1999 — 2001 |
Nath, Avindra |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Effects of Nucleoside Analogs On Hiv-1 Infection of Brai
It has been recognized since the beginning of the AIDS epidemic that the brain may be an important reservoir for the human immunodeficiency virus (HIV). Drug development for treatment of HIV infection has progressed to the remarkable pace of two to three drugs being introduced in the clinic every year. However, we currently know very little about their ability to cross the blood brain and brain-cerebrospinal fluid barriers and almost nothing about their ability to enter susceptible cells in the brain, form active metabolites within these cells, or their ability to incorporate into HIV DNA and inhibit its replication. In this proposal we will examine each of six clinically used antiretroviral nucleoside analogs targeted against the reverse transcriptase enzyme and determine their ability to enter human glial cells, to form active metabolites, and to control HIV infection in these cells.
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1 |
1999 |
Nath, Avindra |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Interactions of Hiv-1gp120 With Brain Cells--Role of Pag
Description (taken from application): Patients with HIV infection develop a dementing illness, the pathogenesis of which is only partially understood. The virus infects microglia and astrocytes and is accompanied by neuronal cell loss, although the neurons themselves are only rarely infected. Both glial cell types may potentially act as a reservoir for the virus and several investigators have raised concern that even if we were to successfully eradicate the virus from the periphery, virus sequestered within these glial cells could potentially re-seed the lymphoid tissue. Although significant progress has been made in our understanding of the mechanism of viral entry in microglial cells, the mechanism of viral entry into astrocytes remains undetermined. An important step to further our understanding of HIV-astrocyte interactions would be to characterize the cell surface molecules on the astrocyte cell surface that interact with the HIV envelope. The interactions of gp120 with astrocytes may be important not only for viral entry, but also for causing functional changes in astrocytes and thus indirectly in neurons. It has been shown that viral proteins, such as gp120, which are released by HIV-infected cells can act on astrocytes to produce large increases in intracellular calcium and increase extracellular levels of glutamate-like substances which can cause neurotoxicity. We present in this proposal, preliminary data showing that we have identified a unique receptor (Pag) on the surface of astrocytes that interacts with gp120 to cause changes in intracellular calcium and neuronal cell death. We have also developed a panel of monoclonal antibodies to this protein. We propose to develop a cDNA library from human fetal astrocytes using a mammalian expression vector and use the antisera to screen the library. Following several rounds of immunoselection, the isolated clones will be sequenced and transfected in Pag negative cell lines. The transfected cells will be screened for gp120 binding properties and for gp120-induced changes in intracellular calcium. The role of Pag in viral entry by itself or in conjunction with other HIV-coreceptors will also be determined.
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1 |
1999 — 2003 |
Nath, Avindra |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Glial Cells and Hiv Protein Induced Neurotoxicity
neuropathology; neurotoxicology; HIV envelope protein gp120; astrocytes; AIDS dementia complex; cell death; microglia; monocyte chemoattractant protein 1; glutamate receptor; tumor necrosis factor alpha; hippocampus; extracellular matrix; immunopathology; disease /disorder model; receptor binding; cytokine receptors; chemosensitizing agent; long term potentiation; tissue /cell culture; human tissue; laboratory mouse; laboratory rat; genetically modified animals; electrophysiology; injection /infusion;
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1 |
2000 — 2001 |
Nath, Avindra |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Interactions of Hiv-1gp120 With Brain Cells: Role of Pag
Description (taken from application): Patients with HIV infection develop a dementing illness, the pathogenesis of which is only partially understood. The virus infects microglia and astrocytes and is accompanied by neuronal cell loss, although the neurons themselves are only rarely infected. Both glial cell types may potentially act as a reservoir for the virus and several investigators have raised concern that even if we were to successfully eradicate the virus from the periphery, virus sequestered within these glial cells could potentially re-seed the lymphoid tissue. Although significant progress has been made in our understanding of the mechanism of viral entry in microglial cells, the mechanism of viral entry into astrocytes remains undetermined. An important step to further our understanding of HIV-astrocyte interactions would be to characterize the cell surface molecules on the astrocyte cell surface that interact with the HIV envelope. The interactions of gp120 with astrocytes may be important not only for viral entry, but also for causing functional changes in astrocytes and thus indirectly in neurons. It has been shown that viral proteins, such as gp120, which are released by HIV-infected cells can act on astrocytes to produce large increases in intracellular calcium and increase extracellular levels of glutamate-like substances which can cause neurotoxicity. We present in this proposal, preliminary data showing that we have identified a unique receptor (Pag) on the surface of astrocytes that interacts with gp120 to cause changes in intracellular calcium and neuronal cell death. We have also developed a panel of monoclonal antibodies to this protein. We propose to develop a cDNA library from human fetal astrocytes using a mammalian expression vector and use the antisera to screen the library. Following several rounds of immunoselection, the isolated clones will be sequenced and transfected in Pag negative cell lines. The transfected cells will be screened for gp120 binding properties and for gp120-induced changes in intracellular calcium. The role of Pag in viral entry by itself or in conjunction with other HIV-coreceptors will also be determined.
