The proposed studies deal with the mechanism by which HIV-1 persists in patients on highly active antiretroviral therapy (HAART). In compliant patients, HAART can decrease levels of free virus in the plasma to below the limit of detection. However, studies completed during the initial funding period demonstrated that HIV-1 persists for life in a small pool of latently infected resting memory CD4 + T cells that carry an integrated copy of the HIV-1 genome. Because latently infected cells represent a major barrier to HIV-1 eradication, it is important to understand the molecular mechanisms that maintain latency. Several potential molecular mechanisms have been proposed based on in vitro studies, but it remains unclear whether any of these accurately account for the persistence of HIV-1 in resting CD4 + T cells in vivo. In the proposed studies, we will use genetic approaches to examine the mechanism of latency in vivo, focusing on the influence of the integration site in the host genome. The first two Specific Aims involve cloning and characterizing sites of HIV-1 integration in resting CD4 + T cells in vivo. A novel method will be used to identify the small subset of integrated proviruses that are functionally significant. Analysis of these integration sites should provide a general picture the chromosomal environments where latent proviruses reside. In the third Specific Aim, we will use integration site information to study the transcriptional activity and chromatin structure of regions of the host chromosome that are sites for HIV-1 integration. In the final Aim, we will test a novel hypothesis concerning the mechanism of HIV-1 latency that is consistent with most published work and that represents a synthesis of several proposed mechanisms. Together, these studies should help to elucidate how HIV-1 latency operates in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Program Projects (P01)
Project #
5P01MH070306-02
Application #
7272386
Study Section
Special Emphasis Panel (ZMH1)
Project Start
Project End
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
2
Fiscal Year
2005
Total Cost
$232,284
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Beck, Sarah E; Queen, Suzanne E; Metcalf Pate, Kelly A et al. (2018) An SIV/macaque model targeted to study HIV-associated neurocognitive disorders. J Neurovirol 24:204-212
Croteau, Joshua D; Engle, Elizabeth L; Queen, Suzanne E et al. (2017) Marked Enteropathy in an Accelerated Macaque Model of AIDS. Am J Pathol 187:589-604
Gannon, Patrick J; Akay-Espinoza, Cagla; Yee, Alan C et al. (2017) HIV Protease Inhibitors Alter Amyloid Precursor Protein Processing via ?-Site Amyloid Precursor Protein Cleaving Enzyme-1 Translational Up-Regulation. Am J Pathol 187:91-109
Gama, Lucio; Abreu, Celina M; Shirk, Erin N et al. (2017) Reactivation of simian immunodeficiency virus reservoirs in the brain of virally suppressed macaques. AIDS 31:5-14
Williams, Dionna W; Engle, Elizabeth L; Shirk, Erin N et al. (2016) Splenic Damage during SIV Infection: Role of T-Cell Depletion and Macrophage Polarization and Infection. Am J Pathol 186:2068-2087
Saylor, Deanna; Dickens, Alex M; Sacktor, Ned et al. (2016) HIV-associated neurocognitive disorder--pathogenesis and prospects for treatment. Nat Rev Neurol 12:234-48
Mangus, Lisa M; Dorsey, Jamie L; Weinberg, Rachel L et al. (2016) Tracking Epidermal Nerve Fiber Changes in Asian Macaques: Tools and Techniques for Quantitative Assessment. Toxicol Pathol 44:904-12
Avalos, Claudia R; Price, Sarah L; Forsyth, Ellen R et al. (2016) Quantitation of Productively Infected Monocytes and Macrophages of Simian Immunodeficiency Virus-Infected Macaques. J Virol 90:5643-5656
Beck, Sarah E; Queen, Suzanne E; Viscidi, Raphael et al. (2016) Central nervous system-specific consequences of simian immunodeficiency virus Gag escape from major histocompatibility complex class I-mediated control. J Neurovirol 22:498-507
Drewes, Julia L; Meulendyke, Kelly A; Liao, Zhaohao et al. (2015) Quinolinic acid/tryptophan ratios predict neurological disease in SIV-infected macaques and remain elevated in the brain under cART. J Neurovirol 21:449-63

Showing the most recent 10 out of 80 publications