通过神经生理、病毒学、认知能力和分子技术等设计多个学科的方法进行分析，美国著名的Script研究所的一个研究组在大脑和渗入大脑以抵御病毒入侵的免疫细胞中都发现了一种低水平病毒感染。研究的结果发表在4月26日的Journal of Neuroscience（神经科学杂志，影响因子：8分）杂志上。
和身体的其他部位中的情况一样，大脑免疫细胞对病毒具有一定的控制水平，但是却不能清除感染。总长远的眼光看来，这种免疫应答是一把双刃剑，既能够防治大脑中病毒的蔓延，还可能导致大脑的功能损伤。
这项研究涉及了一个重要的健康问题：四分之一到三分之一的艾滋病患者都在感染过程中发生了某种形式的中枢神经系统疾病，包括从轻度认知下降和运动障碍到严重的痴呆，这些状况总称neuroAIDS。即使是轻微的神经认知疾病都会影响生活质量。
近年来，抗反转录病毒(antiretroviral)药物已经使各国的HIV感染病人的健康和生产状况得到了显著的改善。但是，由于患者长期携带这种病毒，所以neuroAIDS的总的流行程度仍然在增加。
大脑在患者接触和感染HIV后不久就被感染，但是许多抗反转录病毒药物不能很好地穿过血脑障壁达到大脑以解围。虽然之前的研究已经将晚期痴呆与HIV病毒感染和被活化的免疫细胞联系起来，但是在这种病最初阶段（也就是所谓的慢性阶段）的神经原变化本质还不清楚。
通过利用慢性阶段的猿类免疫缺陷病毒感染模型，研究组在大脑中发现了HIV病毒和深透到大脑中的淋巴细胞CD8+ T细胞。分子分析结果显示，集中免疫应答基因的表达水平增加了，其中就包括CCL5——它对神经元以及免疫细胞具有多种影响。在整个感染过程中，CCL5的表达显著上升，并且在渗入的淋巴细胞中也是如此。
原始出处：
Eleanor S. Roberts et al. "Host Response and Dysfunction in the CNS during Chronic Simian Immunodeficiency Virus Infection." J Neurosci 2006;26:4577- 4585.
美国宾州大学教授Zalman S. Agus, MD专门为此发表专门评论如下
An immune response in the brain to HIV infection probably acts as a double-edged sword—holding the virus at bay for a time but causing neurological damage in the process, according to researchers here.
The finding was based on a detailed study of the effects of simian immunodeficiency virus (SIV) infection in Rhesus macaques during the chronic phase of infection, which is often thought to be asymptomatic both in animals and humans, said Howard Fox, M.D., Ph.D., of the Scripps Research Institute here.
One implication of the study is that "labeling this phase 'asymptomatic' is a dangerous misnomer," Dr. Fox and colleagues said in the April 26 issue of the Journal of Neuroscience.
Before end-stage disease, most people with HIV have a variably long period of chronic infection that is often associated with aberrant central nervous system function, including impairments in verbal memory, psychomotor speed, attention performance, and fine motor control. Imaging studies have documented decreased volumes in cortical, limbic, and striatal structures, as well as thinning of the cerebral cortex.
"Although the period between acute HIV infection and overt AIDS may be reasonably asymptomatic," Dr. Fox and colleagues reported, "the CNS undergoes changes that could be progressive and cause additional damage as the disease worsens."
Because studying the brains of HIV patients is difficult, the researchers turned to animal models. Four rhesus macaques were first trained in a series of cognitive tasks and then infected with SIV.
The researchers monitored their post-infection cognitive abilities and after death their brains were examined for both levels of HIV infections and other alterations.
All of the infected animals developed significant deficits in bimanual motor skills, and three of the four had other abnormalities, including deficits in spatial working memory and slowed reaction times, Dr. Fox and colleagues found.
Also, the investigators studied the electrophysiology of brainstem auditory evoked potentials, both before and after SIV infection. The P3, P4, and P5 waves were significantly delayed post-infection and analysis of the latency between the P1 and P3 waves indicated the problem was in the CNS. The differences were statistically significant at P<0.001.
Post-mortem analysis showed that the brains of the infected animals contained SIV, although there was no correlation between viral RNA levels in the brain and levels in the blood or cerebrospinal fluid. Indeed, one animal—with undetectable virus in plasma and CSF—had a higher viral load in its frontal lobe than in any brain structure of the other animals.
Using gene array technology, the researchers found seven genes up-regulated in the frontal lobes of the animals, including chemokine (C-C motif) ligand 5 (CCL5), or RANTES; HLA-DR-alpha; immunoglobulin heavy constant gamma-3; G1P3, also known as interferon alpha-inducible protein 6-16; interferon-induced transmembrane protein-1, (also known as Leu 13); HLA-A; and HLA-C.
