HSV-1 DNA has been detected within Aβ depositions in postmortem brain tissues of AD patients compared to non-AD controls (Mori et al., 2004). The same study also found HSV-1 antigens within cortical neurons, providing the first evidence of possible HSV-1 reactivation in the AD brain (Mori et al., 2004). A further study reported that most HSV-1 DNA was localized within Aβ plaques in the cortices of AD patients (Wozniak et al., 2009b). Furthermore, transcriptome analyses of brain specimens from cohorts of AD patients have revealed higher abundance of HSV-1 latency-associated transcripts (LATs; transcribed from HSV-1 DNA) than older adults without AD (Readhead et al., 2018). These results indicate that HSV-1 can infect the brain and is associated with AD neuropathology.

When compared to age-matched healthy controls, individuals with AD and aMCI exhibited increased levels of anti-HSV-1 IgG antibodies (Costa et al., 2017; Agostini et al., 2019; Pandey et al., 2019), which also correlated with increased cortical volumes (Mancuso et al., 2014a, b). Similarly, increased antibody levels and avidity index against HSV-1 were found to be elevated in aMCI patients that did not develop AD, compared to those who did. In the same study, HSV-1-specific antibody titers also correlated positively with hippocampal and amygdala volumes (Agostini et al., 2016a). Other studies have also found that aMCI patients displayed higher anti-HSV-1 IgG antibody levels and avidity index compared to that of both healthy controls and AD patients (Kobayashi et al., 2013; Costa et al., 2020). Taken together, these findings imply that robust antibody immunity against HSV-1 may prevent the brain atrophy progression of aMCI into AD, possibly via antibody neutralization of HSV-1 that protects the brain against HSV-1-induced neuropathology (Mancuso et al., 2014a; Agostini et al., 2016a; Costa et al., 2020).

When anti-HSV-1 immunity is inadequate to control HSV-1 infection, periodic HSV-1 reactivation and productive infection may occur. One nationwide retrospective cohort study in Taiwan reported that individuals diagnosed with recurrent HSV-1 infection had a 2.8-fold higher risk of developing AD than uninfected individuals. More importantly, antiherpetic medications reduced such risk by about 90% compared to placebo (Tzeng et al., 2018). In another nationwide retrospective cohort study involving participants with HSV-1 or VZV infections and uninfected matched controls in Sweden, antiherpetic treatment was associated with a 10% reduced risk of dementia. In untreated patients, the risk of dementia increased by 50% compared to uninfected controls (Lopatko Lindman et al., 2021). A four-national (i.e., Wales, Scotland, Denmark and Germany) retrospective cohort study found that persons with HSV infection who were not given anti-herpetic medication had 18% higher risk of dementia compared to uninfected controls, although this effect was present in the Germany cohort only (Schnier et al., 2021). In a smaller retrospective cohort study comprising HSV-1-seropositive older adults, antiherpetic prescription was associated with 70% lower risk of AD development compared to no prescription (Hemmingsson et al., 2021). Two aging prospective cohort studies have also found that the risk of AD was about twofold greater in those with IgM seropositivity for HSV-1 (Letenneur et al., 2008; Lovheim et al., 2015a). Taken together, these studies suggest that HSV-1 productive infection or reactivation may promote AD development, which may also be preventable with antiherpetic agents.

Interestingly, a longitudinal study reported that IgM seropositivity for HSV-1 was associated with memory decline, especially amongst carriers of ApoE4 (Lövheim et al., 2019). Likewise, in another prospective cohort study, ApoE4 carriers had a threefold increased risk of both AD and HSV-1 reactivation (i.e., as indicated by IgM seropositivity or elevated IgG levels) compared to ApoE4-negative individuals (Linard et al., 2020). Therefore, host genetic risk factors such as ApoE4 may modulate the interactions between HSV-1 and AD risk.

