Project Details
Description
In many infected individuals, human immunodeficiency virus type 1 (HIV-1) enters the brain and can cause a broad spectrum of HIV-1-associated neurocognitive disorders (HAND) ranging from mild impairments to severe HIV-associated dementia (HAD). While widespread use of combination antiretroviral therapy (cART) has effectively increased the life span of people living with HIV-1/AIDS (acquired immunodeficiency syndrome), the prevalence of milder forms of HAND has also increased in the cART era. Indeed, recent epidemiological studies indicate that greater than 50% of HIV-1 infected people in the USA develop HAND. As HIV-1 does not infect neurons, HIV-1 infected macrophages and microglia (and possibly astrocytes) are thought to contribute to neuronal dysfunction and death via a direct mechanism (production of viral proteins) or an indirect “bystander” effect (production of cytokines and chemokines). Pathology studies have also shown that a chronic state of HIV replication in the brain increases intra and possibly extracellular -amyloid (A), a classic hallmark of Alzheimer’s disease (AD) and dementia. However, how and why A production is elevated by HIV-1 infection, and whether this contributes to neurodegeneration, remains unclear. Our preliminary data identifies amyloid precursor protein (APP) as an innate restriction factor for both early and late HIV-1 infection in human cells, including microglia. Moreover, we establish that HIV-1 overcomes this restriction by reducing APP levels, but in doing so generates A40 and A42 products that are toxic to primary cortical neurons. In identifying the underlying mechanism for further study, we find that APP is a novel HIV-1 matrix (MA) associated protein that blocks early infection. By transfection of an infectious HIV-1 clone or Gag-expressing plasmids, we find that increasing APP expression also binds HIV-1 Gag through its MA domain and potently suppresses late stage HIV-1 budding, trapping Gag in specific membrane compar
Status | Finished |
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Effective start/end date | 2/1/17 → 1/31/23 |
Funding
- National Institute of Neurological Disorders and Stroke (5R01NS099064-05)
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