**6. Modeling HIVE** *in vitro*

#### **6.1 Simple models – single cell type**

Numerous groups have used *in vitro* models for determining the cellular and molecular events occurring during the development of HIVE. These have ranged from utilizing single cell types including astrocytes (Renner et al., 2011, Eugenin and Berman, 2007), or endothelial cells (MacLean et al., 2001, Oshima et al., 2000) to tease out initial activation steps. An *ex vivo* single cell type model has also been used recently to examine BBB disruption whereby intact microvessels are extracted and incubated with the lentiviral-infected macrophages (Ivey et al., 2009b). This method has an advantage of maintaining original tight junction orientations. However, the downside is that this technique is only suitable for assessing interactions for the first couple of hours due to viability issues with the microvessels.

#### **6.2 2.5D model of BBB** *in vitro*

More complex models involve monolayers of endothelial cells cultured above astrocytes, either on top of a collagen matrix (Biegel and Pachter, 1994, Biegel et al., 1995) or on opposite sides of a membrane (Lu et al., 2008, Persidsky et al., 1997, Eugenin et al., 2006). The coculture allows tight junction formation to occur. The endothelial cells are still a single monolayer, and for this reason, the model is referred to as 2.5D, rather than 3D. These models have been used to examine mechanisms of encephalitis.

#### **6.3 3D model of BBB** *in vitro*

A further refinement involved the growth of endothelial cells in tubes (Stanness et al., 1999), or of culturing the endothelial cells within a matrix surrounded by glial cells allowing the endothelial cells to form tubes with astrocytes extending processes to induce tight junction proteins (Al Ahmad et al., 2010). Collagen gels were used to create 3D cultures with BMEC and astrocytes. Al Ahmad et al. showed that BMEC alone were unable to localize tight junction proteins to the cell border. Coculture with astrocytes corrected this, with Claudin5 and ZO1 localized to functionally relevant positions. This clearly demonstrates the necessity for including astrocytes in BBB culture models. As of yet, these models have not been applied to encephalitis studies.

A further model that has been utilized is slice cultures (Renner et al., 2011, Noraberg, 2004). These *ex vivo* models are essentially a complex co-culture that preserves cell:cell ratios, and functional spatial relationships. This model allows one to determine precise cell types secreting chemokines in response to viral-infected cells. It will also prove useful for mechanistic studies of neuropathogenesis.

### **7. Summary of SIV model of encephalitis**

Under normal conditions the brain allows only limited access by immune cells. Early in HIV infection the virus enters the brain through normal trafficking. This leads to a transient increase in BBB permeability, and a localized immune response. As the disease progresses to encephalitis the immune response is dramatically increased, marked by a loss of tight junction integrity, gliosis, and formation of multinucleated giant cells in the parenchyma. The parallel between the neuropathogenesis of HIV in humans, and SIV in the rhesus

macaque has led to the establishment of rhesus macaque as the predominant *in vivo* model for HIVE. The use of *in vitro* models allows for precise control for investigating pathways of lentiviral neuropathogenesis.

#### **8. Acknowledgements**

Supported by: This work was supported in part by PHS grants RR00164, MH077544 (AGM), Louisiana Board of Regents Fellowship LEQSF(2007-2012)-GF15 (NAR).

#### **9. References**

94 Non-Flavivirus Encephalitis

Microglia are the resident macrophages in brain. These cells are believed to be derived from bone marrow, and present in brain from birth with no replenishment of these cells during the life of an individual (Williams and Hickey, 1995). In normal, healthy brain, microglia play a surveillance role. The high surface area to volume ratio is indicative of a cell "sampling" its environment (Figure 2). On activation, fine processes are no longer visible, with the microglia taking on a more amoeboid morphology. In SIV infection microglia can be recruited and productively-infected themselves (Gonzalez-Scarano and Martin-Garcia, 2005). These cells can also be induced to upregulate CD163 (Roberts et al., 2004b, Borda et

The overall response to SIV or HIV infection of the CNS which primarily involves infected monocyte/macrophages is pro-inflammatory. Neuroinvasion by monocyte/macrophages initiates a positive feedback loop stimulating glial cells to respond further. Glial involvement increases not only the intensity but the area affected by inflammation, damaging local neural circuitry, and recruiting monocytes into the parenchyma. While the glial inflammatory response may seem detrimental, ablation of monocytes led to increased tissue damage in a model of retinal inflammation, implicating lesion formation as a partially neuroprotective response (London et al., 2011). Although the initial monocytes entering the brain carrying HIV/SIV may not be recruited by glial signaling, later neuroinvasion is likely

