Herpes simplex Virus-2 Invades the Brain

Julio Francisco

Florida Institute of Technology
Introduction
Herpesvirus is a large viral family which consists of eight viruses known to cause human

disease (1).This paper will focus on herpes simplex virus 2 (HSV-2). HSV-2 is a sexual

transmitted disease (2). About 1.5 billion people are infected with HSV-2 annually (2). While

HSV-2 is best characterized for painful genital lesions, it can also cause encephalitis (3), aseptic

meningitis (3), recurrent radiculopathy (3), myelitis (4), psychiatric syndromes (4), and other

neurological disorders. This literature review will address how HSV-2 cause encephalitis and

meningitis.

To understand how the virus causes encephalitis and meningitis, the structural

morphology and life cycle of HSV-2 will first be discussed. This review will then discuss about

the invasiveness of HSV-2 to the central nervous system (CNS) and how the brain immune

system response to HSV-2. Lastly, this review addresses potential treatments to prevent or treat

HSV-2.

Structural Morphology of HSV-2

Like most viruses, herpesviruses is composed of a protein coat and a nuclear core.

Unlike other virus, a mature herpesviruses consist of four major components: (a) the trilaminar

lipid envelope, (b) tegument, (c) icosadeltahedral protein capsid, and (d) double-stranded DNA

(5). The trilaminar lipid envelope contains glycoproteins essential for attachment, entry,

cell-to-cell spread, and immune evasion (5). The tegument is an amorphous proteinaceous

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region required for gene expression of HSV-2 (5). Lastly, the icosadeltahedral capsid embeds

the DNA core (6)

Life Cycle of Herpes Simplex Virus 2

There are two phases of HSV-2: lytic and latent cycles. HSV-2 generally resides in

epithelial cells during its lytic phase and sensory neurons in the latent phase (3, 5, 7). The

decision to undergo either lytic or latent cycle lies with the chromatin structure of HSV-2 (7).

Through histone modification, HSV-2 would undergo the latent cycle by repressing its lytic gene

and expressing the latency-associated transcript (LAT) (7). In the latent cycle, the virus is

stationary and undetectable (7). This phase may seems as an ineffective strategy since the

virus remains impassive. However, the latent phase of the virus is essential for immune evasion

due to its slow replication cycle and lifelong latent infection cycle (1,7). Once conditions become

favorable, HSV-2 will reactivate and undergo lytic (7). During the lytic phase, the virus infects

the host, replicates it DNA, lyses the host cell, and moves to adjacent cells for further infection.

The mechanism of how HSV-2 infects the cell and replicates is known. First, the HSV-2

have two type of glycoproteins, gB and gD, that would bind with cell surface receptors of the

host cell (8). Herpesvirus entry mediator (HVEM), nectin-1, nectin-2, and heparan sulfate are

several examples of cell surface receptors in which HSV-2 glycoproteins would bind to (8). Once

the viral glycoproteins bind to the appropriate receptors, the virion envelope fuses with the cell

membrane (7). Next, nucleocapsid and tegument proteins are transported along the

microtubules and docked off to different sites in the cell (1, 7).

There are two main pathways the virus DNA genome can be released, either within the

nucleus (7), or into the cytosol where it would be subjected to immune recognition (1). If the

nucleocapsid and tegument are released within the nucleus, then the tegument protein, VP16,

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coordinates with Oct-1 and HCF-11 proteins to activate immediate-early (IE) genes (1, 7, 15).

This would further lead to the activation of enzymes for HSV-2 DNA synthesis and replication

(1). In addition, new progeny nucleocapsids are assembled and budded off from the nuclear

envelope to the trans-golgi appartus where it is released outside the cell by either exocytosis or

cell lyses (1, 7). HSV would initiate a new life cycle by spreading to other nearby sites (7).

On the other hand, if the virus DNA is released in the cytoplasm, pathogen recognition

receptors (PRRs) would detect the foreign DNA and induce an immune response.

HSV-2 Infection and Encephalitis

As the virus continue on infecting new cells, it would likely make its way to the central

nervous system (CNS) where it can do serious harm. The virus would enter from a peripheral

nervous system (PNS) through the axonal fiber by retrograde transport to CNS (9, 10). Once

inside the CNS, HSV-2 would settle mainly in the trigeminal ganglion due to the lack any

apoptotic pathway (11). Therefore, the trigeminal ganglion is vulnerable toward being infected

than another region of the brain.

