No abstract

The pathogenesis of central nervous system (CNS) disease in acquired immunodeficiency syndrome (AIDS) is poorly understood but may be related to specific effects of the immune system. Cytokines such as tumor necrosis factor and interleukin-1 may have toxic effects on CNS cells and have been postulated to contribute to the pathogenesis of the neurological complications of human immunodeficiency virus (HIV) infection. To characterize viral and immunological activity in the CNS, frozen specimens taken at autopsy from the cerebral cortex and white matter of HIV-seropositive and -seronegative individuals were stained immunocytochemically for mononuclear cells, major histocompatibility complex (MHC) antigens, HIV, astrocytes, and the cytokines interleukin-1 and -6, tumor necrosis factor-alpha and -beta, and interferon gamma. Levels of soluble CD4, CD8, and interleukin-2 receptor, as well as interferon gamma, tumor necrosis factor-alpha, beta 2-microglobulin, neopterin, and interleukin-6 and -1 beta were assayed in the cerebrospinal fluid and plasma of many of these individuals during life. The HIV-seropositive group included individuals without neurological disease, those with CNS opportunistic infections, and those with HIV encephalopathy. Perivascular cells, consisting primarily of macrophages with some CD4+ and CD8+ T cells and rare B cells, were consistently MHC class II positive. MHC class II antigen was also present on microglial cells, which were frequently positive for tumor necrosis factor-alpha. HIV p24 antigen, when present, was found on macrophages and microglia. Endothelial cells were frequently positive for interleukin-1 and interferon gamma and less frequently for tumor necrosis factor and interleukin-6. There were gliosis and significant increases in MHC class II antigen, interleukin-1, and tumor necrosis factor-alpha in HIV-positive patients compared to HIV-negative brains. Cerebrospinal fluid from most of the patients tested had increased levels of tumor necrosis factor, beta 2-microglobulin, and neopterin. There was no correlation in HIV-positive individuals between levels of cytokines and the presence or absence of CNS disease. These data indicate that there is a relative state of "immune activation" in the brains of HIV-positive compared to HIV-negative individuals, and suggest a potential role for the immune system in the pathogenesis of HIV encephalopathy.

The pathogenesis of the dementia associated with human immunodeficiency virus (HIV) infection is unclear, but has been postulated to be due to indirect effects of HIV infection including the local production of cytokines. To determine which cytokines are produced in the nervous system and to identify any correlations with dementia, cytokine and HIV messenger RNA expression was analyzed by reverse transcriptase-polymerase chain reaction in the brains from 24 HIV-infected patients with and without dementia and 9 HIV-uninfected control subjects. Levels of tumor necrosis factor-alpha messenger RNA were significantly higher and levels of interleukin (IL)-4 messenger RNA were significantly lower in demented compared to nondemented HIV-infected patients. Demented patients also had lower IL-1 beta levels than did nondemented patients. No significant differences were detected in the amounts of leukemia inhibitory factor, IL-6, transforming growth factor-beta 1 and -beta 2, monokine induced by gamma interferon-2 (MIG-2), or interferon-gamma messenger RNAs. IL-10 and IL-2 messenger RNAs were undetectable in all brains examined. Cytokine messenger RNA levels in nondemented HIV-positive patients were similar to those in HIV-negative control subjects. HIV transcripts were more abundant in subcortical white matter than in the basal ganglia, cortex, or deep white matter. Our findings suggest a possible role for tumor necrosis factor-alpha in the development of neurological dysfunction. Increased levels of tumor necrosis factor-alpha messenger RNA were not associated with increased levels of IL-1 beta messenger RNA, suggesting differential regulation of these monokines in acquired immunodeficiency syndrome dementia.(ABSTRACT TRUNCATED AT 250 WORDS)

Human immunodeficiency virus (HIV)-associated dementia (HAD) is common among clade B HIV-infected individuals, but less common and less severe among individuals infected with clade C HIV-1, suggesting clade-specific differences in neuropathogenicity. Although differences in neuropathogenicity have been investigated in vitro using viral proteins responsible for HAD, to date there are no virological studies using animal models to address this issue. Therefore, we investigated neuropathogenesis induced by HIV-1 clades using the severe combined immune deficiency (SCID) mouse HIV encephalitis model, which involves intracranial injection of macrophages infected with representative clade B (HIV-1 ADA ) or clade C (HIV-1 Indie-C1 ) HIV-1 isolates into SCID mice. In cognitive tests, mice exposed to similar inputs of HIV-1 clade C made fewer memory errors than those exposed to HIV-1 clade B. Histopathological analysis of mice exposed to clade B exhibited greater astrogliosis and increased loss of neuronal network integrity. In vitro experiments revealed differences in a key characteristic of HIV-1 that influences HAD, increased monocyte infiltration. HIV-1 Indie-C1 -infected macrophages recruited monocytes poorly in vitro compared with HIV-1 ADA -infected macrophages. Monocyte recruitment was HIV-1 Tat and CCL2 dependent. This is the first demonstration, ever since HIV neuropathogenesis was first recognized, that viral genetic differences between clades can affect disease severity and that such studies help identify key players in neuropathogenesis by HIV-1.

No abstract

Alphaviruses infect neurons in the brain and spinal cord and cause acute encephalomyelitis in a variety of mammals. The outcome of infection is determined by whether the neurons survive infection and this, in turn, is determined by the virulence of the virus and the age of the host at the time of infection. We have been studying Sindbis virus (SV) infection of mice as a model system for alphavirus-induced encephalomyelitis. Investigation of intracerebral infection of weanling mice with two different strains of SV has allowed us to analyze the role of the immune response in protection from fatal disease (virulent NSV strain) and in clearance of virus from the nervous system during non-fatal disease (less virulent SV AR339 strain). Neutralizing and non-neutralizing antibodies to the E1 and E2 surface glycoproteins can protect mice from fatal NSV infection when given before or after infection, while T cells are not protective. The mechanism of antibody-mediated protection is not known, but it is likely that more than one mechanism is involved and that different mechanisms are involved in pre-infection and post-infection treatment protection. Clearance of infectious virus from the nervous system of mice during recovery from non-fatal disease is accomplished by antibodies to the E2 glycoprotein. The process does not involve damage to the infected neurons and is independent of complement and mononuclear cells. Bivalent antibody is required and binds to the surface of the infected cell. Initially, release of virus by budding from the cell surface is prevented and, subsequently, intracellular virus replication is inhibited possibly through antiviral mechanisms induced in co-operation with interferon. This non-lytic mechanism for control of virus infection results in the prolonged presence of viral RNA in tissue and the need for prolonged intrathecal synthesis of antiviral antibody by B cells within the central nervous system.

No abstract

Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system (CNS). It predominantly affects young women and is one of the most common causes of disability in young adults. MS is characterized by formation of white matter lesions in the CNS as a result of inflammation, demyelination, and axonal loss. Treatment has been a focus of neurological research for over 60 years. A number of disease-modifying therapies (DMTs) have become available making MS a treatable disease. These compounds target the inflammatory response in MS. They work by decreasing the chances of relapse, decreasing the chances of new lesion formation seen on MRI of the CNS and slowing the accumulation of disability. The first drugs for MS to be available were interferon-β and glatiramer acetate. These work by modulating the inflammatory response via different mechanisms that are briefly discussed. Newer agents have since become available and have significantly changed the dynamics of MS treatment. These include fingolimod, dimethyl fumarate and teriflunomide, which are oral agents. Other second-line and thirdline Food and Drug Administration (FDA) approved medications include natalizumab and alemtuzumab.