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1 |
2002 — 2005 |
Nath, Avindra |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Pathogenesis of Hiv Peripheral Neuropathy @ Johns Hopkins University
Distal Sensory Peripheral Neuropathy is emerging as the commonest neurological complication of HIV infection which is often debilitating. Yet, it has remained largely ignored by researchers. The pathogenesis of this entity is obscure and there is no available treatment. Both HIV infection and the nucleoside reverse transcriptase inhibitor (NRTI) drugs cause a sensory peripheral neuropathy that is clinically indistinguishable. Available evidence suggests that the neurodegenerative changes in the cell bodies of the sensory fibers residing in the dorsal root ganglia are likely the major target of the NRTIs and of the toxic substances released from HIV infected non-neuronal cells. We have established cultures from human and mouse dorsal root ganglia. Preliminary data from our laboratory invokes oxidative stress as an important mechanism involved in HIV and VRTI mediated neurotoxicity. This supports other mounting evidence that oxidative pathways play an important role in HIV pathogenesis. We propose to determine the effect of neurotoxic HIV proteins (gp120 and Tat), HIV infection (lymphotropic and macrophage tropic strains) and NRTIs on DRG neurons. We will also determine the combined effects of HrV or HIV proteins and NRTIs. Several markers of oxidative stress and mitochondrial dysfunction will be monitored in the cultured DRG neurons. Additionally, morphological changes and immunostaining patterns in the neurons and the neuritis will be determined. We will characterize the subpopulations of cells that are particularly vulnerable to these neurotoxic substances. Finally, a panel of novel antioxidants, with potential clinical applicability will be screened for their ability to protect against this neurotoxicity.
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0.948 |
2003 — 2004 |
Nath, Avindra |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Cellular Tropism &Reservoir in Brain With Hiv-Clade C @ Johns Hopkins University
DESCRIPTION (provided by applicant): Studies from populations infected with HIV-clade B virus suggest that patients often develop a dementing illness with important socioeconomic consequences. However, the most common HIV infection worldwide is with HIV-clade C and very little information is available with regards to its neurological manifestations. An important difference between the two clades is that HIV-clade C is nearly exclusively chemokine receptor CCR5 tropic. Since CCR5 expressing cells are present in the central nervous system predominantly in microglia and to a lesser degree in astrocytes, neurons and endothelial cells, it is important to determine the cellular tropism of this virus in brain of HIV-clade C infected patients. Populations infected with HIV-clade C have a high incidence of opportunistic infections and this is often the presenting manifestation of HIV infection. Another important question that remains unanswered is that do HIV infected cells invade the brain during the course of a CNS opportunistic infection? Since the types of cells that make up the inflammatory infiltrates may be different for the various opportunistic infections, it is also important to determine which patients may be at a greater risk for developing HIV encephalitis following treatment of the opportunistic infections. A major obstacle to studying the neuropathological consequences of HIV-clade C infection has been the lack of neurological, neuroradiological or neuropathological services available in areas and populations infected with this virus. The National Institute of Mental Health and Neurosciences in Bangalore, India is unique because all the above services are available at this institute and it has an established brain bank. A unique feature if this brain bank is it has short autopsy times, of 2-8 hours in most cases. Hence, we propose to augment the existing facilities, establish assays for detection and quantification of HIV in brain tissue by immunohistopathology, in situ hybridization, RT-PCR and quantitation of proviral DNA to address the above questions. We believe this will serve as a nidus for the development of several projects to address the neuropathogenesis of HIV infection and develop a rational design for therapeutic approaches and vaccine development.