Nevertheless, this viral infection do not go unnoticed. The CNS is equipped with a

network of innate immune sentinel cells, such as microglia and dendritic cells (9). Microglial cells

possess PRRs that would detect HSV-2 (1). HSV-2 is recognized by two main PRRs,

extracellular TLR2 and intracellular TLR9, respectively (1). Once the TLRs recognize HSV-2, a

cascade cellular events occurs within the microglial cells (as shown in Fig. 1), leading to the

release of pro-inflammatory cytokines and recruitment of immune cells. This overall process

would lead to an inflammatory response (17). If such inflammatory response occurs in the brain,

it is called encephalitis (12). Signs and symptoms of encephalitis include fever, delirium

(confusion), convulsions, paralysis, and loss of consciousness (12). On the other hand, if the

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inflammatory response occurs at the spinal cord membranes, then the disease is called

meningitis (13). This disease is characterized by restlessness and excitement (13).

Figure from Wang JQ, Jeelall YS, Ferguson LL and Horikawa K (2014) Toll-like receptors and
cancer: MYD88 mutation and inflammation. Front. Immunol. 5:367. doi:
10.3389/fimmu.2014.00367

Figure 1. Toll-like Receptors Pathway. Extracellular TLR2 and intracellular TLR9

would recognize HSV-2 virion and DNA genome, respectively (1). This would cause two TLRs to
dimerize, leading to the recruitment and activation of MyD88 (7). MyD88 associates with the TIR
domain, leading to the activation of IRAK1/IRAK4 complex (17). Next, IRAK4 phosphorylates
IRAK1, triggering IRAK1 to bind to TRAF (17). TAK1 phosphorylates IKK, and IKK ubiquitinates
NFB inhibitor, releasing NFB (17). NFB transcribes pro-inflammatory cytokines, leading to
inflammation (17).

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 Despite this immune recognition, herpesviruses can evade the innate immune system

through different approaches. This includes encoding proteins to disrupt intracellular pathways

of the innate immune system (1). For example, herpesviruses are able to inhibit TLR-2 and

TLR-9 pathway by producing ICP0 protein to promote the degradation of MyD88 and

MyD88-adaptor-like (MAL) proteins of TLRs pathway (1). By disrupting the TLRs pathway,

HSV-2, therefore, inhibits the production of pro-inflammatory, such as cytokines and nuclear

factor kappa-B (NF-B) (1), allowing the virus to proliferate to other sites.

Treatments for HSV-2

Some of HSV-2 treatments focus on promoting the immune response (11). Several

examples include immunotherapy and vaccines (11). In addition, new, innovative treatments are

being developed to prevent the spread of the disease. For example, Awasthi, Huang, Shaw, and

Friedman (2014) proposed a vaccine that targets HSV-2 glycoproteins such as gC2 and gE2

(14). Normally, gC2 and gE2 glycoproteins are produced as a way to fuse with the plasma

membrane and enter the cell (14). By targeting and disrupting these glycoproteins, HSV-2 would

be blocked from entering the cell, and would later be recognized and eliminated through the

immune response.

On the other hand, there are treatments for particular symptoms of HSV-2. For example,

intravenous acyclovir is a treatment used to treat HSV-2 encephalitis (3). Still, there are no

effective HSV-2 vaccine and no treatment to prevent spread of HSV-2 from one partner to

another.

Despite the potential hazard of HSV-2, herpes virus is being manipulated and

redesigned as a gene therapy vector for neurological applications (5). With HSV-2 as a gene

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therapy vector, researchers will alleviate disorders such as malignant glioma, chronic pain,

peripheral neuropathy, and neurodegeneration (5). This topic is beyond the scope of this paper.

Conclusion

In summary, HSV-2 enters the cell by receptor-mediated endocytosis. Nucleocapsid and

tegument of HSV-2 is docked to the nucleus where viral DNA is synthesized and replicated.

HSV-2 is transported to adjacent cells, such as neurons, through anterograde transport and

then transported from neuron-to-neuron through retrograded transporter. Once HSV-2 is in the

neuron, it makes the decision to go in the latent or lytic cycles. In the latent phase, the LAT is

activated, while the lytic gene is repressed. Under the latent phase, HSV-2 evade the immune

system. Other mechanism of immune evasion is through disruption of the immune intracellular

pathways.

The virus enter the CNS by PNS through the axonal fiber. Once inside the brain, HSV-2

must try to evade immune cells. There are innate immune sentinels, such as microglia,

constantly scavenging the brain for foreign objects. Once the immune cells detects HSV-2, an

inflammation occur in the brain, known as encephalitis, which would leave the infected host with

uncomfortable symptoms. On the other hand, if inflammatory response occurs in the spinal cord

membrane, then meningitis would occur. Current treatments are looking at different approaches

to prevent infection, mainly by promoting the immune response. Despite such pathological

problems that arise, HSV-2 can be manipulated for gene therapy vector for neurological

applications.

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