However, several studies found no significant differences in HSV-1 IgG seropositivity (Wozniak et al., 2005; Letenneur et al., 2008; Lovheim et al., 2015b) and HSV-1 DNA in the brain (Jamieson et al., 1991; Hemling et al., 2003; Pisa et al., 2017) between individuals with and without AD. This could be attributed to genetic factors that predispose HSV-1-infected individuals to AD. For instance, the presence of HSV-1 DNA or IgG seropositivity with ApoE4 gene has been shown to pose a greater risk factor in AD development than either one by itself (Lin et al., 1995, 1996; Itzhaki et al., 1997; Steel and Eslick, 2015; Lopatko Lindman et al., 2019). Another reason may be that HSV-1 IgG seropositivity and DNA only indicate a history of viral exposure, as HSV-1 may remain latent and non-infective. Other meta-analyses have found that HSV-1-specific IgM seropositivity and high IgG levels (i.e., indicating productive infection or reactivation) were associated with dementia and MCI, but not HSV-1 IgG seropositivity and DNA (Warren-Gash et al., 2019; Ou et al., 2020; Wu et al., 2020).

As mounting evidence supports the link between HSV-1 infection and AD development, HSV-1 may also be associated with the prodromal stage of AD, aMCI. Patients with aMCI may show early signs of AD neuropathological attributes, such as hippocampal shrinkage, neurofibrillary tangles (NFT; aggregates of hyperphosphorylated tau) and Aβ40/42 accumulation, according to a systematic review (Stephan et al., 2012). Hippocampal neuroimaging has also been demonstrated to predict whether MCI patients would develop AD (Jack et al., 1999; Hu et al., 2016; Li et al., 2019). Thus, given that HSV-1 infection can induce hippocampal dysfunction, HSV-1 infection may also be associated with reduced memory function.

For instance, HSV-1 IgG seropositivity has been associated with an 18-fold increased odds of memory deficits in middle-aged adults (Dickerson et al., 2008). Associations between HSV-1 IgG seropositivity and impaired cognition were also reported in other groups, e.g., healthy soldiers (Fruchter et al., 2015), young individuals (Tarter et al., 2014; Vanyukov et al., 2018) and older adults (Zhao et al., 2020; Murphy et al., 2021). Therefore, the clinical biomarker of HSV-1 exposure (i.e., IgG seropositivity) is likely to be linked to impaired memory and other cognitive measures, while biomarkers of HSV-1 reactivation or productive infection (i.e., high IgG levels or IgM seropositivity) is linked to AD (Letenneur et al., 2008; Lovheim et al., 2015a; Warren-Gash et al., 2019). This indicates that HSV-1 reactivation or productive infection may promote more severe cognitive decline than mere HSV-1 exposure. In a population study comprising healthy adolescents, HSV-1 IgG seropositivity was associated with memory decline, whereas HSV-1 IgG levels correlated with both poor memory and executive functioning (Jonker et al., 2014).

Population studies have also reported that IgG levels specific for either HSV-1 or CMV independently predicted cognitive defect in the elderly (Strandberg et al., 2003), schizophrenics and their non-psychotic relatives (Shirts et al., 2008; Watson et al., 2013), and middle-aged adults (Tarter et al., 2014). However, some studies found that only CMV-specific (and not HSV-1-specific) IgG seropositivity or levels correlated with cognitive impairment in elderly populations (Aiello et al., 2006; Barnes et al., 2015; Nimgaonkar et al., 2016) and bipolar disorder patients (Tanaka et al., 2017). On the contrary, other studies showed that only HSV-1-specific IgG (and not CMV-specific) seropositivity or levels were associated with cognitive impairment in healthy adolescents (Jonker et al., 2014) and individuals with or without neuropsychiatric disorders (Dickerson et al., 2003; Yolken et al., 2011; Hamdani et al., 2017).

A putative explanation for these inconsistencies could be that both CMV and HSV-1 contribute to memory dysfunction. It was suggested that CMV, which is known to induce immune dysregulation, may exacerbate HSV-1-induced neurodegeneration, leading to AD (Stowe et al., 2012; Lovheim et al., 2018). This is based upon the finding that HSV-1-specific IgG levels increased with age only in CMV seropositive individuals (Stowe et al., 2012). CMV IgG seropositivity alone also did not elevate the risk of AD, but both CMV and HSV-1 seropositivity did (Lovheim et al., 2018), suggesting that CMV and HSV-1 interact to influence the risk of developing AD. For AD with severe memory impairment, HSV-1 likely plays a more predominant role in memory impairment than other herpesviruses, as suggested by meta-analyses (Steel and Eslick, 2015; Warren-Gash et al., 2019) and reviews (Itzhaki, 2014; Itzhaki and Klapper, 2014).

