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

The pathogenesis of HIV/SIV encephalitis (HIVE/SIVE) remains incompletely understood, but is associated with alterations in the blood brain barrier. In animals infected with pathogenic strains of simian immunodeficiency virus (SIV), such as SIVmac239 and SIVmac251, the virus can be consistently found in the central nervous system (CNS) within 10 to 14 days of infection: at the time of peak viremia (Lackner et al., 1994). This also appears to be true in human immunodeficiency virus (HIV)-infected humans, but the number of cases examined during peak viremia is very small (Davis et al., 1992). In SIV-infected macaques at this early time point, endothelial cells of the blood-brain barrier (BBB) are activated and integrity of the BBB is compromised (Stephens et al., 2003). As viral loads decline toward set point at roughly two months post infection the endothelial activation subsides and BBB integrity is largely restored (Sasseville et al., 1995, Lackner et al., 1994, Annunziata, 2003, Zink et al., 1998). However, in the terminal phases of disease, viral loads rise and approximately one third of animals develop SIV encephalitis (SIVE), which is associated with breakdown of the BBB. The exact mechanisms of BBB disruption are unclear, but it is known that numerous resident and transitory cell populations in the CNS can be infected, with CD14-positive perivascular macrophages being the primary productively-infected cell type (Little et al., 1999, Gorry et al., 2003, Bissel and Wiley, 2004, Ryzhova et al., 2002, Liu et al., 2004, BrackWerner, 1999, Trillo-Pazos et al., 2003, Williams et al., 2001, Fischer-Smith et al., 2001). Nervous system manifestations associated with HIV infection of humans or SIV infection of rhesus macaques include an encephalitis (SIV or HIV encephalitis, SIVE/HIVE) characterized by astrocytic and microglial activation and scattered perivascular aggregates of mononuclear cells and multinucleated giant cells. These perivascular lesions contain large numbers of HIV/SIV-infected cells, the majority of which are monocyte/macrophages. The presence of cells productively-infected with SIV/HIV in the parenchyma has been shown to induce a response in astrocytes (Nath, 1999, Tyor et al., 1992, Persidsky et al., 1999, Persidsky et al., 2000) which in turn may lead to decreased tight junction protein expression and a leaky BBB (Dallasta et al., 1999, Persidsky et al., 1997, Moses and Nelson, 1994, Boven et al., 2000, Luabeya et al., 2000, Andras et al., 2003, Annunziata, 2003, Kanmogne et al., 2005, Kanmogne et al., 2007, MacLean et al., 2004b, Persidsky, 1999). Astrocytes, along with microglia, are resident cells in the brain involved in inflammation. Their role during inflammation is not well understood; it is believed that both cell types are