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0.948 |
2003 — 2006 |
Nath, Avindra |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Immunophilin Ligands For Hiv Dementia and Neuropathy @ Johns Hopkins University
As patients are living longer with HIV infection, neurological complications such as dementia and peripheral neuropathy are becoming more prevalent and an important cause of morbidity in this population. To date, however, there is no effective treatment for these complications. Both the brain and the dorsal root ganglia show evidence of neurodegeneration while the virus replicates in glial cells or infiltrating monocytes. This suggests an important role for neuroprotective and neurotrophic modes of treatment for these conditions. This program project grant brings together researchers from several disciplines to closely interact with one another to develop new modes of treatment. During the duration of this program project we propose to conduct basic mechanistic in vitro studies using unique in vitro models for HIV dementia and peripheral neuropathy and to conduct animal studies as well as a phase 2 clinical trial. These projects will closely interact with a pharmaceutical company that has developed some novel immunophilin ligands that are highly potent neuroprotective and neurotrophic agents. We have taken a bench to bedside approach to evaluate their clinical use. A unique strength of this proposal is that it will identify compounds that are useful for treating both HIV dementia and peripheral neuropathy, since these conditions may coexist and occasionally may be difficult to differentiate. We have proposed five interactive projects and one core. Project l will determine the use of these agents in a human in vitro model for HIV dementia, Project 2 will similarly study the agents in the context of dorsal root ganglia neurons, Project 3 will determine subcellular mechanisms involved in neuroprotection. Project 4 will determine the use of a select compound in an SIV model of HIV dementia and peripheral neuropathy. Project 5 will conduct a phase 2 clinical trial of the compound identified as the lead candidate from the above projects. During the initial years of the Program project animal and clinical projects will develop and validate some novel tests that would serve as critical outcome measures during the trial. An administrative core will coordinate the interactions between all the projects and each of the researchers.
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0.948 |
2004 |
Nath, Avindra |
P20Activity Code Description: To support planning for new programs, expansion or modification of existing resources, and feasibility studies to explore various approaches to the development of interdisciplinary programs that offer potential solutions to problems of special significance to the mission of the NIH. These exploratory studies may lead to specialized or comprehensive centers. |
Ky Cobre: Protective Actions Estradiol &Serms in Brain &Vulnerability to Hiv
neuroimmunomodulation; estrogen receptors; HIV infections; hormone regulation /control mechanism; estradiol; neuroendocrine system; human immunodeficiency virus; immunochemistry; clinical research; female; women's health;
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1 |
2004 — 2006 |
Nath, Avindra |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Project 4: Intracellular Mechanism of Virus Persistence in Astrocytes/Macrophages @ Johns Hopkins University
The brain is likely an important reservoir for the human immunodeficiency virus (HIV). It is clear that HIV infects the invading macrophages, resident microglia and astrocytes in the brain. However, the fundamental mechanisms by which the virus resides in these cells for prolonged periods of time is not understood. It also remains unknown if antiretroviral therapy can control viral replication in these cells or have an impact on the viral reservoirs in brain. We thus propose to determine mechanisms involved in maintaining the virus in these cell types post viral entry and determine the effect of antiretroviral therapy on the viral lifecycle in these cells. We hypothesize that establishment of a viral reservoir in brain involves specific antiviral genes which are differentially regulated in macrophages and astrocytes and once the reservoir is established, antiretroviral therapy will have little or no effect on the persistence of the virus in these cells. We will use a combination of in vitro human brain cultures and blood derived macrophages to address the aims below. These studies will compliment those in project #1 which will study viral persistence in macrophages in vivo and ex vivo and projects #2 and 3 that will determine the effect of antiretroviral therapy on brain in vivo. Preliminary data from our laboratory suggests that the Tat protein of HIV regulates the expression of several interferon inducible antiviral genes. We have generated several novel cell lines and viral constructs that will allow us to address these issues related to viral reservoirs in the brain. We thus propose the following specific aims: 1: To determine the role of antiviral protein, promelyocytic leukemia protein (PML) in HIV replication in astrocytes and macrophages. 2. To determine the effect of HIV in astrocytes and macrophages on antiviral genes, interferon stimulated gene-20 (ISG 20) and oligoadenylate synthetase (OAS-1). 3: To determine the effect of CART on HIV replication and persistence in astrocytes and macrophages.
