Increased dopaminergic neurotransmission in therapy-naïve asymptomatic HIV patients is not associated with adaptive changes at the dopaminergic synapses.

Central dopaminergic (DA) systems are affected during human immunodeficiency virus (HIV) infection. So far, it is believed that they degenerate with progression of HIV disease because deterioration of DA systems is evident in advanced stages of infection. In this manuscript we found that (a) DA levels are increased and DA turnover is decreased in CSF of therapy-naïve HIV patients in asymptomatic infection, (b) DA increase does not modulate the availability of DA transporters and D2-receptors, (c) DA correlates inversely with CD4+ numbers in blood. These findings show activation of central DA systems without development of adaptive responses at DA synapses in asymptomatic HIV infection. It is probable that DA deterioration in advanced stages of HIV infection may derive from increased DA availability in early infection, resulting in DA neurotoxicity. Our findings provide a clue to the synergism between DA medication or drugs of abuse and HIV infection to exacerbate and accelerate HIV neuropsychiatric disease, a central issue in the neurobiology of HIV.

Biostatistical analysis of gene microarrays reveals diverse expression clusters between macaque subspecies in brain SIV infection.

In this study we investigated differences in the gene expression profiling of the brains of rhesus macaques that were uninfected or infected with SIV in the asymptomatic stage or AIDS. The main aim was to use biostatistical methods to classify brain gene expression following SIV infection, without consideration of the biological significance of the individual genes. We also used data from animals treated with different pharmacological substances such as dopaminergic drugs, N-methyl-D-aspartate (NMDA) antagonists or antioxidants during the early stage of infection as these animals exhibited an accelerated or attenuated neuropsychiatric disease progression. We found macaque subspecies to be a more important factor for disease classification based on gene expression profiling than clinical symptoms or neuropathological findings. It is noteworthy that SIV-infected pharmacologically-treated. Chinese animals clustered near uninfected animals independent on the outcome of the treatment, whereas untreated SIV infected animals were clustered in a separate subtree. It is clear from this study that NeuroAIDS is a diverse disease entity and that SIV brain genes can be differentially regulated, depending on the disease type as well as changed dependent on the monkey subspecies.

Dopamine deficits and regulation of the cAMP second messenger system in brains of simian immunodeficiency virus-infected rhesus monkeys.

The basal ganglia, structures rich in the neurotransmitter dopamine, are primarily affected during human immunodeficiency virus (HIV) infection. The authors measured levels of dopamine and its metabolites, homovanillic acid and 3,4-dihydroxyphenylacetic acid, in brains of uninfected and simian immunodeficiency virus (SIV)-infected rhesus monkeys during the asymptomatic stage of the infection. Moreover, the authors investigated changes in cyclic adenosine monophosphate (cAMP) and cAMP response element-binding protein (CREB), two factors involved in the signaling pathway of dopamine. The brain regions examined were the nucleus accumbens and the corpus amygdaloideum, which are limbic structures of the basal ganglia that are involved in the pathophysiology of psychiatric disorders and substance abuse. Dopamine content was reduced in both regions of SIV-infected monkeys compared to uninfected animals. Moreover, dopamine deficits were associated with a decrease in expression of total CREB. Intracellular concentrations of cAMP were decreased in nucleus accumbens and remained unchanged in corpus amygdaloideum of SIV-infected macaques. Changes in dopamine signaling were not related to pathology or viral load of the investigated animals. The results suggest that dopamine defects precede neurologic deficits and implicate dysfunction of the dopaminergic system in the etiopathogenesis of HIV dementia. Therefore, affective complications in HIV subjects should not be interpreted only as reactive psychological changes. The alterations in the mesolimbic dopaminergic system during asymptomatic stage of SIV infection implicate a biological background for psychiatric disorders in HIV infection.

Modulation of simian immunodeficiency virus neuropathology by dopaminergic drugs.

