HIV-infected patients commonly develop autonomic neuropathy (HIV-AN), which is a heterogeneous disorder characterized by varying degrees of both sympathetic and vagal dysfunction. We hypothesize that the vagal component of HIV-AN contributes to chronic inflammation, both directly via loss of cholinergic activity, and indirectlyvia effects on the gastrointestinal (GI) tract, and that these effects will be treatable using the acetylcholinesterase inhibitor pyridostigmine. The autonomic nervous system controls the inflammatory response to lipopolysaccharide (LPS) via the cholinergic anti-inflammatory pathway. This pathway is mediated by the vagus nerve, and is therefore likely impaired in HIV-AN with vagal dysfunction. Vagal dysfunction also causes slowed GI transit, which could exacerbate LPS-driven inflammation by promoting bacterial overgrowth. However, the anti-inflammatory impact of cholinergic pathways is almost completely unstudied in HIV, despite the known importance of inflammation in HIV disease progression. Therefore, in this exploratory pilot, we seek to establish associations between vagal dysfunction, GI motility and inflammation in virally suppressed, CART- treated individuals with HIV-AN.
Specific Aim 1 : To determine whether vagal dysfunction is associated with immune activation in CART- treated participants with HIV-AN, and if so to estimate the extent to which this association is mediated by GI effects (i.e. slowed motility, bacterial overgrowth, microbial translocation) versus direct effects of vaga dysfunction.
Specific Aim 2 : In a subset of participants who have both vagal and GI dysfunction, to investigate whether 8 weeks of pyridostigmine: a) reduces immune activation, and b) improves GI motility; and if the immune effect depends on the GI effect. To achieve these aims, we will recruit 80-100 participants with HIV-AN and GI symptoms who will be assessed for: vagal dysfunction (heart rate variability); GI dysmotility (gastric emptying scintigraphy); small intestinal bacterial overgrowth (breath testing); microbial translocation (LPS and sCD14); and immune activation (IL-6 and CRP). Participants meeting threshold criteria for both vagal and GI dysfunction will then be treated with pyridostigmine for 8 weeks, after which GI and immune measures will be reassessed.

Public Health Relevance

The autonomic nervous system influences vital internal organ functions including blood pressure, heart rate, digestion, and immune function. Dysfunction of the autonomic nervous system is common among people living with HIV/AIDS (PLWHA), but poorly understood. This research will study the interactions between autonomic dysfunction, gastrointestinal function and immune function in PLWHA and determine whether a medication called pyridostigmine is helpful in the treatment of these conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DK105917-01A1
Application #
8991372
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Hamilton, Frank A
Project Start
2015-07-15
Project End
2017-06-30
Budget Start
2015-07-15
Budget End
2016-06-30
Support Year
1
Fiscal Year
2015
Total Cost
$250,601
Indirect Cost
$100,601
Name
Icahn School of Medicine at Mount Sinai
Department
Neurology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Robinson-Papp, Jessica; Nmashie, Alexandra; Pedowitz, Elizabeth et al. (2018) Vagal dysfunction and small intestinal bacterial overgrowth: novel pathways to chronic inflammation in HIV. AIDS 32:1147-1156
Obermeit, Lisa C; Beltran, Jessica; Casaletto, Kaitlin B et al. (2017) Evaluating the accuracy of self-report for the diagnosis of HIV-associated neurocognitive disorder (HAND): defining ""symptomatic"" versus ""asymptomatic"" HAND. J Neurovirol 23:67-78
Dyck, Peter J; Kincaid, John C; Dyck, P James B et al. (2017) Assessing mNIS+7Ionis and international neurologists' proficiency in a familial amyloidotic polyneuropathy trial. Muscle Nerve 56:901-911