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0.948 |
2005 — 2009 |
Nath, Avindra |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Role of Hiv Tat Protein in Pathogenesis of Hiv Dementia @ Johns Hopkins University
DESCRIPTION (provided by applicant): Current antiretroviral therapy is instituted upon immunosuppression when HIV has already entered the brain. Further, this mode of treatment has no effect on the integrated virus or on the production of early viral gene transcripts such as Tat, Nef and Rev. Of these gene products, only Tat is released extracellularly and has a variety of effects on neurons and glial cells. To date, most studies have been performed by only 1 or 2 Tat proteins derived from HIV clade B, but there is significant divergence in the amino acid sequences between clade B and C derived Tat proteins, even in the so called conserved regions of the gene. Further, HIV clade C virus infects the largest populations in the world, and interestingly little or no dementia has been reported from the clade C infected countries. Although there may be multiple reasons for the differences, very little is known about the functional properties of Tat derived from clade C. Further, the role of the second exon of both clade B and C is poorly understood. Tat also has residues that undergo post-translational modification the functional significance of needs to be characterized. Because of the critical role of Tat in HIV replication and its effects on brain cells, there is need to establish therapeutic approaches that would target this protein or host factors that are critical in mediating Tat effects. We thus propose to 1) determine HIV clade specific differences in Tat effects on brain cells. Tat will be sequenced from brain and spleen from well-characterized patients with HIV clade B and C infections. Recombinant Tat proteins and Tat expressing cell lines will be compared for their functional differences. 2) determine physical properties of Tat necessary for mediating Tat effects on brain cells. The amino acids involved in posttranslational modification will be mutated to determine their role in Tat function. 3) identify novel therapeutic approaches for targeting Tat mediated effects on brain cells. Drugs approved for human use targeted against host proteins that interact with Tat will be screened to determine their therapeutic potential against clade B and C derived Tat proteins.
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0.948 |
2006 — 2010 |
Nath, Avindra |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neuropathogenesis of Immune Reconstitution Syndrome With Hiv Infection @ Johns Hopkins University
[unreadable] DESCRIPTION (provided by applicant): Immune reconstitution inflammatory syndrome (IRIS) in the brain is a devastating disease that can cause severe encephalitis and death upon initiation of combination antiretroviral therapy particularly in patients with high CSF viral load. As antiretroviral therapy is now becoming available world wide this could emerge as a single most important neurological complication that will have a major impact on the ability to treat large populations with antiretroviral drugs where viral loads cannot be measured easily. Understanding the pathogenesis of this syndrome and developing new approaches for treatment are critically important in our battle against AIDS. Pathological studies suggest that in patients with CNS IRIS there is massive infiltration of T cells within the brain. Preliminary data from our laboratory suggest that granzyme B (GB) is the key molecule released by activated T cells that causes neurotoxicity. Furthermore, we have made a novel observation that GB can cause neurotoxicity by interaction with G-protein coupled receptors (GPCP) on the neuronal cell membrane with activation of a voltage gated potassium channel Kv1 .3 resulting in neuronal apoptosis. These observations challenge conventional wisdom that GB requires perforin to enter cells and then initiates the apoptotic cascade. We also demonstrate for the first time that blockers of the Kv1.3 channels have neuroprotective properties. These observations suggest that it may be possible to develop novel pharmacological approaches that could intervene in this cascade. In this proposal, we focused our efforts on the Kv1.3 channel. Pharmacological blockers of this channel not only protect against GB mediated neurotoxicity but also prevent GB release from activated T cells thus providing a novel therapeutic approach. These observations may also be important for other T cell mediated neuroinflammatory diseases. We thus propose three interrelated specific aims. Specific aim 1: To determine if HIV proteins can activate T cells to cause release of GB. Specific aim 2: To determine the mechanism of GB mediated neurotoxicity Specific aim 3: To determine the mechanism of neuroprotection with Kv1.3 blockers [unreadable] [unreadable] [unreadable]
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0.948 |
