Abstract
Combination antiretroviral therapy (cART) targets viral replication, but early viral protein production by astrocytes may still occur and contribute to the progression of HIV-1 associated neurocognitive disorders and secondary complications seen in patients receiving cART. In prior work with our model, astrocytic HIV-1 Nef expression exhibits neurotoxic effects leading to neurological damage, learning impairment, and immune upregulation that induces inflammation in the lungs and small intestine (SI). In this follow-up study, we focus on the sympathetic nervous system (SNS) as the important branch for peripheral inflammation resulting from astrocytic Nef expression. Male and female Sprague Dawley rats were infused with transfected astrocytes to produce Nef. The rats were divided in four groups: Nef, Nef + propranolol, propranolol and naïve. The beta-adrenergic blocker, propranolol, was administered for 3 consecutive days, starting one day prior to surgery. Two days after the surgery, the rats were sacrificed, and then blood, brain, small intestine (SI), and lung tissues were collected. Levels of IL-1β were higher in both male and female rats, and treatment with propranolol restored IL-1β to basal levels. We observed that Nef expression decreased staining of the tight junction protein claudin-5 in brain tissue while animals co-treated with propranolol restored claudin-5 expression. Lungs and SI of rats in the Nef group showed histological signs of damage including larger Peyer’s Patches, increased tissue thickness, and infiltration of immune cells; these findings were abrogated by propranolol co-treatment. Results suggest that interruption of the beta adrenergic signaling reduces the peripheral organ inflammation caused after Nef expression in astrocytes of the brain.
Highlights
With the development of combination antiretroviral therapy, people living with human immunodeficiency virus (HIV) have increased life expectancy
enzyme-linked immunosorbent assay (ELISA) was selected based on our earlier reports that transfected astrocytes secrete Nef [27], and that such astrocytic Nef expression compromises the blood brain barrier (BBB) according to Evans blue dye extravasation and reduction of the tight junction protein claudin-5 [10]
We confirmed similar staining for Nef by immunohistochemistry in the hippocampus independent of propranolol treatment (S1 Fig) Together, these results indicate that astrocytes express Nef throughout the experimental protocol, consistent with our prior report that this model maintains Nef expression for seven days in-vitro and in-vivo [27]
Summary
With the development of combination antiretroviral therapy (cART), people living with human immunodeficiency virus (HIV) have increased life expectancy. Despite successfully controlling systemic viremia, patients often develop comorbid pathologies such as interstitial pneumonitis, gut mucosal barrier dysfunction, and autonomic neuropathy [1,2,3]. These HIV-associated pathologies may not necessarily result from the viral replication, given the observed low plasma virus levels. Instead, they may result from inflammatory cytokine levels that remain elevated due to viral proteins still present in the body. Infected women receiving cART present elevated levels of TNFα and IL-1β [5]. HIV viral proteins are an essential topic to study due to their toxic effects, including inflammation
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