Effect of HIV‐1 Tat on enteric neuropathogenesis (653.6)

Abstract

The gastrointestinal (GI) tract is a major target and reservoir of the HIV virus. Acute and chronic HIV infection induces a higher level of CD4 T cell depletion in the GI tract compared to peripheral blood and affects motility and digestion. Since the enteric nervous system regulates these processes, it may be a potential target of HIV infection. The majority of HIV effects are not achieved by lytic propagation of the virus but by viral proteins. HIV‐1 Tat, a regulatory protein between 86 to 101 amino acids is released by infected cells and together with other HIV proteins has been shown to modulate neuronal function in the central nervous system. However little is known about its effects on the GI tract. In this study, we examined the effects of Tat on single isolated enteric neurons and in isolated ileum tissue. At the cellular level, in whole cell patch clamp experiments, Tat increased enteric neuronal excitability both in Tat treated (n=20) and in ileum neurons isolated from mice expressing the tat gene (n=9) by a significant increase in number of action potentials evoked, decrease in rheobase (from 20pA to 10pA) and threshold potential (from ‐13.2mV to ‐16.1 mV). This increase was mediated by a leftward shift of the sodium channel activation curve (‐ 10mV decrease in V0.5 of activation) thereby increasing the steady state availability of sodium channels. Tat selectively increased the mRNA and protein expression of Nav1.7 and Nav1.8 isoforms of the sodium channel. In isolated ileum tissues, Tat elicited an inflammatory response which was observed by an up regulation of pro‐inflammatory cytokines and increased GI motility thereby contributing to the HIV mediated GI dysmotilities observed in HIV patientsGrant Funding Source: Supported by the National Institute of Health grants DK046367 and DA024009 and the VCU‐IMSD 541332