2007 — 2009 |
Nath, Avindra |
R25Activity Code Description: For support to develop and/or implement a program as it relates to a category in one or more of the areas of education, information, training, technical assistance, coordination, or evaluation. |
Diversity Related Neuro-Aids and Mental Health Research @ Johns Hopkins University
[unreadable] DESCRIPTION (provided by applicant): HIV infection of the nervous system frequently results in neuropsychiatric complications and is a major cause of disability in the HIV infected population. To date there is no effective treatment for the illness and is further complicated by the fact that this infection disproportionately affects racial and ethnic minorities. Several barriers need to be overcome if we want to make a significant impact on this illness. Not only do we need to understand the social and cultural diversities that impact the spread of this infection and our ability to treat these populations, but even the pathophysiological studies and development of treatment strategies need to pay close attention to racial and ethic diversity. Few published studies suggest that host genetic factors may be critical in determining host susceptibility to HIV dementia and as the field of pharmacogenetics is evolving, it is also becoming clear that treatment strategies also need to be tailored based of host genetics. Another major barrier is the lack of scientists from racial and ethnic minority groups in the field of NeuroAIDS research. We have taken several steps to address each of these issues. We have developed a program on the premise that the principal barrier to diversity in science is not a lack of talent, but rather a lack of opportunity. We devised a course in NeuroAIDS that not only uses the state of the art technology and the best teachers and researchers in the field, but the subject content is specifically geared to address each of the issues and point out areas of research that are needed to accomplish these goals. This 12 week course will be webcast so that students will be able to take it from anywhere in the country and yet actively engage in a discussion with the teachers. This didactic course will be followed up with a laboratory based project for a duration of 3-6 months for select students to generate preliminary data for a application focused on neuro-AIDS. To accomplish these goals, we will exploit our existing collaborations with University of Puerto Rico and University of Hawaii to train students and postdoctoral fellows from racial and ethnic minorities. We will also train researchers at Johns Hopkins University in issues that face HIV infected populations of racial and ethnic minorities. [unreadable] [unreadable] [unreadable]
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0.948 |
2007 — 2008 |
Nath, Avindra |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Intracellular Mechanisms Maintaining Virus Persistence in Astrocytes &Macrophage @ Johns Hopkins University
The brain is likely an important reservoir for the human immunodeficiency virus (HIV). It is clear that HIV infects the invading macrophages, resident microglia and astrocytes in the brain. However, the fundamental mechanisms by which the virus resides in these cells for prolonged periods of time is not understood. It also remains unknown if antiretroviral therapy can control viral replication in these cells or have an impact on the viral reservoirs in brain. We thus propose to determine mechanisms involved in maintaining the virus in these cell types post viral entry and determine the effect of antiretroviral therapy on the viral lifecycle in these cells. We hypothesize that establishment of a viral reservoir in brain involves specific antiviral genes which are differentially regulated in macrophages and astrocytes and once the reservoir is established, antiretroviral therapy will have little or no effect on the persistence of the virus in these cells. We will use a combination of in vitro human brain cultures and blood derived macrophages to address the aims below. These studies will compliment those in project #1 which will study viral persistence in macrophages in vivo and ex vivo and projects #2 and 3 that will determine the effect of antiretroviral therapy on brain in vivo. Preliminary data from our laboratory suggests that the Tat protein of HIV regulates the expression of several interferon inducible antiviral genes. We have generated several novel cell lines and viral constructs that will allow us to address these issues related to viral reservoirs in the brain. We thus propose the following specific aims: 1: To determine the role of antiviral protein, promelyocytic leukemia protein (PML) in HIV replication in astrocytes and macrophages. 2. To determine the effect of HIV in astrocytes and macrophages on antiviral genes, interferon stimulated gene-20 (ISG 20) and oligoadenylate synthetase (OAS-1). 3: To determine the effect of CART on HIV replication and persistence in astrocytes and macrophages.
