Even in HIV-infected individuals on active anti-retroviral therapy (ART), low-level viral replication and inflammation persists in both the periphery and in the central nervous system (CNS). HIV enters the brain early and there is compelling evidence that the brain is a putative reservoir for HIV that is responsible for the neuropathogenic sequelae. Indeed, even with ART, the prevalence and incidence of HAND remains high. While progress has been made in understanding the pathophysiology of HAND under conditions of high viral load, the hosts? inflammatory responses to low-level chronic systemic infection and how this exacerbates neuronal injury and dysfunction in the brain are incompletely understood. Osteopontin (OPN), an early marker of inflammation is elevated in HAND. OPN may be a key intercellular signaling linker between neurons, macrophages/microglia and astrocytes in the CNS. We, and other groups, found that OPN is increased in HAND, even in those on therapy. OPN is significantly expressed in astrocytes, microglia and neurons in HAND. Thus, OPN increases in response to HIV infection. These findings suggest that OPN is a putative contributor to neuropathogenic processes in HAND. A feedback loop exists between OPN and HIV. Indeed, we showed a strong relationship between viral gene expression and the induction of OPN. Knockdown of OPN in macrophages led to a 50% reduction in HIV production, suggesting that this cytokine stimulates viral replication. Indeed inhibition of OPN blocks HIV transcription and replication in macrophages. Our findings show that OPN enhances HIV replication through NF-?B and via activation of OPN receptors, integrins and CD44. In macrophages, OPN is required for the downstream activation of mitogen-activated kinases (MAPKs), innate and inflammatory pathways, implicated in HAND. Together, our data suggests that OPN is an important regulator of both HIV replication and proinflammatory signaling in cells of the CNS. Hence, it is critical that we understand OPN signaling and downstream inflammatory cascades in order to develop new therapeutic interventions. Our central hypothesis is that in the context of systemic HIV infection, OPN expression in activated macrophages/microglia, astrocytes and neurons promotes integrin and CD44 signaling cascades resulting in chronic inflammation and subsequent injury of neurons. A three-pronged approach will be used to explore our hypothesis: 1) in vivo, using HIV-infected NOD-scid IL-2R? mouse engrafted with human hCD34+. In this model, several key neuropathological hallmarks seen in HAND are observed, it allows persistent HIV replication, and mice can be treated with antivirals, 2) in vitro, using primary macrophage, neuronal, and astrocytic cultures to deconstruct the molecular mechanisms, and 3) ex vivo, using human brain postmortem tissue to validate experimental findings. We expect that the new knowledge gained will allow for future translational studies aimed at alleviating neuronal and cognitive damage in HAND. This is especially important as to date, no viable adjunctive therapy has yet been identified.

Public Health Relevance

The hosts? inflammatory response to low-level chronic infection, and how this exacerbates neuronal injury and impacts behavior and memory are incompletely understood. The proinflammatory cytokine osteopontin (OPN) is elevated in neurodegenerative disorders including HIV-associated neurocognitive disorders (HAND). We will identify and study the molecular mechanisms by which OPN contributes to CNS injury and HIV persistence, with the ultimate aim to pursue translational studies aimed at ameliorating neurodegeneration in HAND.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS102006-02
Application #
9360018
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Wong, May
Project Start
2016-09-30
Project End
2021-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205