Drug abuse and human immunodeficiency virus (HIV) infection seem to cause cumulative damage in the central nervous system (CNS). Elevated extracellular dopamine is thought to be a prime mediator of the reinforcing effects of addictive substances. To investigate the possible role of increased dopamine availability in the pathogenesis of HIV dementia, simian immunodeficiency virus (SIV)-infected monkeys were treated with dopaminergic drugs (selegiline or L-DOPA). Both substances increased intracerebral SIV expression, combined with aggravation of infection-related neuropathology and ultrastructural alterations of dendrites in dopaminergic areas (spongiform polioencephalopathy) in asymptomatic animals. Moreover, this treatment resulted in enhanced TNF-alpha expression in the brains of SIV-infected animals. These findings indicate a synergistic interaction between dopamine and SIV infection on microglia activation, leading to increased viral replication and production of neurotoxic substances. Our results suggest that increased dopamine availability through dopaminergic medication or addictive substances may potentiate HIV dementia.

Monoamine oxidase inhibition and CNS immunodeficiency infection.

HIV invades CNS subcortical areas, particularly the dopamine-rich basal ganglia and induces a subcortical dementia. Data suggest that the basal ganglia dysfunction plays a critical role in the neuropsychiatric manifestation of HIV infection. Therefore, therapeutic approaches for HIV dementia nowadays wish to include apart from the highly active antiretroviral therapy (HAART) also adjunctive medication. In this short article, we report briefly on neurotoxicity associated with the immunodeficiency virus and discuss the effects of selegiline, a monoamine oxidase inhibitor which enhances dopamine availability in CNS on immunodeficiency virus-induced neurological disease.

Dendritic cells and measles virus infection.

Measles is a major cause of childhood mortality in developing countries which is mainly attributed to the ability of measles virus (MV) to suppress general immune responses. Paradoxically, virus-specific immunity is efficiently induced, which leads to viral clearance from the host and confers long-lasting protection against reinfection. As sensitisers of pathogen encounter and instructors of the adaptive immune response, dendritic cells (DCs) may play a decisive role in the induction and quality of the MV-specific immune activation. The ability of MV wild-type strains in particular to infect DCs in vitro is dearly established, and the receptor binding haemagglutinin protein of these viruses essentially determines this particular tropism. DC maturation as induced early after MV infection is likely to be of crucial importance for the induction of MV-specific immunity. DCs may, however, be instrumental in MV-induced immunosuppression. (1) T cell depletion could be brought about by DC-T cell fusion or TRAIL-mediated induction of apoptosis. (2) Inhibition of stimulated IL-12 production from MV-infected DCs might affect T cell responses in qualitative terms in favouring Th2 and suppressing Th1 responses. (3) The viral glycoprotein complex expressed at high levels on infected DCs late in infection is able to directly inhibit T cell proliferation by surface contact-dependent negative signalling. This most likely accounts for the failure of infected DC cultures to stimulate allogeneic and inhibit mitogen-stimulated T cell proliferation in vitro and the pronounced proliferative unresponsiveness of T cell ex vivo to polyclonal and antigen-specific stimulation which is a central finding of MV-induced immunosuppression.

Psychiatric complications in human immunodeficiency virus infection.

Human immunodeficiency virus (HIV) infection is associated with psychiatric complications, including cognitive impairment, affective disorders, and psychosis. These psychiatric complications impair quality of life, affect disease prognosis, and impede treatment by compromising medication adherence. They also increase the likelihood of HIV transmission, either directly or via their high prevalence rate among drug abusers. In this article, the authors provide a brief overview of the most common psychiatric complications associated with HIV infection and discuss the role of dopamine as a link between psychiatric manifestations and the progression of immunodeficiency infection.

Macaque animal model for HIV-induced neurological disease.

The pathogenesis of HIV-induced neurological disorders is still incompletely understood. Since many aspects of this disease are difficult to explore in humans, animal models are necessary to fill the gaps in our knowledge. Based on the high concordance with the human system, the SIV-infection of macaques currently provides the best animal model to study pathogenesis, therapy and prevention of HIV-infection. In this review, important features of the CNS-infection in this model are outlined. Recent virological, immunological, neurophysiological and neurochemical findings obtained with this animal model are presented and key factors in the development of neurological disease are identified.

Parkinsonism in HIV dementia.