One key limitation of these studies is that HSV-1 seropositivity indicates the history of prior HSV-1 exposure. Seropositivity alone does not inform the status of HSV-1 infection; that is, active or latent infection, or viral replication in the central or peripheral nervous systems or peripheral epithelial cells (Dickerson et al., 2008; Murphy et al., 2021). Therefore, the possible link of causality or pathophysiological pathways between HSV-1 seropositivity and memory impairment remains unclear (Vanyukov et al., 2018). Besides, the majority of the global adult population (i.e., > 60%) is seropositive for HSV-1 (Looker et al., 2015; Harfouche et al., 2019; Khadr et al., 2019), whereas only relatively few develop memory impairment (i.e., 10–20% of adults over 50 years) (Overton et al., 2019; Pais et al., 2020; Lu et al., 2021). This suggests that HSV-1 seropositivity may only play a subtle role in the development of memory impairment in certain cases.

First, HSV-1 attachment to cells depends on the binding of envelop glycoprotein B (gB) to surface heparan sulfate proteoglycans (HSPGs), with an optional gC to augment the interaction (WuDunn and Spear, 1989; Herold et al., 1991, 1994). Alternatively, gB can bind to myelin-associated glycoprotein (MAG) (Suenaga et al., 2009) and non-muscle myosin heavy chain IIA and IIB (NHMC-IIA and -IIB) to initiate viral entry (Arii et al., 2010, 2015). The subsequent binding of gD to 3-O-sulfated heparan sulfate, herpesvirus entry mediator (HVEM) and/or nectin-1 (Montgomery et al., 1996; Whitbeck et al., 1997; Geraghty et al., 1998; Shukla et al., 1999) catalyzes viral fusion and entry via activation of gH/gL (Atanasiu et al., 2010).

Following HSV-1 entry, the DNA-containing nucleocapsid and tegument proteins are released into the cell cytoplasm. One of the tegument proteins may proceed to turn off protein translation in the cell (Kwong and Frenkel, 1987). The nucleocapsid moves and docks on the nuclear pore, which then disassembles to release the DNA into the cell nucleus (Sodeik et al., 1997; Dohner et al., 2002). This initiates a cascade of HSV-1 gene expression, in the order of α-genes, β-genes and γ-genes, where viral structural proteins and DNA are synthesized and re-assembled (Honess and Roizman, 1974). The assembled viral particles may bud into the inner nuclear membrane and undergo primary envelopment for nuclear egress. HSV-1 particles may subsequently undergo de-envelopment at the outer nuclear membrane to allow for further viral assembly in the cytoplasm, and complete the secondary envelopment at Golgi vesicles before the mature virions egress out of the host cell (Hutchinson and Johnson, 1995; Granzow et al., 2001), as reviewed in Mettenleiter (2002).

After this lytic phase in peripheral epithelial cells, HSV-1 can proceed to the latent phase in neurons, typically in the trigeminal ganglion (Takasu et al., 1992; Theil et al., 2001; Hufner et al., 2009). The latent phase of HSV-1 starts similarly to the lytic phase, until HSV-1 reaches the nucleopore by retrograde axonal transport (Antinone and Smith, 2010). In the latent phase, HSV-1 lytic gene expression in the nucleus is silenced, and no infectious viral progeny is produced. Instead, HSV-1 DNA undergoes histone modifications with nucleosomes of the chromatin in cell nucleus (Deshmane and Fraser, 1989; Kubat et al., 2004; Wang et al., 2005). During latency, HSV-1 gene expression is limited to LATs and a few microRNAs, which may inhibit (i) lytic gene transcription to maintain latency and (ii) apoptosis to promote survival of infected neurons (Perng et al., 2000; Wang et al., 2005; Umbach et al., 2008).