Several of those genes have immune system functions, while others have antiviral functions, the researchers noted.
In particular, CCL5 has direct antiviral activity, and also is able to recruit immune cells, including cytotoxic T-lymphocytes, into the brain, the researchers said. In turn, the enhanced immune response results over time in damage to neurons.
The implication, Dr. Fox said in a statement, is that "as in the rest of the body, in the brain immune cells achieve a level of control of the virus, but are unable to clear the infection."
As the infection persists, "this immune response may act as a double-edged sword, protecting against rampant viral replication in the brain but leading to brain dysfunction," he said.
通讯作者Fox HS近年来发表的相关文章
Gaskill, P.J., Watry, D.D., Burdo, T.H., Fox, H.S. Development and characterization of positively selected brain-adapted SIV. Virol. J. 2:44, 2005.
Katner, S.N., Flynn, C.T., Von Huben, S.N., Kirsten, A.J., Davis, S.A., Lay, C.C., Cole, M., Roberts, A.J., Fox, H.S., Taffe, M.A. Controlled and behaviorally relevant levels of oral ethanol intake in rhesus macaques using a flavorant-fade procedure. Alcohol. Clin. Exp. Res. 28:873, 2004.
Madden, L.J., Flynn, C.T., Zandonatti, M.A., May, M., Parsons, L.H., Katner, S.H., Henriksen, S.J., Fox, H.S. Modeling human methamphetamine exposure in nonhuman primates: chronic dosing in the rhesus macaque leads to behavioral and physiological abnormalities. Neuropsychopharmacology 30:350, 2005.
Marcondes, M.C.G., Furtado, G.C., Wensky, A., de Lafaille, M.A.C., Fox, H.S., LaFaille, J. Immune regulatory mechanisms influence early pathology in spinal cord injury and in spontaneous autoimmune encephalomyelitis. Am. J. Pathol., in press.
Masliah, E., Roberts, E.S., Langford, D., Everall, I., Crews, L., Adame, A., Rockenstein, E., Fox, H.S. Patterns of gene dysregulation in the frontal cortex of patients with HIV encephalitis. J. Neuroimmunol. 157:163, 2004.
Pardo, F.S, Lien, W.W., Fox, H.S., Efird, J.T., Aguilera, J.A., Burton, D.W., Deftos, L.J. Parathyroid hormone-related protein expression is correlated with clinical course in patients with glial tumors. Cancer 101:2622, 2004.
Roberts, E.S., Burudi, E.M.E., Flynn, C., Madden, L.J., Roinick, K.L., Watry, D.D., Zandonatti, M.A., Taffe, M.A., Fox, H.S. Acute SIV infection of the brain leads to upregulation of IL6 and interferon-regulated genes: expression patterns throughout disease progression and impact on neuroAIDS. J. Neuroimmunol. 157:81, 2004.
Roberts, E.S., Masliah, E., Fox, H.S. CD163 identifies a unique population of ramified microglia in HIV encephalitis (HIVE). J. Neuropathol. Exp. Neurol. 63:1255, 2004.
Tensing, E.K., Ma, J., Hukkanen, M., Fox, H.S., Li, T.F., Tornwall, J., Konttinen, Y.T. Protein kinase C expression in salivary gland acinar epithelial cells in non-obese diabetic mice, an experimental model for Sjögren’s syndrome. Rheumatol. Int. 25:28, 2005.
Wen, H., Watry, D.D., Marcondes, M.C.G., Fox, H.S. Selective decrease in paracellular conductance of tight junctions: role of the first extracellular domain of claudin-5. Mol. Cell. Biol. 24:8408, 2004.
另一篇新闻报道
The findings may ultimately lead to new therapeutic interventions to prevent or reverse nervous system disorders in HIV-infected individuals.
Using multi-disciplinary analysis that included cognitive, neurophysiologic, virologic, and molecular techniques, the team found both a low-level viral infection in the brain and immune cells that had infiltrated the brain in order to protect against the virus.
"As in the rest of the body, in the brain immune cells achieve a level of control of the virus, but are unable to clear the infection," says Howard Fox, associate professor at Scripps Research and director of Scripps NeuroAIDS Preclinical Studies center, who led the study. "Over the long-term, this immune response may act as a double-edged sword, protecting against rampant viral replication in the brain but leading to brain dysfunction."
The paper was published in the April 26 issue of the Journal of Neuroscience, the official journal of the Society of Neuroscience.
