High Specificity HIV-1 Markers Predictive of Neuro-AIDS
Principal Investigator: Brian Wigdahl
Affiliation: Drexel University College of Medicine
Abstract: The progression of human immunodeficiency virus type 1 (HIV-1 )-associated disease in the immune and central nervous systems is associated with the ability of the virus to localize and replicate in specific cell populations within these compartments. Recent studies have suggested the possibility that genetic alterations within the HIV-1 genome introduced during viral replication may be correlated with either the stage of HIV-1 disease and/or neurologic status. We have recently demonstrated that a viral transactivator protein, Vpr, exhibits enhanced affinity for specific HIV-1 LTR C/EBP binding site configurations that can result in enhanced long terminal repeat (LTR) activation and correlate with end stage disease and HIVD. Additional studies have led to the identification of a number of HIV-1 LTR sequence signatures that increase in frequency within the peripheral blood compartment during progressive disease and track with the development of HIVD. These observations form the basis for the proposed investigations. The working hypothesis of these studies is that C/EBP and Sp binding site signatures within the LTR, which are selected for during viral replication over the course of HIV-1 disease, can be used as molecular markers to identify HIV-1-infected individuals that may be more prone to develop HIVD. The specific aims of this application are to (1) establish an HIV-1 LTR clone bank and sequence database derived from HIV-1-infected immune cell populations in the peripheral blood collected longitudinally from patients with defined clinical histories with respect to anti-retroviral therapy, drugs of abuse, and neurologic status, and from CNS-resident cells (microglial cells, perivascular macrophages, and astrocytes) at the time of autopsy; (2) analyze the LTR sequence database for the presence of the 3T C/EBP site I and 5TSp site III markers (and potential markers in other LTR regions), and establish correlations between marker prevalence and disease progression and severity, neurologic status, anti-retroviral therapy, and use of drugs of abuse; (3) develop a single nucleotide polymorphism (SNP) genotype assay for the detection of the 3T C/EBP site I and 5T Sp site III marker (and potential markers in other regions of the LTR) for use as a diagnostic assay indicative and/or predictive of peripheral disease progression and neurologic status; and (4) determine the ability of LTR clones containing the viral marker(s) to support transient expression in cell types of immune, neuroglial and bone marrow origin, and establish correlations between LTR function and clinical parameters established in previous aims. These studies may lead to the identification of additional tools to predict the development of HIVD and, in turn, provide more information to guide the therapeutic management of the HIV-1-infected patient.
Funding Period: 2004-09-30 - 2009-07-31
more information: NIH RePORT
- Cholesterol-depleting statin drugs protect postmitotically differentiated human neurons against ethanol- and human immunodeficiency virus type 1-induced oxidative stress in vitroEdward Acheampong
Dorrance H Hamilton Laboratories, Division of Infectious Diseases, Department of Medicine, Thomas Jefferson University, 1020 Locust Street, Suite 329, Philadelphia, Pennsylvania 19107, USA
J Virol 81:1492-501. 2007..The results of this study provide new insights into HIV-1 neuropathogenesis aimed at the development of future HIV-1 therapeutics to eradicate viral reservoirs from the brain...
- PMA-induced differentiation of a bone marrow progenitor cell line activates HIV-1 LTR-driven transcriptionAikaterini Alexaki
Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129, USA
DNA Cell Biol 26:387-94. 2007..These studies elucidate the impact of infected bone marrow monocytic cell differentiation on LTR activity and its potential impact on HIV-1-associated disease...
- Cellular reservoirs of HIV-1 and their role in viral persistenceAikaterini Alexaki
Department of Microbiology and Immunology, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129, USA
Curr HIV Res 6:388-400. 2008..The contribution of these and other cell populations in HIV-1 persistence, as well as the possible strategies to eliminate latently infected cells are critically examined in this review...
- HIV-1 infection of bone marrow hematopoietic progenitor cells and their role in trafficking and viral disseminationAikaterini Alexaki
Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA
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- CCAAT/enhancer-binding proteins and the pathogenesis of retrovirus infectionYujie Liu
Department of Microbiology and Immunology, Center for Molecular Virology and Neuroimmunology, Center for Cancer Biology, Philadelphia, PA 19129, USA
Future Microbiol 4:299-321. 2009..The structure and function of the C/EBPbeta gene and the related protein isoforms are discussed along with the transcription factors, coactivators, viral proteins, cytokines and chemokines that affect C/EBP function...
- Regulation of HIV-1 transcription in cells of the monocyte-macrophage lineageEvelyn M Kilareski
Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, 245 N 15th St, Philadelphia, Pennsylvania 19102, USA
Retrovirology 6:118. 2009..The impact of genetic variation on LTR-directed transcription during the course of retrovirus disease is also reviewed...