HSV-1 can transition from latent to lytic phase under conditions of cellular stress, such as chemotherapy, hyperthermia, ultraviolet radiation, fever, immunosuppression and psychological stress, as reviewed in Suzich and Cliffe (2018) and Yan et al. (2020). During HSV-1 reactivation, the HSV-1 DNA-associated chromatin relaxes and transcription of the viral regulatory VP16 protein begins, which consequently activates a cascade of viral lytic gene expression that lead to the production of infectious viral progeny (Thompson et al., 2009; Kim et al., 2012; Sawtell and Thompson, 2016). Newly manufactured HSV-1 then travels by anterograde transport from the cell body to axon termini to infect neighboring epithelial cells or neurons (Snyder et al., 2008; Miranda-Saksena et al., 2009). HSV-1 reactivation can lead to the appearance of disease (e.g., cold sores and HSE), asymptomatic viral replication or spread into the CNS, as reviewed in Bearer (2012) and Marcocci et al. (2020).

Neurons with actively replicating HSV-1 via reactivation or primary infection begins to undergo various mechanisms that lead to pathological changes, as reviewed in Harris and Harris (2018) and Duarte et al. (2019). Neuronal culture studies have demonstrated that HSV-1 induced tau hyperphosphorylation by upregulating several enzymes such as caspase-3, protein kinase A and glycogen synthase kinase 3β (Wozniak et al., 2009a; Lerchundi et al., 2011; Alvarez et al., 2012). HSV-1-infected neurons have also been shown to exhibit impaired autophagy and amyloid precursor protein (APP) processing, resulting in increased Aβ40/42 accumulation (De Chiara et al., 2010; Santana et al., 2012; Piacentini et al., 2015). These HSV-1-induced AD-related neuropathology can be inhibited with antiviral treatment targeting HSV-1 in vitro (Wozniak et al., 2011, 2013, 2005). These studies indicate that HSV-1 spread into the brain may facilitate the development of AD-related neuropathology. Animal models further provided support wherein HSV-1 infection or reactivation have been shown to induce AD neuropathology in the brain, which was also associated with learning and memory impairments (Martin et al., 2014; De Chiara et al., 2019).

In the brain, HSV-1 invasion has been shown to target the olfactory system and hippocampus, followed by the higher cortical areas in animal studies (Table 1). According to Braak’s staging scheme in human AD samples, the hippocampus–entorhinal circuitry within the temporal lobe deteriorates the earliest, followed by higher cortical areas (Braak and Braak, 1991). Increasing evidence has also suggested that dysfunction of the olfactory system may indicate prodromal AD in humans, as Murphy (2019) reviewed. With this anatomical resemblance, Fewster et al. (1991) and Ball et al. (2013) have previously suggested that HSV-1 might induce the neuron-to-neuron tauopathy and Aβ spread in AD as HSV-1 propagates along its infection pathways.

Upon oral infection in animal models, HSV-1 can infect the mandibular trigeminal nerve to establish latency at the trigeminal ganglion (Barnett et al., 1994; Lewandowski et al., 2002; De Chiara et al., 2019). Alternatively, the nasal cavity can be an infection site wherein HSV-1 can travel along the olfactory and trigeminal maxillary nerves and become latent in the olfactory bulb and trigeminal ganglion of animals (Stroop et al., 1990; Beers et al., 1993; Jennische et al., 2015). Autopsy studies have also detected HSV-1 DNA, including LATs, in the trigeminal ganglion, trigeminal nerves and olfactory bulb of deceased humans (Liedtke et al., 1993; Theil et al., 2001; Hufner et al., 2009). In animal studies, HSV-1 could also infect the eye, propagating along the corneal subbasal nerve plexus innervated by trigeminal ophthalmic nerve, to initiate latency in the olfactory bulb and trigeminal ganglion (He et al., 2017; Menendez and Carr, 2017; Figure 1). Although congenital herpes is usually contracted upon vaginal delivery, in utero infection can occur in 5% of human infant cases (Hutto et al., 1987; Marquez et al., 2011). In such instances, using the murine model, genital HSV-1 likely enters the bloodstream and crosses the placenta into the fetal nervous system following the trigeminal infection route (Burgos et al., 2006).

Following reactivation from the trigeminal ganglion, HSV-1 may infiltrate the pons innervated by trigeminal nerves and then travel along the brainstem to the limbic system, as demonstrated in animal models (Tomlinson and Esiri, 1983; Webb et al., 1989; Barnett et al., 1994; Paivarinta et al., 1994). The olfactory bulb constitutes part of the limbic system and has direct projections to the hippocampus. Thus, reactivation from the olfactory bulb may provide HSV-1 and other neurotropic viruses direct access to the hippocampus, as proposed by Mori et al. (2005) and Duarte et al. (2019).