A great number of human immunodeficiency virus (HIV)-infected patients develop a central nervous system disorder, commonly called HIV dementia or AIDS dementia complex (ADC). HIV dementia is independent of opportunistic infections and is due to the virus itself. Symptoms include psychomotor slowing, apathy and motor disorders similar to the bradykinesia and postural and gait abnormalities observed in late Parkinson's disease. Consequently, HIV has been discussed during the last few years as an additional cause for parkinsonism, and parkinsonian syndromes as manifestations of HIV dementia. Moreover, the early phase of HIV infection gains increasing interest because of studies which report subtle neurological symptoms at this stage. Accordingly, we found in SIV-infected monkeys that dopamine is reduced by 44% within as few as two months of infection, indicating that changes during early infection must be thoroughly evaluated. In this short review, we discuss alterations in the nigrostriatal dopaminergic system during early and late immunodeficiency virus infection and the common clinical and biochemical features shared by HIV dementia and Parkinson's disease.

Involvement of dopamine in the progression of AIDS Dementia Complex.

HIV compromises immunological functions. Immune responses are regulated to a great extent by several molecules such as cytokines, neurotransmitters and hormones which interact with different immune effector cells and ultimately mediate the homeostatic responses to disease. Among these mediators, dopamine plays an important role. In this article we review AIDS Dementia Complex (ADC) and describe lines of evidence implying increased dopamine availability as a potent mediator of neurologic deficits in HIV infection and a factor exhibiting adverse effects on the progression of ADC.

Measles virus interactions with cellular receptors: consequences for viral pathogenesis.

Although CNS complications occurring early and late after acute measles are a serious problem and often fatal, the transient immunosuppression lasting for several weeks after the rash is the major cause of measles-related morbidity and mortality worldwide. This review is focused on the interactions of measles virus (MV) with cellular receptors on neural and lymphoid cells which are important elements in viral pathogenesis. First, the cognate MV receptors, CD46 and CD150, are important components of viral tropism by mediating binding and entry. Second, however, additional unknown cellular surface molecules may (independently of viral uptake) after interaction with the MV glycoprotein complex act as signaling molecules and thereby modulate cellular survival, proliferation, and specific functions.

Neurotransmission in HIV associated dementia: a short review.

Human immunodeficiency virus (HIV) infection is frequently associated with specific neurological and psychiatric symptoms. Our understanding of how HIV-related CNS deficits develop is still preliminary and the cause remains obscure. However, some clues have emerged which may clarify uncertainties. Following a brief discussion of the epidemiology underlying neuropathological mechanisms and clinical symptoms in HIV-infected patients, we focus our attention on neurochemical data obtained by studies in humans and rhesus monkeys which provide information on the effect of the retroviral infection on neurotransmission and assist in the evaluation of potential therapeutic treatments.

Recombinant measles viruses expressing altered hemagglutinin (H) genes: functional separation of mutations determining H antibody escape from neurovirulence.

Measles virus (MV) strain CAM/RB, which was adapted to growth in the brain of newborn rodents, is highly neurovirulent. It has been reported earlier that experimentally selected virus variants escaping from the monoclonal antibodies (MAbs) Nc32 and L77 to hemagglutinin (H) preserved their neurovirulence, whereas mutants escaping MAbs K71 and K29 were found to be strongly attenuated (U. G. Liebert et al., J. Virol. 68:1486-1493, 1994). To investigate the molecular basis of these findings, we have generated a panel of recombinant MVs expressing the H protein from CAM/RB and introduced the amino acid substitutions thought to be responsible for antibody escape and/or neurovirulence. Using these recombinant viruses, we identified the amino acid changes conferring escape from the MAbs L77 (377R-->Q and 378M-->K), Nc32 (388G-->S), K71 (492E-->K and 550S-->P), and K29 (535E-->G). When the corresponding recombinant viruses were tested in brains of newborn rodents, we found that the mutations mediating antibody escape did not confer differential neurovirulence. In contrast, however, replacement of two different amino acids, at positions 195G-->R and 200S-->N, which had been described for the escape mutant set, caused the change in neurovirulence. Thus, antibody escape and neurovirulence appear not to be associated with the same structural alterations of the MV H protein.

Disruption of Akt kinase activation is important for immunosuppression induced by measles virus.