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0.948 |
2008 — 2010 |
Nath, Avindra |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Ssri-Neuroprotection For Hiv/Drug Abuse @ Johns Hopkins University
DESCRIPTION (provided by applicant): HIV infection in United States and several other developed countries is now largely driven by drug abusing populations. Since both HIV and drugs of abuse independently cause injury to the brain, researchers face multiple challenges in the design of studies to address the pathogenesis or develop effective therapies. This is further complicated by the fact that these patients often abuse multiple drugs and have other co-morbidities. Nonetheless, it is clear that the use of antiretroviral drugs alone is not sufficient and neuroprotective strategies need to be used in these patient populations. Yet no clinical trials have been conducted to date in this patient population. On the contrary, drug abusers have been excluded from most clinical trials on HIV dementia. While the research community recognizes the importance of studying the combined effects of these substances challenges faced include the large number of variables that need to be considered and the lack of ideal small animal models to study these combined effects. Despite these drawbacks, we rationalize that information available to date clearly suggests that there are common subcellular mechanisms involved in neural injury by HIV proteins and drugs of abuse, which can be exploited to develop novel therapeutic approaches for this patient population. HIV proteins and select drugs of abuse may contribute to the pathogenesis of HIVD through non-mutually exclusive mechanisms including 1) direct neurotoxicity, 2) glial activation, and 3) increased viral replication. We recently screened over 2000 compounds that have been approved by the Federal Drug Administration for human use and found that two compounds within the class of the selective serotinergic release inhibitors (SSRI), fluoxetine and paroxetine, have potent neuroprotective effects against the combined effects of drugs of abuse and HIV proteins. Interestingly, in a recent retrospective clinical study it was found that HIV patients on antidepressants had better neurocognitive function and lower CSF viral loads (Letendre et al, 2007). In another study with magnetic resonance spectroscopy, HIV infected patients on SSRIs had higher levels of N-acetyl aspartate suggestive of neuroprotection (Linda Chang, University of Hawaii, personal communication). For these reasons, we have designed an experimental study to determine if fluoxetine and paroxetine can impact the combined effects of HIV and drugs of abuse in various cell types in the brain and determine the mechanisms by which such neuroprotection may occur. Another novel aspect of our study is that we will study the combined effects of opiates and cocaine, since they are commonly used together. Thus this study will provide critical information needed to design future clinical trials with these agents for HIV infected drug abusers. We propose three specific aims. (1). Determine if SSRI can modulate the effect of HIV proteins and drugs of abuse on neuronal function (2) Determine if SSRI can modulate effects of HIV proteins and drugs of abuse on glial cell function (3) Determine if SSRI can modulate the effect of HIV proteins and drugs of abuse on neural progenitor cell function. PUBLIC HEALTH RELEVANCE Currently, there is no available neuroprotective therapy for HIV infected drug abusers who may be afflicted by a dementing illness. We have screened over 2,00 compounds and identified a class of antidepressant compounds that have novel brain protective properties. We will explore their mechanism of action and conduct other preclinical studies that are needed to take them to clinical trials.