The theoretical model depicting neuronal pathways of HSV-1 infection in the brain (Figure 1) is also consistent with autopsy examinations of HSV-1 antigen distribution amongst HSE patients. Specifically, HSV-1 antigens were localized mostly in the hippocampus with the highest number of cases and viral abundance found, as well as in the temporal lobe, olfactory bulb and amygdala (Dinn, 1979; Twomey et al., 1979; Esiri, 1982a, b). Notably, postmortem analysis of AD victims detected HSV-1 DNA more frequently in the hippocampus and temporal cortex compared to other brain areas (Jamieson et al., 1991, 1992). Damasio and Van Hoesen (1985) also hypothesized that HSV-1 travels to the limbic system via the trigeminal nerve, wherein HSV-1 may exhibit higher affinity for the hippocampus, and subsequently spread to cortices during HSE.

Most animal models investigating HSV-1 neurotropism following reactivation, primary infection, or both have supported the predilection of HSV-1 to infect the hippocampus (Table 1). Some studies induced stress in animal models to reactivate HSV-1 and showed that the consequent viral replication was particularly prominent in the hippocampus (Burgos et al., 2006; De Chiara et al., 2019). Further supporting evidence can be derived from animal findings that demonstrated impairment in hippocampus-dependent memory and learning tasks following HSV-1 infection (McLean et al., 1993; Beers et al., 1995; Armien et al., 2010; De Chiara et al., 2019).

AD-associated neuropathology induced by HSV-1 can be observed in the hippocampus. For instance, multiple reactivations of HSV-1 caused memory deficits that were correlated with increased Aβ accumulation, tau phosphorylation and neuroinflammation in the neocortex and hippocampal DG of mice (De Chiara et al., 2019). It was demonstrated that HSV-1 could form a protein corona layer that served as catalytic surfaces for Aβ accumulation in the hippocampus and cortex of mice (Ezzat et al., 2019). Neurodegeneration and lymphocytic infiltration were also observed in the hippocampus, entorhinal cortex, amygdala and temporal cortex in HSV-1-infected mice (Ando et al., 2008; Armien et al., 2010; Toscano et al., 2020). Moreover, HSV-1 has been shown to inhibit the proliferation and differentiation of hippocampal NSCs (Li Puma et al., 2019). In mature hippocampal neurons, acute HSV-1 infection has been shown to increase Aβ42 accumulation and hyperphosphorylated tau compared to uninfected neurons (Powell-Doherty et al., 2020). Taken together, findings from neuronal culture, animal models and human autopsy studies implicate the hippocampus as the nexus between HSV-1 and memory-related disorders, such as AD and aMCI/MCI.

HSV-1 entry and infection in cells rely on the presence of viral envelop gB, gD and gH/gL and cell surface receptors for gB and gD. According to the Allen Brain Atlas transcriptome database of the adult human brain, the expression of receptors for the envelop glycoproteins of HSV-1, specifically gB (i.e., NHMC-IIA and MAG receptors) and gD (i.e., HVEM and nectin-1 receptors), were found to be highest in the hippocampus by 2–3-fold compared to other brain regions (Lathe and Haas, 2017). The same study also found similar HSV-1 receptors being highly expressed in the murine hippocampus (Lathe and Haas, 2017). Immunohistochemical analyses have also revealed that nectin-1 expression was particularly high in the hippocampus of mice and humans (Horvath et al., 2006; Prandovszky et al., 2008). Similarly, nectin-1 RNA was detected in large quantities in the murine hippocampus compared to other brain regions (Haarr et al., 2001). Aside from nectin-1, the distribution of other HSV-1 receptors in the brain has not been widely studied.

Furthermore, it was shown that the cerebellum lacks gD receptors (Lathe and Haas, 2017), which may explain the finding that HSV-1 inoculation into the cerebellum did not induce lethal disease in mice (McFarland and Hotchin, 1987). This was in contrast to the pervasive viral spread and death when HSV-1 was inoculated into the murine hippocampus instead (McFarland and Hotchin, 1987). Another study also showed that HSV-1 binds more strongly to the murine hippocampus than the brainstem and cerebellum (McFarland et al., 1982). Based on animal models investigating HSV-1 spread in the brain, HSV-1 infects the hippocampus in most studies, and rarely targets the cerebellum (Table 1). Therefore, the HSV-1 tropism for the hippocampus may be attributed to the high expression of viral gB and gD receptors in the hippocampus.