Numerous groups have used *in vitro* models for determining the cellular and molecular events occurring during the development of HIVE. These have ranged from utilizing single cell types including astrocytes (Renner et al., 2011, Eugenin and Berman, 2007), or endothelial cells (MacLean et al., 2001, Oshima et al., 2000) to tease out initial activation steps. An *ex vivo* single cell type model has also been used recently to examine BBB disruption whereby intact microvessels are extracted and incubated with the lentiviral-infected macrophages (Ivey et al., 2009b). This method has an advantage of maintaining original tight junction orientations. However, the downside is that this technique is only suitable for assessing interactions for the

More complex models involve monolayers of endothelial cells cultured above astrocytes, either on top of a collagen matrix (Biegel and Pachter, 1994, Biegel et al., 1995) or on opposite sides of a membrane (Lu et al., 2008, Persidsky et al., 1997, Eugenin et al., 2006). The coculture allows tight junction formation to occur. The endothelial cells are still a single monolayer, and for this reason, the model is referred to as 2.5D, rather than 3D. These

A further refinement involved the growth of endothelial cells in tubes (Stanness et al., 1999), or of culturing the endothelial cells within a matrix surrounded by glial cells allowing the

al., 2008) which can be quite prominent in areas of BBB breakdown.

first couple of hours due to viability issues with the microvessels.

models have been used to examine mechanisms of encephalitis.

**5. Microglia** 

**5.1 Summary of gliosis** 

driven, at least in part, by gliosis.

**6.1 Simple models – single cell type** 

**6. Modeling HIVE** *in vitro*

**6.2 2.5D model of BBB** *in vitro*

**6.3 3D model of BBB** *in vitro* 


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Adhesion Molecule-1 (VCAM-1) Induced By Theiler's Murine Encephalomyelitis


**5** 

*Turkey* 

Feyzi Birol Sarica

**Herpes Simplex Type 1 Encephalitis** 

*Başkent University, Faculty of Medicine, Department of Neurosurgery* 

Encephalitides, an acute infection of the brain parenchyma, are characterized by fever, headache and altered consciousness. Neurological deficits and focal or generalized epileptic seizures may also be seen. There are important differences in clinical presentations between encephalitides caused by viruses. While some viral encephalitides, such as Herpes simplex virus type-1 (HSV type-1) encephalitis, cause sporadic infection; others, such as Japanese B encephalitis virus and Eastern equine encephalitis virus, cause epidemic infections with specific geographic distribution. Some viruses like HSV cause fulminant encephalitis leading to death within a couple of days whereas viruses such as Measles virus can cause progressive subacute sclerosing panencephalitis lasting several months and years. HSV type-1, HSV type-2, LaCrosse encephalitis virus, St. Louis encephalitis virus usually causes encephalitis in healthy individuals, whereas HSV type-1, Cytomegalovirus, Varicella-zoster virus, Epstein-Barr virus, Human herpes virus type-6 and Enteroviruses are associated with encephalitides in immunodeficient or immunocompromised patients (Mathewson

Herpes simplex virus (HSV) is the most common cause of sporadic fatal encephalitis (Mathewson Commission, 1929; Meyer et al.,1960; Smith et al., 1941). Smith et al. detected inclusion bodies consistent with HSV infection from a newborn's brain with encephalitis and virus was isolated from brain tissue then (Smith et al., 1941). The first adult case of HSE was reported by Zarafonetis et al. (Zarafonetis et al., 1944). The pathological findings in this patient's brain were prominent perivascular cuffing of lymphocytes and a large number small hemorrhages in left temporal lobe. Later in several studies, this temporal lobe localization was reported to be characteristic for HSE in patients older than 3 months. In the mid 1960s, Nahmias and Dowdle found two distinct antigenic type of HSV, as HSV type-1

The HSE, observed in adults, is caused by HSV type-1 predominantly (Dennett et al., 1997; Whitley & Lakeman, 1995). HSV type-2 is rarely seen in healthy adults and usually causes benign CNS infection, whereas severe meningoencephalitis is seen in immunosuppressed individuals (Mommeja-Marin et al., 2003). Herpes neonatorum, transmitted from perinatal area, causes severe encephalitis in neonates (Corey et al., 1983). HSV type-1 and HSV type-2 are from Herpesviridae family. The common feature of Herpesviridae family is that they stay in life-long latent (persistent) form in the organism and they can reactivate later leading recurrent infections. Also other viruses from Herpesviridae group may lead CNS diseases

**1. Introduction** 

Commission, 1929; Meyer et al.,1960; Roos,1999).

and HSV type-2 (Nahmias & Dowdle, 1968).

(Garcia-Blanco et al., 1991).

