Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2001-04-06
2004-02-10
Stucker, Jeffrey (Department: 1648)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C435S320100, C435S069100, C435S070100, C435S071100
Reexamination Certificate
active
06689877
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the fields of molecular biology and virology. More specifically, the present invention provides materials and methods for inhibiting HIV infection in targeted host cells.
BACKGROUND OF THE INVENTION
Several publications are referenced in this application by author name, year and journal of publication in parentheses in order to more fully describe the state of the art to which this invention pertains. The disclosure of each of these publications is incorporated by reference herein.
Human Immunodeficiency Virus Type-1 (HIV-1)-associated dementia (HAD) is the result of cumulative pathogenic insults that ultimately affect brain synaptic function and neuronal death resulting in cognition and memory impairments. The mechanism by which functional changes occur in neurons during disease remains unknown. Nonetheless, neural injury correlates with immune activation of brain mononuclear phagocytes (MPs; infiltrating perivascular macrophages and resident brain macrophages or microglia). MPs are key mediators of central nervous system (CNS) inflammation. It is these cells that are recruited in response to trauma (12), infection, autoimmune reactions (11), and toxin (metabolic/drug) related injury (17). In the presence of an ongoing inflammatory response, both infiltrating macrophages and endogenous microglia become immune-activated. Activated MPs recruit additional leukocytes to sites of tissue injury and engage in a wide range of secretory activities. Such events may be mediated through chemokines and/or other inflammatory mediators that promote cellular adhesion and brain leukocyte infiltration. Importantly, MPs are capable of altering neuronal function/viability by disrupting the delicate homeostatic balance of the CNS microenvironment. Activated MP can generate cytotoxic factors that perpetuate paracrine-amplified inflammation (1, 4) leading to neuronal injury and loss.
The mechanism by which MPs become activated in the brain remains poorly understood but several lines of evidence indicate biochemical comunication between the central nervous system and the immune system. It is likely that certain mechanisms involved in the CNS response to systemic immune challenge cause brain inflammation. Up- or down-regulation of gene expression of specific MP genes appears to mediate this process, leading to the culmination of a neurotoxic response and disease progression. Mammals have about 100,000 different genes, approximately 30,000 of which are thought to be expressed in the brain (21). Controlled regulation of gene expression ensures that small fractions of these genes are expressed in individual brain cells, gene expression being related to particular brain cell functions. It has been hypothesized that the pathological changes that arise in HAD are driven by aberrant changes in this regulated gene expression.
As those skilled in the treatment of HAD appreciate, a need exists for improved therapeutic agents for the treatment of this disorder.
SUMMARY OF THE INVENTION
In accordance with the present invention, methods and compositions for inhibiting HIV replication in host cells are provided. One embodiment of the invention comprises a nucleic acid encoding a truncated NEBR1 transcriptional repressor consisting essentially of amino acids 1-300 of SEQ ID NO: 2. Nucleic acids encoding truncated NEBR1 transcriptional repressors consisting essentially of amino acids 1-241 of SEQ ID NO: 2 or amino acids 1-115 of SEQ ID NO:2 are also provided herein.
In a further aspect of the invention, vectors containing the above-described nucleic acids are disclosed. The invention also encompasses host cells comprising a vector encoding the NEBR1 truncated transcriptional repressor of the invention. In a preferred embodiment, the host cell is a macrophage.
Truncated NEBR1 transcriptional repressor proteins are also within the scope of the invention. Such truncated NEBR1 proteins may be selected from the group consisting of amino acids 1-300 of SEQ ID NO: 2; amino acids 1-241 of SEQ ID NO: 2; and amino acids 1-115.
In another aspect of the invention, an antibody immunologically specific for NEBR1 is provided. Such antibodies may be monoclonal, polyclonal or antigen binding fragments of such antibodies.
Methods for detecting NEBR1 expression in a biological sample are also disclosed. Exemplary methods comprise contacting a sample with a detectably labeled antibody immunologically specific for NEBR1 and determining the presence of NEBR1 expression as a function of the amount of detectably labeled antibody bound by the sample relative to control cells.