As demonstrated ex vivo, the hippocampus and periventricular areas of neonate mice were particularly susceptible to HSV-1 infection (Braun et al., 2006). The viral dissemination into these brain regions where neuronal differentiation is active suggests that dividing cells are more vulnerable to HSV-1 infection (Braun et al., 2006). Using organotypic hippocampal cultures, it was shown that the hippocampal DG (i.e., the chief neurogenic niche) was most vulnerable to HSV-1 infection compared to hippocampal glia and other neuronal types (Ando et al., 2008). Another study also showed that HSV-1 preferentially infects undifferentiated NSCs rather than mature hippocampal neurons, resulting in impaired hippocampal neurogenesis (Li Puma et al., 2019). More recent studies have shown that HSV-1 readily infects NSCs/NPCs and induces Aβ42 accumulation, neuroinflammation and neuronal impairments, which can be prevented with valacyclovir antiherpetic treatment (Abrahamson et al., 2020; Cairns et al., 2020; Zheng et al., 2020).

The vulnerability of dividing, undifferentiated NSCs in the hippocampal DG to HSV-1 infection could be attributed to the high expression of surface HSPGs. HSPGs comprise a family of two glycoproteins, syndecans and glypicans, which are highly expressed throughout mammalian neurogenesis (Hagihara et al., 2000; Wang et al., 2012; Oikari et al., 2016; Yu et al., 2017). HSPGs regulate basic fibroblast growth factor (bFGF; NSCs mitogen) to initiate neurogenesis (Rapraeger et al., 1991; Yayon et al., 1991; Vicario-Abejon et al., 1995). However, HSPGs also mediate HSV-1 attachment to mammalian cell surfaces (WuDunn and Spear, 1989; Herold et al., 1991, 1994). HSV-1 infection in mice has also been shown to downregulate FGF-2 expression and NSCs proliferation (Rotschafer et al., 2013). Similarly, reactivating HSV-1 in mice resulted in Aβ40/42 accumulation in the hippocampal NSCs, disrupting neurogenesis (Li Puma et al., 2019). Therefore, HSPGs play dual roles in promoting NSCs proliferation and HSV-1 cell attachment.

In addition, surface HSPGs have been implicated in the pathogenesis of AD (Zhang et al., 2014). HSPGs expression has been detected in Aβ plaques and NFTs in cortical areas and more frequently in the hippocampus of AD patients (Snow et al., 1992; Bignami et al., 1994; Verbeek et al., 1999). This indicates that existing NFTs and Aβ plaques in the hippocampus may bind to HSV-1 via HSPGs, perhaps to advance AD progression. Indeed, the heparin-binding domain of Aβ oligomers has been shown to bind to HSV-1 glycoproteins, which entrapped and neutralized HSV-1 to prevent encephalitis in mice, but at the consequence of increased Aβ42 accumulation (Eimer et al., 2018). Conversely, HSV-1 infection has been shown to form a protein corona layer that bound to amyloidogenic peptides and catalyzed Aβ42 accumulation in the hippocampus and cortex of mice (Ezzat et al., 2019). Taken together, HSPGs-mediated interactions between HSV-1 and Aβ peptides at the NSCs-rich hippocampus may initiate and/or facilitate AD neurodegenerative processes.

NPCs have also been found to be susceptible to HSV-1 infection and latency establishment in murine and neuronal 3D models (Menendez et al., 2016; Zheng et al., 2020). In cultured NPCs, HSV-1 infection decreased neuronal survival, which was prevented in co-cultures of NPCs with microglia (Chucair-Elliott et al., 2014). This protective effect can be reversed by the addition of IL-6-specific neutralizing antibodies. Likewise, exposing NPCs to recombinant IL-6 demonstrated similar protective effects against HSV-1 infection (Chucair-Elliott et al., 2014). IL-6 activation has also been associated with increased in vivo resistance against HSV-1 infection (Carr and Campbell, 1999; LeBlanc et al., 1999a). Immunohistochemical analyses have revealed that IL-6 expression was localized in the ventricles and lesser in other areas, including the hippocampus, in mice (Aniszewska et al., 2015). Hence, the low protein levels of IL-6 in the hippocampus may not provide sufficient antiviral immunity against HSV-1 infection.

