not known which of the numerous interferon-stimulated genes (ISG) mediate the antiviral effect. A prominent family of ISGs is the interferon-induced with tetratricopeptide repeats (Ifit) genes comprising three members in mice, Ifit1/ISG56, Ifit2/ISG54 and Ifit3/ISG49. Intranasal infection with a low dose of VSV is not lethal to wild-type mice and all three Ifit genes are induced in the central nervous system of the infected mice. We tested their potential contributions to the observed protection of wild-type mice from VSV pathogenesis, by taking advantage of the newly generated knockout mice lacking either Ifit2 or Ifit1. We observed that in Ifit2 knockout (Ifit2 ^−/−) mice, intranasal VSV infection was uniformly lethal and death was preceded by neurological signs, such as ataxia and hind limb paralysis. In contrast, wild-type and Ifit1 ^−/− mice were highly protected and survived without developing such disease. However, when VSV was injected intracranially, virus replication and survival were not significantly different between wild-type and Ifit2^−/− mice. When administered intranasally, VSV entered the central nervous system through the olfactory bulbs, where it replicated equivalently in wild-type and Ifit2 ^−/− mice and induced interferon-β. However, as the infection spread to other regions of the brain, VSV titers rose several hundred folds higher in Ifit2 ^−/− mice as compared to wild-type mice. This was not caused by a broadened cell tropism in the brains of Ifit2 ^−/− mice, where VSV still replicated selectively in neurons. Surprisingly, this advantage for VSV replication in the brains of Ifit2^−/− mice was not observed in other organs, such as lung and liver. Pathogenesis by another neurotropic RNA virus, encephalomyocarditis virus, was not enhanced in the brains of Ifit2 ^−/− mice. Our study provides a clear demonstration of tissue-, virus- and ISG-specific antiviral action of interferon.     

Dopamine Increases CD14+CD16+ Monocyte Migration and Adhesion in the Context of Substance Abuse and HIV Neuropathogenesis

Drug abuse is a major comorbidity of HIV infection and cognitive disorders are often more severe in the drug abusing HIV infected population. CD14⁺CD16⁺ monocytes, a mature subpopulation of peripheral blood monocytes, are key mediators of HIV neuropathogenesis. Infected CD14⁺CD16⁺ monocyte transmigration across the blood brain barrier mediates HIV entry into the brain and establishes a viral reservoir within the CNS. Despite successful antiretroviral therapy, continued influx of CD14⁺CD16⁺ monocytes, both infected and uninfected, contributes to chronic neuroinflammation and the development of HIV associated neurocognitive disorders (HAND). Drug abuse increases extracellular dopamine in the CNS. Once in the brain, CD14⁺CD16⁺ monocytes can be exposed to extracellular dopamine due to drug abuse. The direct effects of dopamine on CD14⁺CD16⁺ monocytes and their contribution to HIV neuropathogenesis are not known. In this study, we showed that CD14⁺CD16⁺ monocytes express mRNA for all five dopamine receptors by qRT-PCR and D1R, D5R and D4R surface protein by flow cytometry. Dopamine and the D1-like dopamine receptor agonist, {"type":"entrez-protein","attrs":{"text":"SKF38393","term_id":"1157151916","term_text":"SKF38393"}}SKF38393, increased CD14⁺CD16⁺ monocyte migration that was characterized as chemokinesis. To determine whether dopamine affected cell motility and adhesion, live cell imaging was used to monitor the accumulation of CD14⁺CD16⁺ monocytes on the surface of a tissue culture dish. Dopamine increased the number and the rate at which CD14⁺CD16⁺ monocytes in suspension settled to the dish surface. In a spreading assay, dopamine increased the area of CD14⁺CD16⁺ monocytes during the early stages of cell adhesion. In addition, adhesion assays showed that the overall total number of adherent CD14⁺CD16⁺ monocytes increased in the presence of dopamine. These data suggest that elevated extracellular dopamine in the CNS of HIV infected drug abusers contributes to HIV neuropathogenesis by increasing the accumulation of CD14⁺CD16⁺ monocytes in dopamine rich brain regions.     

AIDS now

Two philosphers from the University of Helsinki argue that, despite beliefs to the contrary in the Western world, AIDS is no longer predominantly a problem limited to homosexuals. First they clarify this claim by presenting epidemiological data. They then consider three ethical issues that have resulted from fearful public reaction to the rapid spread of AIDS: discrimination against those infected with the human immunodeficiency virus (HIV); proposed legal restrictions on personal choices, especially sexual; and screening for HIV antibodies without consent. The H?yrys then discuss whether there is a right not to know one's HIV status. Their essay concludes with suggestions of three ways to fight the spread of AIDS that should be implemented immediately: more support for AIDS research, organization of sociomedical actions such as information campaigns to slow the spread of the disease, and enactment of antidiscrimination legislation.     

Rethinking AIDS

AIDS and Intravenous Drug Use: The Influence of Morality, Politics, Social Science, and Race in the Making of. Tragedy. M. Daniel Fernando. Westport, CT: Praeger Publishers, 1993.167 pp.