HIV can enter the CNS during acute infection. However, virus replication appears to be controlled since HIV-associated dementia generally does not develop until the onset of AIDS. The goals of these studies are to elucidate glial cell inflammatory mechanisms that regulate HIV/SIV replication in the CNS. Using a SIV/macaque model of HIV dementia in which over 90% of infected animals develop encephalitis and all develop AIDS by 3 months, we demonstrated that during acute infection, virus replication in the brain is accompanied by enhanced expression of glial cell activation markers. Suppressed expression of glial activation markers and downregulation of viral RNA (to undetectable levels) occurred in parallel with increased expression of IFNbeta in the brain from acute through asymptomatic infection, despite continued virus replication in the periphery during this time. Because viral DNA levels in the brain remained constant from acute through asymptomatic infection, these findings suggest that non-cytolytic mechanisms involving glial cell activation and production of IFNbeta mediated downregulation of acute HIV/SIV gene expression. IFNbeta has been shown to inhibit ongoing HIV replication in macrophages but not lymphocytes, via transcriptional mechanisms involving expression of a dominant-negative isoform of the transcription factor C/EBPbeta. In addition to suppressing virus replication at a transcriptional level, IFNbeta may also inhibit post-transcriptional events required for viral gene expression by upregulating expression of PML (promyelocytic leukemia protein). During late stage infection of the CNS, resurgent virus replication occurs in the presence of both IFNbeta and enhanced expression of glial cell activation markers, and is accompanied by marked apoptosis, increased expression of neurodegenerative markers and development of encephalitis. Analysis of signaling pathways activated in glial cells during SIV infection revealed that acute infection is associated with activation of anti-apoptotic kinases (ERK) while late stage infection is associated with activation of pro-apoptotic/neurodegenerative kinases (JNK/p38). Thus, we hypothesize that activation of specific inflammatory pathways in glial cells differentially modulates IFNbeta-mediated antiviral mechanisms and hence, SIV replication.
Aim 1 will determine the level of transcriptional suppression during SIV infection of the CNS.
Aim 2 will identify cell-types producing and responding to IFNbeta and examine expression of specific C/EBP isoforms as well as expression and cellular distribution of PML.
Aim 3 will identify specific sites in the LTR occupied by transcription factors expressed longitudinally during SIV infection in the CNS.
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