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0.948 |
2008 — 2009 |
Nath, Avindra |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Role of Cns Opportunistic Infections in Subsequent Development of Hiv Encephaliti @ Johns Hopkins University
[unreadable] DESCRIPTION (provided by applicant): HIV dementia has only rarely been reported from countries infected with clade C virus. Opportunistic infections of the nervous system, however, are a major cause of morbidity and mortality in these developing countries. For example, in India where there are nearly 5 million patients are infected with the virus, it was estimated that nearly 25% of patients have CNS manifestations, most of which are opportunistic infections. Since these infections are treatable, it is imperative to determine the long-term impact of these infections on the brain. Preliminary data shows that the inflammatory infiltrates associated with these infections have a large number of HIV infected macrophages. It remains unknown, however, if inflammatory infiltrates associated with the opportunistic infection may serve as a portal of entry for HIV and if the virus may then establish residence in the brain and then continue to evolve within the brain. The degree to which these strains may cause neuro-glial cell dysfunction remains unknown. Further it remains unknown if patients with meningeal infiltrates would be at similar risks as those with parenchymal infiltrates. A major limitation to studying these neuropathological consequences of HIV clade C virus infection is the lack of autopsy tissues from these countries. NIMHANS is a unique institution that has conducted autopsies on patients that have died of AIDS since 1990. To the best of our knowledge, this is the only source of well characterized brain tissue specimens from HIV infected patients in Asia and Africa. This represents an excellent opportunity to address questions about disease pathogenesis that could not have been done otherwise. We thus propose to, 1. To determine the extent of glial cell activation and neuronal injury in HIV infected patients with CNS toxoplasmosis or tuberculosis. 2. To identify and compare viral sequences from HIV infected cells in inflammatory infiltrates associated with CNS toxoplasmosis or tuberculosis. 3. To determine if brain derived sequences of env and tat in inflammatory infiltrates cause glial cell activation or neuronal injury in vitro. These goals will be accomplished through collaborative efforts between Johns Hopkins University and NIMHANS. An excellent working relationship has already been established between the two institutions over the last several years. We have also devised a plan for training and technology transfer for the NIMHANS investigators. [unreadable] [unreadable] PUBLIC HEALTH RELEVANCE: CNS opportunistic infections are the major cause of morbidity and mortality in HIV infected populations in the developing world, however, the long-term impact of these diseases on the brain of patients successfully treated for these infections remains unknown. Using a unique resource of human brain autopsy tissue from India and a combined histopathological, molecular and cellular approach we will determine the mechanism of viral entry into the brain in the setting of the opportunistic infection and will also determine the impact of these infections on uninfected brain cells. This information will be critical in developing guidelines for long-term management of HIV-infected patients with opportunistic infections. [unreadable] [unreadable] [unreadable]
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0.948 |
2021 |
Lipkin, W. Ian Nath, Avindra Wilson, Michael R |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Investigation and Treatment of Undiagnosed Neuroinflammatory Diseases @ University of California, San Francisco
PROJECT SUMMARY Of all neurological diseases, the neuroinflammatory diseases are the most challenging. Many of these remain undiagnosed and are a major cause of morbidity and mortality. Several studies have shown that nearly a third of the patients on the neurology service at any tertiary care facility have undiagnosed neuroimmune diseases, many of whom have prolonged hospitalizations over several months and nearly a third of these patients die from the illness during this admission. These patients often undergo extensive investigations and multiple empirical therapies with poor results. They also bounce between physicians and major medical centers undergoing repeated investigations with no additional benefit. It is critically necessary that we develop a structured program to diagnose these patients, properly classify these disorders and develop a rational approach to treatment. Comprehensively investigating individual patients cannot only clarify their underlying diagnosis and lead to more directed therapies, but it can also fundamentally alter how we treat a neuroinflammatory disease more generally. For example, we discovered elevated PD-1 levels on lymphocytes in CSF of patients with progressive multifocal leukoencephalopathy which led to the development of a novel treatment for this otherwise fatal illness. Despite these efforts by individual laboratories, many cases still remain undiagnosed and untreated. This intramural and extramural highly collaborative proposal brings together for the first time physician-scientists and scientists across top academic and government institutions who have dedicated their careers to developing deep clinical phenotyping protocols for patients with idiopathic neuroinflammatory diseases as well as high-throughput and comprehensive tools for identifying microbial nucleic acid in the central nervous system, viral and autoantibody antibody profiling in the cerebrospinal fluid, immune cell profiling and T-cell antigen profiling. These investigations will not only lead to the identification of novel diseases in individual patients but also serve as a model for how neuroinflammatory diseases can be deciphered more widely.
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0.961 |