Innate immune responses and control of acute simian immunodeficiency virus replication in the central nervous system

Abstract

Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) can invade the central nervous system (CNS) during acute infection but virus replication is apparently controlled because clinical and pathological manifestations of CNS disease in HIV/SIV-infected individuals usually present later in infection, coincident with immunosuppression and acquired immuno-deficiency syndrome (AIDS). Using an established SIV/macaque model of HIV dementia, the authors recently demonstrated that acute virus replication is down-regulated (to undetectable viral RNA levels) in the brain, but not the periphery, as early as 21 days post inoculation (p.i.). Viral DNA levels in the brain remain constant, suggesting that infected cells persist in the CNS and that replication is inhibited largely at a transcriptional level. In vitro, active replication of HIV in macrophages can be inhibited by treatment with interferon (IFN)beta via a mechanism involving induction of a dominant-negative form of the transcription factor C/EBP (CCAAT/enhancer-binding protein)beta. Because macrophages are the primary cell types infected with HIV/SIV in the CNS and HIV replication in macrophages requires C/EBP sites within the viral long terminal repeat (LTR), the authors considered the possibility that suppression of C/EBP-dependent transcription contributes to the mechanism by which acute HIV/SIV replication is inhibited in the CNS. Here, the authors report that IFNbeta can also inhibit ongoing SIV replication in macaque macrophages in vitro. Further, the authors demonstrate that IFNbeta levels in the brain increase between 7 and 21 days p.i. in parallel with increased expression of the dominant-negative isoform of C/EBPbeta. These results suggest that innate immune responses involving IFNbeta may contribute to the mechanism(s) controlling acute SIV replication in the CNS.

IFNβ Protects Neurons from Damage in a Murine Model of HIV-1 Associated Brain Injury

“…Transient expression of IFNβ has also been observed in the CNS of SIV-infected macaques in association with extended viral control and delayed progression to disease in the brain2860, suggesting that the HIVgp120tg mouse model recapitulates a relevant aspect of brain injury by lentiviral infection.…”

“…In contrast, IFNβ has been implicated in the control of HIV and SIV infection in the brain2728. Exposure to IFNβ induces in lymphocytes, MΦ and microglia the expression and secretion of the β-chemokines CCL3, −4 and −5.…”

Illuminating viral infections in the nervous system

“…LIP blocks the acetylation of histones bound to SIV DNA and reduces viral replication 75,77 . Interestingly, an inverse correlation between SIV viral loads and the ratio of C/EBPβ to LIP was observed in macaque brains 76 , suggesting a role for IFNβ-induced genes in CNS antiviral responses following SIV infection. However, in vitro studies in primary peripheral and bone marrow-derived macrophages have demonstrated that IFN responses eventually wane during viral persistence owing to microRNA-mediated regulation of IFNβ expression 78 and/or induction of suppressor of cytokine signalling 3 (SOCS3) expression by the HIV Tat protein 79 .…”

“…Furthermore, in an animal model of SIV infection, antiviral innate immune mechanisms in the CNS (such as the expression of mRNA encoding IFNβ and IFN-induced GTP-binding protein MXA (also known as MX1)) were noted just 4 days after infection 74 . In macrophage cell lines, IFNβ can induce the production of a dominant-negative form of CCAAT/enhancer-binding protein-β (C/EBPβ) that has been referred to as LIP 75,76 . LIP blocks the acetylation of histones bound to SIV DNA and reduces viral replication 75,77 .…”

Toll-like receptor 3 signaling inhibits simian immunodeficiency virus replication in macrophages from rhesus macaques

“…Macrophages are the most important target of HIV in the central nervous system. Circulating cells from the monocyte/macrophage lineage become infected and traffic to the brain where they induce cytokine signaling and infect other macrophage lineage cells and astrocytes (Barber et al, 2004; Roberts et al, 2003). Macrophages mount broad antiviral responses through producing CC chemokines and antiviral cytokines, including type I interferons (IFNs).…”