通過神經(jīng)生理,、病毒學(xué)、認(rèn)知能力和分子技術(shù)等設(shè)計(jì)多個學(xué)科的方法進(jìn)行分析，美國著名的Script研究所的一個研究組在大腦和滲入大腦以抵御病毒入侵的免疫細(xì)胞中都發(fā)現(xiàn)了一種低水平病毒感染,。研究的結(jié)果發(fā)表在4月26日的Journal of Neuroscience（神經(jīng)科學(xué)雜志，影響因子：8分）雜志上,。
和身體的其他部位中的情況一樣,，大腦免疫細(xì)胞對病毒具有一定的控制水平，但是卻不能清除感染,?？傞L遠(yuǎn)的眼光看來，這種免疫應(yīng)答是一把雙刃劍,，既能夠防治大腦中病毒的蔓延,，還可能導(dǎo)致大腦的功能損傷。
這項(xiàng)研究涉及了一個重要的健康問題：四分之一到三分之一的艾滋病患者都在感染過程中發(fā)生了某種形式的中樞神經(jīng)系統(tǒng)疾病,，包括從輕度認(rèn)知下降和運(yùn)動障礙到嚴(yán)重的癡呆,，這些狀況總稱neuroAIDS。即使是輕微的神經(jīng)認(rèn)知疾病都會影響生活質(zhì)量。
近年來,，抗反轉(zhuǎn)錄病毒(antiretroviral)藥物已經(jīng)使各國的HIV感染病人的健康和生產(chǎn)狀況得到了顯著的改善。但是,，由于患者長期攜帶這種病毒,，所以neuroAIDS的總的流行程度仍然在增加。
大腦在患者接觸和感染HIV后不久就被感染,，但是許多抗反轉(zhuǎn)錄病毒藥物不能很好地穿過血腦障壁達(dá)到大腦以解圍,。雖然之前的研究已經(jīng)將晚期癡呆與HIV病毒感染和被活化的免疫細(xì)胞聯(lián)系起來，但是在這種病最初階段（也就是所謂的慢性階段）的神經(jīng)原變化本質(zhì)還不清楚,。
通過利用慢性階段的猿類免疫缺陷病毒感染模型,，研究組在大腦中發(fā)現(xiàn)了HIV病毒和深透到大腦中的淋巴細(xì)胞CD8+ T細(xì)胞。分子分析結(jié)果顯示,，集中免疫應(yīng)答基因的表達(dá)水平增加了,，其中就包括CCL5——它對神經(jīng)元以及免疫細(xì)胞具有多種影響。在整個感染過程中,，CCL5的表達(dá)顯著上升,，并且在滲入的淋巴細(xì)胞中也是如此。
原始出處：
Eleanor S. Roberts et al. "Host Response and Dysfunction in the CNS during Chronic Simian Immunodeficiency Virus Infection." J Neurosci 2006;26:4577- 4585.
美國賓州大學(xué)教授Zalman S. Agus, MD專門為此發(fā)表專門評論如下
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.
通訊作者Fox HS近年來發(fā)表的相關(guān)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.
另一篇新聞報(bào)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研究所網(wǎng)址：http://www.scripps.edu/
以前的研究：
HIV病毒對腦部分破壞的成像圖
