Coordinated Regulation of SIV Replication and Immune Responses in the CNS

Abstract

Central nervous system (CNS) invasion during acute-stage HIV-infection has been demonstrated in a small number of individuals, but there is no evidence of neurological impairment at this stage and virus infection in brain appears to be controlled until late-stage disease. Using our reproducible SIV macaque model to examine the earliest stages of infection in the CNS, we identified immune responses that differentially regulate inflammation and virus replication in the brain compared to the peripheral blood and lymphoid tissues. SIV replication in brain macrophages and in brain of SIV-infected macaques was detected at 4 days post-inoculation (p.i.). This was accompanied by upregulation of innate immune responses, including IFNβ, IFNβ-induced gene MxA mRNA, and TNFα. Additionally, IL-10, the chemokine CCL2, and activation markers in macrophages, endothelial cells, and astrocytes were all increased in the brain at four days p.i. We observed synchronous control of virus replication, cytokine mRNA levels and inflammatory markers (MHC Class II, CD68 and GFAP) by 14 days p.i.; however, control failure was followed by development of CNS lesions in the brain. SIV infection was accompanied by induction of the dominant-negative isoform of C/EBPβ, which regulates SIV, CCL2, and IL6 transcription, as well as inflammatory responses in macrophages and astrocytes. This synchronous response in the CNS is in part due to the effect of the C/EBPβ on virus replication and cytokine expression in macrophage-lineage cells in contrast to CD4+ lymphocytes in peripheral blood and lymphoid tissues. Thus, we have identified a crucial period in the brain when virus replication and inflammation are controlled. As in HIV-infected individuals, though, this control is not sustained in the brain. Our results suggest that intervention with antiretroviral drugs or anti-inflammatory therapeutics with CNS penetration would sustain early control. These studies further suggest that interventions should target HIV-infected individuals with increased CCL2 levels or HIV RNA in the CNS.

Regulation of SIVmac239 Basal Long Terminal Repeat Activity and Viral Replication in Macrophages

“…Tat has been shown to increase expression of the C/EBP␤ protein and binding of C/EBP␤ to DNA in vitro (55), in addition to physically and functionally interacting (in vitro and in vivo) with C/EBP␤ to induce interleukin 6 and MCP-1 (monocyte chemoattractant protein 1 or CCL2 (55)(56)(57)(58)). Moreover, Mameli et al (58) demonstrated that the Tat-C/EBP␤ functional and physical association is mediated through cyclin T1/cdk9 in U-87MG astrocytic cells and possibly influences cates in perivascular macrophages, and spreads to resident macrophages (1,2,8,69). At this early time point there is an abundance of the C/EBP␤ isoform in macrophages (5,69) that bind the JC1 and DS1 sites of the SIV-LTR.…”

“…Moreover, Mameli et al (58) demonstrated that the Tat-C/EBP␤ functional and physical association is mediated through cyclin T1/cdk9 in U-87MG astrocytic cells and possibly influences cates in perivascular macrophages, and spreads to resident macrophages (1,2,8,69). At this early time point there is an abundance of the C/EBP␤ isoform in macrophages (5,69) that bind the JC1 and DS1 sites of the SIV-LTR. C/EBP␤ recruits histone acetyltransferases such as CBP/p300 and PCAF (15,16,70), leading to chromatin remodeling events.…”

“…Once Tat is expressed, it binds to the TAR element, assisted by C/EBP␤ bound to the DS1 site and thus contributes, in part, to the surge of SIV RNA production and virus replication during acute infection (peaking at 10 days p.i.) in the brain (3,69). Virus replication in macrophages in the brain triggers the innate immune responses and production of IFN␤ (8,69), which activates CUGBP-1 required for IFN␤-induced translation of the dominant-negative LIP isoform (47).…”

“…in the brain (3,69). Virus replication in macrophages in the brain triggers the innate immune responses and production of IFN␤ (8,69), which activates CUGBP-1 required for IFN␤-induced translation of the dominant-negative LIP isoform (47). Between 10 and 21 days p.i., LIP expression predominates in the brain (5), which effectively competes with the C/EBP␤ for occupancy of JC1 and DS1 sites due to the higher affinity of LIP compared with C/EBP␤ for both sites.…”

Blood-Brain Barrier Disruption and Encephalitis in Animal Models of AIDS

“…The Clements group at Johns Hopkins has shown increased CCL2 mRNA in brain extracts using a highly accelerated encephalitis model (Witwer et al, 2009), although mRNA does not always equate with secreted protein. Additionally, the Berman group at Einstein College of Medicine has shown numerous effects of CCL2 on HIV-infected macrophages (Eugenin et al, 2003, Eugenin et al, 2006.…”