RON receptor tyrosine kinase expression is decreased during simian immunodeficiency virus associated central nervous system disease

Abstract

The receptor tyrosine kinase, RON, is expressed on tissue-resident macrophages. RON functions by activating genes that promote wound repair and resolve inflammation, while repressing genes that perpetuate tissue damage and cell death. Chronic HIV infection is associated with dysregulated inflammation, and we hypothesize that diminished macrophage RON expression contributes to the development of end organ diseases including HIV-associated central nervous system (CNS) inflammation. We utilized CNS tissue from a SIV macaque model to examine the temporal regulation of RON in the brain during infection. Following prolonged SIV infection, RON expression was inversely correlated with the development of CNS disease: RON was highly expressed in animals that did not develop CNS lesions and lower in SIV infected macaques that demonstrated moderate to severe inflammatory lesions. Arginase-1 expression was low during late infection whereas expression of the inflammatory genes, IL-12 p40 and TNF &alpha, was elevated compared to uninfected animals. To validate a role for RON in regulating HIV, we infected human tonsillar tissue-resident macrophages. RON inhibited HIV replication in tissue-resident macrophages. Furthermore, HIV infection diminished RON in tonsil macrophages. We propose a model in which RON expression is decreased, genes that quell inflammation are repressed, and inflammatory mediators are induced to promote tissue inflammation following chronic HIV infection in the brain.

The cyclin dependent kinase inhibitor p21 is a factor that, like RON, negatively regulates HIV transcription. Elevated expression of p21 in HIV+ elite controllers, or by ectopic expression in primary CD4+ T cells, resulted in reduced HIV expression. Furthermore, these elite controllers had increased binding of factors that negatively regulate transcription elongation at the HIV long terminal repeat.

RON and p21 are examples of cellular factors that limit HIV transcription and contribute to HIV latency. Latently infected cells are not targeted by anti-retroviral therapy and permit rapid rebound of viremia following treatment interruption. Understanding intrinsic mechanisms that establish latency may provide targets for purging these HIV reservoirs or maintaining their transcriptionally silent state.