Tat 101-Mediated Enhancement of Brain Pericyte Migration Involves Platelet-Derived Growth Factor Subunit B Homodimer: Implications for Human Immunodeficiency Virus-Associated Neurocognitive Disorders

Abstract

In the era of antiretroviral therapy, although the human immunodeficiency virus (HIV) replication can be successfully controlled, complications of the CNS continue to affect infected individuals. Viral Tat protein is not only neurotoxic but has also been shown to disrupt the integrity of the blood-brain barrier (BBB). Although the role of brain microvascular endothelial cells and astrocytes in Tat-mediated impairment has been well documented, pericytes, which are important constituents of the BBB and play a key role in maintaining the integrity of the barrier, remain poorly studied in the context of HIV-associated neurocognitive disorders (HAND). In the present study, we demonstrated that exposure of human brain microvascular pericytes and C3H/10T1/2 cells to HIV-1 Tat101 resulted in increased expression of platelet-derived growth factor subunit B homodimer (PDGF-BB) and increased migration of the treated cells. Furthermore, we also demonstrated that this effect of Tat was mediated via activation of mitogen-activated protein kinases and nuclear factor-B pathways. Secreted PDGF-BB resulted in autocrine activation of the PDGF-BB/PDGF ␤ receptor signaling pathway, culminating ultimately into increased pericyte migration. Ex vivo relevance of these findings was further corroborated in isolated microvessels of HIV Tg26 mice that demonstrated significantly increased expression of PDGF-BB in isolated brain microvessels with a concomitant loss of pericytes. Intriguingly, loss of pericyte coverage was also detected in sections of frontal cortex from humans with HIV-encephalitis compared with the uninfected controls. These findings thus implicate a novel role of PDGF-BB in the migration of pericytes, resulting in loss of pericyte coverage from the endothelium with a subsequent breach of the BBB.

Macrophage‐derived extracellular vesicles mediate smooth muscle hyperplasia: role of altered miRNA cargo in response to HIV infection and substance abuse

“…Inflammation plays a crucial role in vascular remodeling associated with chronic lung, neurologic and cardiovascular diseases associated with HIV infection (5, 45–47). Various reports demonstrate the presence of inflammatory cells within the plexiform lesions and in the vicinity of pulmonary vessels with intimal and medial wall thickening in pulmonary hypertension patients (48–50).…”

“…Also, HIV-1 virions can get packaged within the EVs to escape immune surveillance and replicate. Viral proteins, such as negative regulatory factor have been found in HIV-infected cell–derived EVs that have the ability to cause immune activation as well as promote neuroimmune or cardiovascular complications (43, 46, 61, 62). Cocaine is known to impair the functions of macrophages and CD4 + lymphocytes.…”

Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders

“…Post-mortem studies of brain tissue from patients with HIV-1-associated dementia or HIV encephalitis have found evidence of microvascular degeneration and BBB breakdown, including reduced pericyte coverage 177 . Vascular insults, including enlarged perivascular spaces 64,151,178 and mineralization of mural cells of deep penetrating blood vessels 171 , have also been found in brain tissue from patients with CTE 64,151,171,178 .…”

Pericytes of the neurovascular unit: key functions and signaling pathways

“…Pericytes degenerate and likely play a role in cerebrovascular dysfunction in complex neurological diseases such as AD 26,49,50 , amyotrophic lateral sclerosis (ALS) 51 , and type 2 diabetes mellitus (T2DM)-related microangiopathy and retinopathy 52–54 . Pericyte dysfunction has been also associated with human immunodeficiency virus (HIV)-related dementia 55 , epilepsy 56 , cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) 57 , and brain cancer 58,59 .…”

“…Increased BBB permeability and pericyte loss, present in HAND and HAD, is thought to promote neurological impairments via increased transport of the HIV-1 viral neurotoxic protein, Tat101, into the brain 55 . Interestingly, Tat101 increases PDGF-BB expression and PDGF-BB/PDGFRβ signaling, specifically via MAPK and NFκB activation, resulting in elevated pericyte migration and deficiency 55 .…”