Despite the success of highly active antiretroviral therapy (HAART) in reducing plasma virus levels to below the limit of detecfion, eradication of the infection has not been achieved due to the persistence of virus in stable reservoirs. A major problem in the analysis of such strategies is the rapidly changing therapeutic landscape. Improved HAART regimens offer patients the prospect of complete control of viral replication with minimal toxicity. In this situation, it is more difficult to test experimental attempts to purge viral reservoirs if there is the possibility of negative consequences for the patient. Progress towards curing HIV-1 infection will therefore be critically dependent upon a reliable animal model in which eradication strategies can be realistically evaluated. We have previously shown that a latent viral reservoir in resting CD4+ T cells is established in SIV infected macaques. The collaborative studies carried out in the initial funding period have led to the development of an SIV/macaque model in which viremia can be controlled by HAART. In the proposed studies, we will establish that the degree of suppression of viral replication and the nature of the residual viremia'that confinues despite HAART are similar to what is observed in humans on HAART. In collaboration with other PPG investigators, we will explore other potential reservoirs, including those that cannot be readily studied in humans. In preliminary studies, we have developed a novel primary cell assay for HIV-1 latency, and we are using this assay to identify compounds that activate latent HlV-1 without inducing global T cell activation. Several promising hits have been identified, all distinct from previously described activators. The toxicity profiles of some of these compounds may allow them to be tested for ability to reduce the size of the latent reservoir in SIV-infected macaques on HAART. Together, these preliminary studies put us in a unique position to explore the feasibility of HlV-1 eradication in a realistic animal model.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Program Projects (P01)
Project #
5P01MH070306-08
Application #
8374981
Study Section
Special Emphasis Panel (ZMH1-ERB-F)
Project Start
Project End
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
8
Fiscal Year
2012
Total Cost
$226,434
Indirect Cost
$76,032
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. (2017) An SIV/macaque model targeted to study HIV-associated neurocognitive disorders. J Neurovirol :
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
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
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
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 90:5643-56
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
Hosseini, Iraj; Gama, Lucio; Mac Gabhann, Feilim (2015) Multiplexed Component Analysis to Identify Genes Contributing to the Immune Response during Acute SIV Infection. PLoS One 10:e0126843

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