The study addresses a significant health problem. About one quarter to one third of all AIDS patients suffer from some form of central nervous system disorder in the course of their infection, ranging from minor cognitive and motor disorders to severe dementia, collectively known as neuroAIDS. Even subtle neurocognitive disorders limit quality of life with symptoms such as fatigue, and are correlated with difficulties ranging from a higher rate of traffic tickets to increased mortality.
In recent years, access to potent antiretroviral drugs in the United States and other developed countries has significantly improved the health, survival, and functioning of HIV-infected individuals. But since people are living longer with the virus, the overall prevalence of neuroAIDS appears to be increasing.
"Now that we're better at treating the immune/viral aspect of HIV, in many ways [AIDS] has turned into a chronic disease," says Fox. "The fact that many of the antiretroviral drugs do not show good penetration of the blood-brain barrier further puts the brain at risk, since the brain is infected soon after HIV exposure and infection."
While previous studies had linked end-stage dementia due to HIV to the presence of infected and activated immune cells, the nature of neurological changes in earlier stages of the disease, the so-called "chronic phase," were unknown-until now.
Using simian immunodeficiency virus-infected models in the chronic phase, the research team found both virus and infiltrating lymphocytes (CD8+ T cells) in the brain. Molecular analysis revealed that the expression of several immune response genes was increased, including CCL5, which has multiple effects on neurons as well as immune cells. CCL5 was significantly upregulated throughout the course of infection, and was present in the infiltrating lymphocytes.
In addition to Fox, authors of the April 26, 2006 Journal of Neuroscience (Volume 26, Number 17) paper, titled "Host Response and Dysfunction in the CNS During Chronic SIV Infection," are: Eleanor Roberts, Salvador Huitron-Resendiz, Michael Taffe, Cecilia Marcondes, Claudia Flynn, Caroline Lanigan, Jennifer Hammond, Steven Head, and Steven Henriksen.
The recent research was supported by research grants from the National Institute of Mental Health (NIMH) of the National Institutes of Health, as well as an NIMH center grant, which provides support for research-associated infrastructure and training.
Moving Research Forward
The publication coincides with an $11.2 million award for a five-year renewal of the center called Scripps NeuroAIDS Preclinical Studies (a.k.a. SNAPS), which works with Scripps Research, local San Diego, national, and international investigators to understand, treat, and prevent neurological complications of HIV infection.
"The renewal of the center's grant will bring exciting new changes in the approaches and techniques used to further the mission of the NIMH and Scripps investigators," says Fox. "This work is an example of how the center is moving research forward."
The multi-disciplinary center is built around a number of core facilities.
The Physiology Core, directed by Scripps Research Associate Professor Donna Gruol, provides in vivo, ex vivo, and in vitro studies essential to understanding how infection affects the central nervous system.
The Phenomics Core, led by Gary Siuzdak, senior director of Scripps Research's Mass Spectroscopy facility, with the assistance of Steve Head, director of Scripps Research's DNA Microarray Facility, combines genomics, proteomics, and metabolomics.
The Chemical Library Screening Core, led by Scripps Research Professor John Elder, is being instituted to provide the relevant biochemical and cell-based screening for preclinical therapeutics. The core uses chemical libraries provided by several members of the Scripps Research Department of Chemistry.
A Systems Biology Core, led by Trey Ideker of the Bioengineering Department at the University of California, San Diego, is also being launched. This core enables the development of integrative models of HIV infection, particularly in macrophages and brain tissue, by combining expression data, transcription factor location data, protein-protein interaction data, and metabolomic data, helping scientists to study multiple aspects of the system as a single entity.
To support the existing neuroAIDS research at Scripps Research and to encourage other scientists to become interested in the area, the SNAPS center holds monthly meetings focusing on recent research on neuroAIDS and its basic scientific underpinnings.
For more information on the center, see the SNAPS' web site at
http://www.scripps.edu/services/snaps/
About The Scripps Research Institute
The Scripps Research Institute, headquartered in La Jolla, California, in 18 buildings on 40 acres overlooking the Pacific Ocean, is one of the world's largest independent, non-profit biomedical research organizations. It stands at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel.
Scripps Florida, a 364,000 square-foot, state-of-the-art biomedical research facility, will be built in Palm Beach County. The facility will focus on basic biomedical science, drug discovery, and technology development. Palm Beach County and the State of Florida have provided start-up economic packages for development, building, staffing, and equipping the campus. Scripps Florida now operates with approximately 160 scientists, technicians, and administrative staff at 40,000 square-foot lab facilities on the Florida Atlantic University campus in Jupiter.
Script研究所网址：http://www.scripps.edu/
以前的研究：
HIV病毒对脑部分破坏的成像图
