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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA019807-02
Application #
6954088
Study Section
Special Emphasis Panel (ZMH1-BRB-S (11))
Program Officer
Lawrence, Diane M
Project Start
2004-09-30
Project End
2009-07-31
Budget Start
2005-09-30
Budget End
2006-07-31
Support Year
2
Fiscal Year
2005
Total Cost
$375,000
Indirect Cost
Name
Drexel University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Dampier, Will; Antell, Gregory C; Aiamkitsumrit, Benjamas et al. (2017) Specific amino acids in HIV-1 Vpr are significantly associated with differences in patient neurocognitive status. J Neurovirol 23:113-124
Banerjee, Anupam; Li, Luna; Pirrone, Vanessa et al. (2017) cAMP Signaling Enhances HIV-1 Long Terminal Repeat (LTR)-directed Transcription and Viral Replication in Bone Marrow Progenitor Cells. Clin Med Insights Pathol 10:1179555717694535
Antell, Gregory C; Dampier, Will; Aiamkitsumrit, Benjamas et al. (2017) Evidence of Divergent Amino Acid Usage in Comparative Analyses of R5- and X4-Associated HIV-1 Vpr Sequences. Int J Genomics 2017:4081585
Strazza, Marianne; Maubert, Monique E; Pirrone, Vanessa et al. (2016) Co-culture model consisting of human brain microvascular endothelial and peripheral blood mononuclear cells. J Neurosci Methods 269:39-45
Strazza, Marianne; Pirrone, Vanessa; Wigdahl, Brian et al. (2016) Prolonged Morphine Exposure Induces Increased Firm Adhesion in an in Vitro Model of the Blood-Brain Barrier. Int J Mol Sci 17:
Nonnemacher, Michael R; Pirrone, Vanessa; Feng, Rui et al. (2016) HIV-1 Promoter Single Nucleotide Polymorphisms Are Associated with Clinical Disease Severity. PLoS One 11:e0150835
James, Tony; Nonnemacher, Michael R; Wigdahl, Brian et al. (2016) Defining the roles for Vpr in HIV-1-associated neuropathogenesis. J Neurovirol 22:403-15
Datta, Prasun K; Kaminski, Rafal; Hu, Wenhui et al. (2016) HIV-1 Latency and Eradication: Past, Present and Future. Curr HIV Res 14:431-441
Antell, Gregory C; Dampier, Will; Aiamkitsumrit, Benjamas et al. (2016) Utilization of HIV-1 envelope V3 to identify X4- and R5-specific Tat and LTR sequence signatures. Retrovirology 13:32
Kollias, Christina M; Huneke, Richard B; Wigdahl, Brian et al. (2015) Animal models of herpes simplex virus immunity and pathogenesis. J Neurovirol 21:8-23

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