The focus of this renewal application is on the traffic and accumulation of monocyte/macrophages in the central nervous system (CNS) in neuro-AIDS. In the previous funding period, we established immune-phenotypic differences between perivascular macrophages and parenchymal microglia, and identified perivascular macrophages as a primary target of productive SIV infection at viremia and terminally with AIDS. Our focus in upcoming period is to identify potential precursors to CNS perivascular macrophages within the bone marrow and blood and to study their activation, expansion, and infection by SIV. We hypothesize that monocytelmacrophages, which can carry virus to the CNS, can be identified in the bone marrow and blood; the immune system controls the infection, activation, and expansion of these cells; and that traffic and accumulation of these infected monocytes that become perivascular macrophages contribute to productive CNS infection. We propose 3 specific aims to study these hypotheses. Studies in Aim 1 propose to identify monocyte/macrophages in the bone marrow and blood that have a similar immune phenotype of CNS perivascular macrophages, to define subpopulations that are SIV-infected at viremia and with AIDS, to determine the timing of latent and productive infection, and to identify populations that have similar env sequences. Studies in aim 2 propose to determine the role of the peripheral immune system and CD4 + and CD8 +specific T lymphocyte responses and CTL function in controlling infection, activation, and expansion of bone marrow and blood monocyte/macrophages with immune phenotypes similar to CNS perivascular macrophages. Studies in aim 3 propose to define the timing of SIV-infected monocyte entry that contributes to productive infection of the CNS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037654-09
Application #
7162189
Study Section
Special Emphasis Panel (ZRG1-MDCN-5 (03))
Program Officer
Wong, May
Project Start
1998-04-01
Project End
2007-08-31
Budget Start
2007-01-01
Budget End
2007-08-31
Support Year
9
Fiscal Year
2007
Total Cost
$382,699
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Mallard, Jaclyn; Papazian, Emily; Soulas, Caroline et al. (2017) A method for obtaining simian immunodeficiency virus RNA sequences from laser capture microdissected and immune captured CD68+ and CD163+ macrophages from frozen tissue sections of bone marrow and brain. J Immunol Methods 442:59-63
Srinivasa, Suman; Fitch, Kathleen V; Lo, Janet et al. (2015) Plaque burden in HIV-infected patients is associated with serum intestinal microbiota-generated trimethylamine. AIDS 29:443-52
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
Srinivasa, Suman; Fitch, Kathleen V; Petrow, Eva et al. (2014) Soluble CD163 is associated with shortened telomere length in HIV-infected patients. J Acquir Immune Defic Syndr 67:414-418
Burdo, Tricia H; Weiffenbach, Allison; Woods, Steven P et al. (2013) Elevated sCD163 in plasma but not cerebrospinal fluid is a marker of neurocognitive impairment in HIV infection. AIDS 27:1387-95
Fitch, Kathleen V; Srinivasa, Suman; Abbara, Suhny et al. (2013) Noncalcified coronary atherosclerotic plaque and immune activation in HIV-infected women. J Infect Dis 208:1737-46
Zanni, Markella V; Burdo, Tricia H; Makimura, Hideo et al. (2012) Relationship between monocyte/macrophage activation marker soluble CD163 and insulin resistance in obese and normal-weight subjects. Clin Endocrinol (Oxf) 77:385-90
Subramanian, Sharath; Tawakol, Ahmed; Burdo, Tricia H et al. (2012) Arterial inflammation in patients with HIV. JAMA 308:379-86
Burdo, Tricia H; Orzechowski, Krystyna; Knight, Heather L et al. (2012) Dorsal root ganglia damage in SIV-infected rhesus macaques: an animal model of HIV-induced sensory neuropathy. Am J Pathol 180:1362-9
Campbell, Jennifer H; Burdo, Tricia H; Autissier, Patrick et al. (2011) Minocycline inhibition of monocyte activation correlates with neuronal protection in SIV neuroAIDS. PLoS One 6:e18688

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