Canonical Type I IFN Signaling in Simian Immunodeficiency Virus-Infected Macrophages Is Disrupted by Astrocyte-Secreted CCL2

Abstract

HIV-associated neurologic disorders are a mounting problem despite the advent of highly active antiretroviral therapy. To address mechanisms of HIV-associated neurologic disorders, we used an SIV pigtailed macaque model to study innate immune responses in brain that suppress viral replication during acute infection. We previously reported that during acute infection in brain, noncanonical type I IFN signaling occurs, where IFN-β mRNA is induced while IFN-α is simultaneously suppressed. Two downstream IFN-stimulated genes, MxA and TRAIL, also show differential expression patterns. In this study, we show that differential signaling is due to interactions between macrophages and astrocytes. Astrocytes produce high levels of CCL2 upon SIV infection, which binds to CCR2 receptors on macrophages, leading to a selective suppression of IFN-α and the IFN-stimulated gene TRAIL while simultaneously inducing IFN-β and MxA. The interactions between chemokine and cytokine pathways are a novel finding that may specifically occur in the CNS.

Immuno-Pharmacological Targeting of Virus-Containing Compartments in HIV-1-Infected Macrophages

“…Of particular interest for the present article, CCL2 (a CC chemokine binding to CCR2) was found to be significantly elevated in the CSF of AIDS patients affected by encephalitis caused either by either HIV-1 or by cytomegalovirus, but not by other opportunistic infections or tumors of the CNS [52,53]. Similar evidence has been obtained in macaques infected with simian immunodeficiency virus (SIV) in which a major source of CCL2 in the CNS was identified in infected astrocytes [54], as also observed upon in vitro infection of these cells with HIV-1 [55]. Increased levels of CCL2, but not of other chemokines, in the CNS have been linked to the enhanced transmigration of leukocytes across the BBB [56].…”

A comparative transcriptomic analysis of astrocytes differentiation from human neural progenitor cells

“…NOTCH1 is among the upregulated genes, and notch signaling is known to inhibit maturation of neurons and oligodendrocytes from precursor cells while promoting astrocytes differentiation (Givogri et al, 2003;Louvi & Artavanis-Tsakonas, 2006). Among other upregulated genes were APCDD1, which is a negative regulator of Wnt signaling that promotes astrocyte precursor migration (Kang et al, 2012), the chemokine CCL2 that recruit CCR2-expressing monocytes into the CNS and is mainly expressed by astrocytes upon viral infection and TBI (Semple et al, 2010;Zaritsky et al, 2012), and the colony stimulating factor-1 (CSF1) which is expressed by astroglial cells during CNS development and following inflammatory response (Shafit-Zagardo et al, 1993;Alterman & Stanley, 1994). When we looked at the downregulated genes, we noticed that the majority of these genes are normally expressed by oligodendrocytes, by the precursor cells (OPCs) or they are genes important for oligodendrocytes differentiation.…”

Innate Immune Evasion Strategies by Human Immunodeficiency Virus Type 1

“…It was documented that HIV-1 gp120 blocks cytokines including IFN and the cytolytic activity of NK cells by interfering with TLR9 activation in pDCs [54]. In a SIV model of central nervous system, it has been shown that SIV infected astrocytes produce monocyte chemotactic protein (MCP)-1 or CCL2 that binds to the CCR2 receptors on macrophages resulting in suppression of specific ISGs such as TRAIL [55]. In macrophages, HIV-1 exploits another cellular factor, suppressor of cytokine signaling (SOCS) 3 to facilitate its replication.…”