HAND HIV-associated neurocognitive disorders (HAND) including asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorders (MND) and HIV-associated dementia (HAD) persist despite effective antiretroviral therapy (ART). HAD is markedly decreased but ANI and MND persist and affecting 25-50% of ART-treated individuals. With durable ART, there is emergent evidence of chronic immune system activation that contributes to AIDS-related co-morbidities including HAND and cardiovascular disease (CVD). Chronic immune activation that includes activated monocyte/macrophages and markers on these cells are consistently associated with these comorbidities. While the mechanisms for chronic immune activation with HIV and ART aren?t well understood, microbial translocation, secondary infections and residual viral replication in cell and tissue reservoirs likely play a role. Central to all these mechanisms is activated monocyte/macrophages. In addition to memory CD4+ T cells, macrophages are cellular reservoirs for latent HIV, and the central nervous system (CNS) is a tissue reservoir for HIV- DNA. Thus, there is a great need for adjunctive therapies to be used with cART that target monocyte/macrophage activation, accumulation in parenchymal tissues and latent-replication competent virus. In this proposal we use a rapid AIDS with ART that does not results in encephalitis with 1) methylglyoxal bis(guanylhydrazone) (MGBG) and 2) a rhesus monkey (Rh) anti-?4?1 integrin mAb, as adjunctive therapies targeting activated and infected monocyte/macrophages. Extending findings from our previous funding period, we propose these two approaches; targeting monocyte/macrophage activation and maturation, accumulation in the CNS and blocking SIVE. We propose to define mechanisms by which these adjunctive therapies function. Moreover, we propose to test the ability of MGBG and anti-?4?1 integrin mAb with ART to clear latent, replication competent virus within macrophages within and leaving the CNS, following therapy interruption.

Public Health Relevance

There is emerging evidence that activated monocyte/macrophages and their activation markers correlate with and contribute to HIV infection comorbidities including CNS and cardiovascular disease. And, there is increasing evidence in the CNS that monocyte/macrophages in encephalitic and non encephalitis lesions, accumulate and are reservoirs for replication competent HIV. Studies in this application use non SIV encephalitis model of AIDS, using CD8 lymphocyte depletion and SIVmac251 infection, with combination anti-retroviral therapy, to test the use, and define the mechanism(s) of function of two potential macrophage targeted adjunctive therapies, MGBG and alphas-4, beta-1 mAb targeting CNS macrophage accumulation, infection and traffic from the CNS. Successful completion will lead to potential therapeutics in humans with early HIV infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040237-18
Application #
9675338
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Wong, May
Project Start
1999-09-30
Project End
2022-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
18
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Boston College
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
045896339
City
Chestnut Hill
State
MA
Country
United States
Zip Code
González, R Gilberto; Fell, Robert; He, Julian et al. (2018) Temporal/compartmental changes in viral RNA and neuronal injury in a primate model of NeuroAIDS. PLoS One 13:e0196949
Dufour, Jason P; Russell-Lodrigue, Kasi E; Doyle-Meyers, Lara et al. (2018) Hydrocephalus after Intrathecal Administration of Dextran to Rhesus Macaques (Macaca mulatta). Comp Med 68:227-232
Nowlin, Brian T; Wang, John; Schafer, Jamie L et al. (2018) Monocyte subsets exhibit transcriptional plasticity and a shared response to interferon in SIV-infected rhesus macaques. J Leukoc Biol 103:141-155
Lakritz, Jessica R; Yalamanchili, Samshita; Polydefkis, Michael J et al. (2017) An oral form of methylglyoxal-bis-guanylhydrazone reduces monocyte activation and traffic to the dorsal root ganglia in a primate model of HIV-peripheral neuropathy. J Neurovirol 23:568-576
Zanni, Markella V; Toribio, Mabel; Wilks, Moses Q et al. (2017) Application of a Novel CD206+ Macrophage-Specific Arterial Imaging Strategy in HIV-Infected Individuals. J Infect Dis 215:1264-1269
Walker, Joshua A; Miller, Andrew D; Burdo, Tricia H et al. (2017) Direct Targeting of Macrophages With Methylglyoxal-Bis-Guanylhydrazone Decreases SIV-Associated Cardiovascular Inflammation and Pathology. J Acquir Immune Defic Syndr 74:583-592
Rife Magalis, Brittany; Nolan, David J; Autissier, Patrick et al. (2017) Insights into the Impact of CD8+ Immune Modulation on Human Immunodeficiency Virus Evolutionary Dynamics in Distinct Anatomical Compartments by Using Simian Immunodeficiency Virus-Infected Macaque Models of AIDS Progression. J Virol 91:
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
Lakritz, Jessica R; Thibault, Derek M; Robinson, Jake A et al. (2016) ?4-Integrin Antibody Treatment Blocks Monocyte/Macrophage Traffic to, Vascular Cell Adhesion Molecule-1 Expression in, and Pathology of the Dorsal Root Ganglia in an SIV Macaque Model of HIV-Peripheral Neuropathy. Am J Pathol 186:1754-1761
Williams, Kenneth; Lackner, Andrew; Mallard, Jaclyn (2016) Non-human primate models of SIV infection and CNS neuropathology. Curr Opin Virol 19:92-8

Showing the most recent 10 out of 69 publications