The interferon beta response to simian immunodeficiency virus infection of the central nervous system: Induction, regulation, and effects

Neurological complications of human immunodeficiency virus (HIV) infection are significant, growing health problems despite general reduction in HIV-associated mortality and morbidity by combined antiretroviral therapy. Because human brain is inaccessible until post mortem, the progression and determinants of neurocognitive disorders must be studied in animal models. Dual-inoculation of pigtailed macaques (Macaca nemestrina) with neurovirulent simian immunodeficiency virus (SIV) and an immunosuppressive SIV swarm results in accelerated progression to AIDS in all animals, with development of encephalitis in over 90% by three months post-infection.;The goal of the studies described herein was to use the SIV/macaque model to investigate early infection leading to neurological disease, with a special emphasis on the role and regulation of the cytokine interferon beta---the most important Type I interferon in brain---and its downstream effectors.;Our investigation of acute phase central nervous system (CNS) infection revealed early viral invasion and a robust, coordinately regulated CNS innate immune response. Interferon beta was integral to this response: small changes in interferon beta translated into large fluctuations of downstream molecules such as MxA. By 42 days p.i., when neuropathogenic effects are apparent, the relative isoform levels of an interferon-stimulated factor, C/EBPbeta, correlated with the severity of encephalitis.;Promyelocytic leukemia protein (PML) is another interferon-stimulated gene with reported antiviral effects. We found that PML levels in astrocytes rise and fall in concert with interferon beta in the SIV-infected brain, a cell type-specific response not observed in activated macrophages. A proposed but controversial mechanism for anti-HIV properties of PML holds that PML translocates from the nucleus to the cytoplasm soon after infection. However, in our experimental systems, neither SIV nor ovine Visna virus prompted PML translocation. The anti-lentiviral function of PML remains elusive.;Exquisite sensitivity to interferon beta implies that a redundant regulatory system must keep the molecule within physiologically acceptable bounds. To the known control mechanisms for IFN beta, the work described here adds microRNA-mediated regulation. This thesis presents in vitro evidence that miRs -26a, -34a, -145, and let-7b may participate in IFN beta regulation and shows in vivo data consistent with this regulatory mechanism.