In a further aspect of the invention methods for treating HIV infection comprising administering a therapeutic amount of NEBR1 to HIV infected cells in a patient in need thereof are provided. The NEBR1 so administered may be truncated or full-length. Such treatment methods may optionally comprise the administration of at least one antiviral agent selected from the group consisting of reverse transcriptase (RT)inhibitors, non-nucleoside inhibitors, and HIV-protease inhibitors.
REFERENCES:
patent: 5831058 (1998-11-01), Fujiwara et al.
patent: 0796913 (1997-09-01), None
Akiyama, Haruhiko. “Inflammatory Response in Alzheimer's Disease.”J. Exp. Med. (1994) 295-303.
Bellefroid, Eric J., et al. “The Evolutionarily Conserved Kruppel-associated Box Domain Defines a Subfamily of Eukaryotic Multifingered Proteins.”Proc. Natl. Acad. Sci. May 1991: 3608-3612.
Bernstein, Michael S., et al. “Activation of Human Monocyte-derived Macrophages with Lipopolysaccharide Decreases Human Immunodeficiency Virus Replication in Vitro at the Level of Gene Expression.”J. Clin. Invest. vol. 88, Aug. 1991: 540-545.
Suio Chen, Robert C. A. Frederickson and Kurt R. Brunden. “Neuroglial-Mediated Immunoinflammatory Responses in Alzheimer's Disease: Complement Activation and Therapeutic Approaches.”Neurobiology of Aging. vol. 17, No. 5, (1996) 781-787.
Cocchi, Fiorenza et. al. “Identification of RANTES, MIP-1&agr;, and MIP-1&bgr; as the Major HIV-Suppressive Factors Produced by CD8+T Cells.”Science. vol. 270, Dec. 15, 1995: 1811-1815.
Elmquist, Joel K. “Mechanisms of CNS response to systemic immune challenge: the febrile response.”Tins. vol. 20, No. 12, (1997) 565-570.
Evans, Ronald M. and Stanley M. Hollenberg. “Zinc Fingers: Gilt by Association.”Cell. vol. 52, Jan. 15, 1988: 1-3.
Fauci, Anthony S. “Host factors and the pathogenesis of HIV-induced disease.”Nature. vol. 384, Dec. 12, 1996: 529-534.
Franchin, Giovanni et al. “Lipoplysaccharide Inhibits HIV-1 Infection of Monocyte-Derived Macrophages Through Direct and Sustained Down-Regulation of CC Chemokine Receptor 51.”The Journal of Immunology. (2000) 2592-2601.
Haga, S. et al. “Demonstration of microglial cells in and around senile (neuritic) plaques in the Alzheimer brain.”Acta Neuropathologica. vol. 77, (1989) 569-575.
Huitinga, Ingeborg. “Suppression of Experimental Allergic Encephalomyelitis in Lewis Rats After Elimination of Macrophages.”J. Exp. Med. vol. 172, Oct. 1990: 1025-1033.
Imamoto, K. and C. P. Leblond. “Presence of Labeled Monocytes, Macrophages and Microglia in a Stab Wound of the Brain Following an Injection of Bone Marrow Cells Labeled with3H-uridine into Rats.”Comp. Neuro. vol. 174: 255-280.
Kadonaga, James T. et al. “Isolation of cDNA Encoding Transcription Factor Sp1 and Functional Analysis of the DNA Binding Domain.”Cell. vol. 51, Dec. 24, 1987: 1079-1090.
Kornbluth, Richard S. “Interferons and Bacterial Lipopolysaccharide Protect Macrophages from Productive Infection by Human Immunodeficiency Virus in Vitro.”J. Exp. Med. vol. 169, Mar. 1989: 1137-1151.
Lavi, Ehud. “CXCR-4 (Fusin), a Co-Receptor for the Type 1 Human Immunodeficiency Virus (HIV-1), Is Expressed in the Human Brain in a Variety of Cell Types, Including Microglia and Neurons.”American Journal of Pathology, vol. 151, No. 4, Oct. 1997: 1035-1042.
Martin, Juan C. and Juan C. Bandres. “Cells of the Monocyte-Macrophage Lineage and Pathogenesis of HIV-1 Infection.”Journal of Acquired Immune Deficiency Synd
Carlson Kimberly A.
Gendelman Howard E.
Ikezu Tsuneya
Leisman Gary
Dann Dorfman Herrell and Skillman
Stucker Jeffrey
The Board of Regents of the University of Nebraska
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