Microglia have been identified as the primary activator of cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING)-dependent type I interferon antiviral defense against HSV-1. Specifically, mice deficient in cGAS or STING showed impaired microglial type I interferon responses and elevated HSV-1 replication in the brain, leading to increased vulnerability to HSE (Reinert et al., 2016). A genome-wide study analyzing the microglia immunophenotype in the adult mice brain found that the immune vigilance (e.g., antiviral interferon activities) of hippocampal microglia was more robust than other brain areas. Interestingly, the hippocampal microglia were most vulnerable to age-related decline in immune function (Grabert et al., 2016). HSV-1 might become opportunistic as a result, targeting the hippocampus when microglial immunosurveillance weakens. This is consistent with the findings that senescence or aged microglia often preceded AD-related neuropathology in the brain, including the hippocampus (Kaneshwaran et al., 2019; Rodriguez-Callejas et al., 2020), as also reviewed in Streit et al. (2009). Henceforth, specific antiviral immunity against HSV-1 might be inadequate in brain regions susceptible to HSV-1 infection. Kramer and Enquist (2013) also hypothesized that not all cells of the nervous system are equally prone to HSV-1 infection due to variations of immune defenses involved.

In the mammalian brain, high GR expression has been found in the hippocampus throughout life (Reul et al., 1989; Wang et al., 2013). Hence, the hippocampus is known to be highly vulnerable to glucocorticoid- or stress-related pathology, as reviewed in McEwen et al. (2016). Activated GR is known to interact with viral promoters to facilitate viral replication and infectivity in the brain (Fouty and Solodushko, 2011). The HSV-1 genome has several GR response elements that have been shown to stimulate viral promoters (i.e., VP16 and ICP0) to initiate reactivation and replication (Harrison et al., 2019; Ostler et al., 2019). These studies further demonstrated that GR antagonists prevented HSV-1 shedding in neuronal cells and reactivation in mice (Harrison et al., 2019; Ostler et al., 2019). Inhibiting glucocorticoid synthesis with cyanoketone also inhibited HSV-1 reactivation in mice (Noisakran et al., 1998). In contrast, dexamethasone (i.e., synthetic glucocorticoid) treatment has been shown to induce HSV-1 reactivation and replication in vitro and in vivo (Sawiris et al., 1994; Halford et al., 1996; Hardwicke and Schaffer, 1997; Noisakran et al., 1998; Erlandsson et al., 2002; Du et al., 2012; Harrison et al., 2019). Therefore, the hippocampus has a prominent GR expression that could promote HSV-1 virulence in the CNS.

HSV-1 infection has been shown to upregulate enzymes that cleave APP following the amylogenic pathway to generate Aβ40/42 peptides (Wozniak et al., 2007; De Chiara et al., 2010; Piacentini et al., 2015). APP is ubiquitously expressed in the brain, with higher expression found in the olfactory system, cerebral cortex and hippocampus (Card et al., 1988; Imaizumi et al., 1993). These areas are also known to be targeted by HSV-1 (Table 1). HSV-1 capsids have been shown to bind to APP to expedite viral transport in both squid and epithelial cell culture models (Satpute-Krishnan et al., 2003; Cheng et al., 2011). The infected epithelial cells further displayed abnormal APP processing, resulting in mislocalized APP that may contribute to AD (Cheng et al., 2011).

Recent studies have also demonstrated that HSV-1 infection induced Aβ42 or Aβ40/42 accumulation, indicative of pathological APP metabolism, in the hippocampus in vitro and in vivo (De Chiara et al., 2019; Ezzat et al., 2019; Powell-Doherty et al., 2020). Interestingly, Aβ40/42 accumulation was observed in the hippocampus in a mouse model of HSV-1 reactivation, but such neuropathology did not occur in mice with APP gene knockout (Li Puma et al., 2019). Thus, APP appears imperative for the cellular propagation and spread of HSV-1, generating Aβ40/42 peptides in the process. This might also contribute to the hippocampal susceptibility to HSV-1 infection, given that the hippocampus has high APP expression.