The overall goal of this program project grant is to define the role that HIV infected macrophages play in the pathogenesis of advanced HIV disease, and the long lived HIV infected macrophage reservoir by studying simian models and subsequently humans with HIV associated dementia (HAD). Preliminary studies with a novel class of drugs (polyamine biosynthesis inhibitors, PBI) in vitro showed selective killing of HIV DNA containing blood macrophages from patients with HAD and advanced HIV disease. Initial studies with a PBI in a rhesus monkey simian immunodeficiency virus (SIV) encephalitis induction model showed selective loss of SIV containing blood and brain tissue macrophages in vivo after three injections of drug. The proposed studies will be coordinated by Michael McGrath M.D., PhD. at UCSF who has a long history of evaluating the role of MOs in the pathogenesis of HIV disease and in macrophage targeted drug development. This program project will incorporate centers of excellence for studying SIV disease in vivo (Ken Williams, Harvard), clinical evaluation of anti-HIV and dementia drugs in vivo (Valcour, Shikuma, Shiramizu, U of Hawaii), and the development of novel diagnostic and therapeutic approaches to the HIV DNA reservoir and macrophage associated diseases (Ken Hadlock, Pathologica LLC, Burlingame CA.) This program fulfills requirements of the RFA-AI-06-009 announcement in that it incorporates both academic and corporate research programs aimed at developing novel HIV therapies, integrating both preclinical and clinical programs in animal and human systems. Three projects, one at each center and 3 cores are proposed for the program project grant. Specific components of this program include: Project 1) PL: Ken Hadlock, Pathologica LLC. Mechanism of polyamine biosynthesis inhibitors (PBI) in killing/regulation of HIV infected macrophages, Project 2) PL: Ken Williams, Harvard. Studies of PBI activities in simian models of HAD, Project 3) Preclinical and clinical studies of HIV DNA reservoir in patients with advanced HIV disease and HAD, Administrative Core A) Director Michael McGrath, UCSF. This core provides the oversight and coordination of all of the studies defined in the three projects and two other cores, Assay Core B) Director: Ken Hadlock, Pathologica, LLC. This core program provides quantitative molecular assay support for all three projects. PBI drug manufacture Core C) Director: Ken Hadlock, Pathologica, LLC. This core provides drug for use in all three projects, from the preclinical studies in Projects 1 and 3 to the clinical studies in animals (project 2) and humans (project 3).

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19MH081835-03
Application #
7618645
Study Section
Special Emphasis Panel (ZAI1-TP-A (J2))
Program Officer
Joseph, Jeymohan
Project Start
2007-05-24
Project End
2012-04-30
Budget Start
2009-05-01
Budget End
2010-04-30
Support Year
3
Fiscal Year
2009
Total Cost
$1,923,686
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Chow, Dominic C; Kagihara, Jamie M; Zhang, Guangxiang et al. (2016) Non-classical monocytes predict progression of carotid artery bifurcation intima-media thickness in HIV-infected individuals on stable antiretroviral therapy. HIV Clin Trials 17:114-22
Soulas, Caroline; Autissier, Patrick J; Burdo, Tricia H et al. (2015) Distinct phenotype, longitudinal changes of numbers and cell-associated virus in blood dendritic cells in SIV-infected CD8-lymphocyte depleted macaques. PLoS One 10:e0119764
Meyza, Ksenia; Nikolaev, Tomasz; Kondrakiewicz, Kacper et al. (2015) Neuronal correlates of asocial behavior in a BTBR T (+) Itpr3(tf)/J mouse model of autism. Front Behav Neurosci 9:199
Jin, Xia; McGrath, Michael S; Xu, Hua (2015) Inhibition of HIV Expression and Integration in Macrophages by Methylglyoxal-Bis-Guanylhydrazone. J Virol 89:11176-89
Ndhlovu, Lishomwa C; Umaki, Tracie; Chew, Glen M et al. (2014) Treatment intensification with maraviroc (CCR5 antagonist) leads to declines in CD16-expressing monocytes in cART-suppressed chronic HIV-infected subjects and is associated with improvements in neurocognitive test performance: implications for HIV-associa J Neurovirol 20:571-82
Chow, Dominic; Nakamoto, Beau; So, Edison et al. (2013) Rates of autonomic dysfunction in HIV patients receiving antiretroviral therapy. J Neurovirol 19:511-2
Nakamoto, Beau K; Shikuma, Cecilia M; Ogata-Arakaki, Debra et al. (2013) Feasibility and potential role of ferumoxytol-enhanced neuroimaging in HIV-associated neurocognitive disorder. J Neurovirol 19:601-5
Kallianpur, Kalpana J; Shikuma, Cecilia; Kirk, Gregory R et al. (2013) Peripheral blood HIV DNA is associated with atrophy of cerebellar and subcortical gray matter. Neurology 80:1792-9
Shikuma, Cecilia M; Nakamoto, Beau; Shiramizu, Bruce et al. (2012) Antiretroviral monocyte efficacy score linked to cognitive impairment in HIV. Antivir Ther 17:1233-42
Kallianpur, Kalpana J; Kirk, Gregory R; Sailasuta, Napapon et al. (2012) Regional cortical thinning associated with detectable levels of HIV DNA. Cereb Cortex 22:2065-75

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