Surface-contact-mediated signaling induced by the measles virus (MV) fusion and hemagglutinin glycoproteins is necessary and sufficient to induce T-cell unresponsiveness in vitro and in vivo. To define the intracellular pathways involved, we analyzed interleukin (IL)-2R signaling in primary human T cells and in Kit-225 cells. Unlike IL-2-dependent activation of JAK/STAT pathways, activation of Akt kinase was impaired after MV contact both in vitro and in vivo. MV interference with Akt activation was important for immunosuppression, as expression of a catalytically active Akt prevented negative signaling by the MV glycoproteins. Thus, we show here that MV exploits a novel strategy to interfere with T-cell activation during immunosuppression.

CD150 (SLAM) is a receptor for measles virus but is not involved in viral contact-mediated proliferation inhibition.

Measles virus (MV) interacts with cellular receptors on the surface of peripheral blood lymphocytes (PBL) which mediate virus binding and uptake. Simultaneously, the direct contact of the viral glycoproteins with the cell surface induces a negative signal blocking progression to the S phase of the cell cycle, resulting in a pronounced proliferation inhibition. We selected a monoclonal antibody (MAb 5C6) directed to the surface of highly MV-susceptible B cells (B95a), which inhibits binding to and infection of cells with MV wild-type and vaccine strains. By screening a retroviral cDNA library from human splenocytes (ViraPort; Stratagene) with this antibody, we cloned and identified the recognized molecule as signaling lymphocytic activation molecule (SLAM; CD150), which is identical to the MV receptor recently found by H. Tatsuo et al. (Nature 406:893-897, 2000). After infection of cells, and after surface contact with MV envelope proteins, SLAM is downregulated from the cell surface of activated PBL and cell lines. Although anti-SLAM and/or anti-CD46 antibodies block virus binding, they do not interfere with the contact-mediated proliferation inhibition. In addition, the cell-type-specific expression of SLAM does not correlate with the sensitivity of cells for proliferation inhibition. The data indicate that proliferation inhibition induced by MV contact is independent of the presence or absence of the virus-binding receptors SLAM and CD46.

Influenza vaccination in MS: absence of T-cell response against white matter proteins.

BACKGROUND: Natural infections bear the risk of triggering MS bouts, whereas epidemiologic studies have not delineated an increased risk for disease activity after influenza virus vaccination. OBJECTIVE: To examine influenza A virus-specific and myelin protein-reactive T-cell frequencies by interferon gamma (IFNgamma)-enzyme-linked immunospot and the response of these cells by IFNgamma-reverse transcription (RT) PCR after immunization and any incidental upper respiratory tract infection (URI) in 12 patients with MS (seven with a relapsing-remitting course; five with a secondary progressive course; Kurtzke Expanded Disability Status Scale [EDSS] score from 1.0 to 6.5, without immunosuppressive treatment) and 28 healthy volunteers. RESULTS: A cellular immune response against influenza A virus was mounted in both populations at 2 weeks after vaccination. Patients with MS showed a higher relative increase (p = 0.008) than controls with respect to the number of influenza-specific T cells. Mean antibody responses against influenza A virus were increased in both populations after 2 weeks (p < 0.01). Despite these virus-specific reactions, no increase in T-cell frequencies responsive to human myelin basic protein (MBP) or recombinant human myelin oligodendrocyte protein (MOG) was observed after immunization, arguing against a general immune stimulation by influenza vaccination. In contrast, MBP-specific T-cell responses became detectable in several individuals after febrile infection. CONCLUSION: These data support the clinical observations that influenza vaccination is effective and safe in patients with MS with respect to cellular immunoreactivity against two main CNS myelin proteins.

Inhibition of major histocompatibility complex class II-dependent antigen presentation by neutralization of gamma interferon leads to breakdown of resistance against measles virus-induced encephalitis.

BALB/c mice are resistant to measles virus (MV)-induced encephalitis due to their strong MV-specific CD4(+) T-cell response. Resistance is broken by neutralization of gamma interferon with monoclonal antibodies, indicating an important role for this pleiotropic cytokine. Here, we demonstrate that mouse gamma interferon has no direct antiviral effect in vitro and in vivo. The breakdown of resistance is due neither to a switch in the T-helper response nor to an impaired migration of CD4(+) T cells. Neutralization of gamma interferon interferes with the major histocompatibility complex class II-dependent antigen presentation and subsequent proliferation of CD4(+) T cells in vitro and in vivo. In consequence, the reduction in numbers of CD4(+) T cells below a protective threshold leads to susceptibility to MV-induced encephalitis.