Despite successful ART that keeps HIV at non-detectable levels in plasma, HIV is not eradicated and when patients are taken off therapy, virus can quickly rebound. In addition, it is recognized that chronic immune activation occurs in patients on successful ART and the CNS effects of this include cognitive dysfunction. The source of the rebounding virus and cells that are activated with chronic infection include monocyte/macrophages. In this competitive renewal application we propose to study: 1) mechanisms that establish and maintain persistence of SIV- DNA in the CNS, 2) monocyte/macrophages that traffic out of the CNS that can be viral infected. We propose to use ART alone and in combination with a new oral form of a polyamine synthesis inhibitor, termed PA300, that targets monocyte/macrophage activation, traffic and infection. We propose to study monocyte/macrophages in blood that traffic to the CNS, macrophage accumulation in the CNS that establishes and maintains reservoirs of proviral DNA, and study the effects of ART and PA300 on this reservoir. Next, the effects of ART and PA300 on the traffic of CD163+ macrophages out of the CNS to peripheral lymph organs will be studied. Successful completion of this application will ascertain monocyte/macrophage subtypes in blood and the CNS that are proviral reservoirs, the effects of ART and PA300 to clear these reservoirs, and their effects on SIV infected cells leaving the CNS.
With effective antiretroviral therapy (ART), there is emerging evidence of chronic system immune activation including lymphocytes and monocyte/macrophages that continues to contribute to AIDS-related pathology and HAND (HIV-associated neurocognitive disorders). In this application, we will use a rhesus macaque SIV- infection model to define monocyte/macrophage reservoirs of SIV-DNA, and to use effective ART alone and with an adjunctive monocyte-directed therapy, to define the establishment, maintenance, and clearance of SIV- DNA in the CNS. Moreover, we propose to define the routes of egress of monocyte/macrophage, and the effect of therapy to eradicate this important HIV reservoir that can potentially reseed the periphery with virus from the CNS, even if there are non-detectable levels of virus in the plasma.
|Walker, Joshua A; Sulciner, Megan L; Nowicki, Katherine D et al. (2014) Elevated numbers of CD163+ macrophages in hearts of simian immunodeficiency virus-infected monkeys correlate with cardiac pathology and fibrosis. AIDS Res Hum Retroviruses 30:685-94|
|Campbell, Jennifer H; Hearps, Anna C; Martin, Genevieve E et al. (2014) The importance of monocytes and macrophages in HIV pathogenesis, treatment, and cure. AIDS 28:2175-87|
|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 67:414-8|
|Burdo, Tricia H; Lackner, Andrew; Williams, Kenneth C (2013) Monocyte/macrophages and their role in HIV neuropathogenesis. Immunol Rev 254:102-13|
|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|
|Wu, William E; Tal, Assaf; Zhang, Ke et al. (2013) Structure-specific glial response in a macaque model of neuroAIDS: multivoxel proton magnetic resonance spectroscopic imaging at 3 Tesla. AIDS 27:2519-28|
|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|
|Williams, Kenneth; Burdo, Tricia H (2012) Monocyte mobilization, activation markers, and unique macrophage populations in the brain: observations from SIV infected monkeys are informative with regard to pathogenic mechanisms of HIV infection in humans. J Neuroimmune Pharmacol 7:363-71|
|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|
|Lentz, Margaret R; Kim, Woong-Ki; Kim, Hyun et al. (2011) Alterations in brain metabolism during the first year of HIV infection. J Neurovirol 17:220-9|
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