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Editorial

How plausible is a link between HSV-1 infection and Alzheimer’s disease?

, &
Pages 275-278 | Published online: 06 Feb 2014

Abstract

Alzheimer’s disease is a leading cause of dementia with a multifactorial and still barely understood etiology. A growing body of epidemiologic and experimental data support a role for infectious agents in this process; herpes simplex virus 1 (HSV-1), in particular, is a strong suspect. We briefly summarize the data pointing at a pathogenic role for HSV-1 in the development of Alzheimer's disease and review results indicating that antiviral might be beneficial in the therapy of this condition.

Alzheimer’s disease (AD), the most common type of senile dementia, is characterized by a slowly progressive neuronal loss leading to an impairment of cognition, memory and personality. Great progresses have been made in understanding the components of the pathological lesions observed in the disease, but the knowledge about the mechanisms that trigger the onset of AD is still very limited. Among the different hypotheses that have been presented over the years, a viral involvement has long been suspected to play an important role in the pathogenesis and the progression of this disease Citation[1]. Currently, the most compelling theory is that human herpesviruses, with their high rate of infection in general population, neurotropism and lifelong persistence in neuronal cells, could play a key role in neurodegeneration upon interacting with important characteristics of the host Citation[2].

Herpeviridae are a complex family of viruses and, whereas contradictory findings were found about a possible involvement of common herpesviruses like CMV, EBV and HHV-6 in AD, results indicating a possible association between herpes simplex virus 1 (HSV-1) and this disease seems more consistent Citation[3]. Thus, experimental and epidemiological data have accumulated over the years, strengthening the hypothesis that HSV-1 could be a risk factor for development of dementia. These evidences are nevertheless not rock solid and, in particular, discordant results have been published regarding serum titers of HSV-1-specific IgG and IgM when AD patients are compared with age-matched controls Citation[4,5]. Notably, a linear association between HSV-1-specific antibodies (Ab) and AD is difficult to establish given the very high prevalence of seropositivity observed in the elderly population, independently of the disease. Detection of HSV-1 DNA in brain autopsies of AD patients would be strongly suggestive of a role for this virus in pathogenesis. However, HSV-1 DNA is also observed in brain autopsy of a large part of the non-AD elderly population, suggesting that brain HSV-1 latent infection is a relatively frequent event. Overall, these data indicate that non-AD individuals frequently harbor HSV-1 Citation[6] and, on the other hand, many HSV-1 carriers do not develop AD.

In the light of these considerations, why is HSV-1 a strong candidate in the pathogenesis of AD? HSV-1 primary infection usually occurs during childhood and involves initially the epithelial cells of the face mucosal membranes and secondarily the sensory nerve terminals. From these sites, the virus invades the nervous system where it can remain in a latent condition in the sensory ganglia. Secondary HSV-1 reactivation is relatively frequent, resulting in cold sores, a harmless nuisance, in about 25% of infected individuals, and much more seldomly in serious neurological complications including encephalitis Citation[7]. From an epidemiological standpoint, many neurological chronic pathologies are suspected to be triggered by viral persistence. Thus, not only herpesviruses, but many other DNA and RNA viruses (e.g., measles, HIV, varicella zoster virus, JCV) are known to be associated with severe pathologies of the nervous system (e.g., subacute sclerosing panencephalitis, HIV-associated dementia, progressive multifocal leukoencephalopathy). All these diseases can develop decades after the primary infection. Molecular evidences show that HSV-1 infection of neuronal and glial cells results in an increase of the intracellular levels of β amyloid (Aβ), a decrease of the amyloid precursor protein and the phosphorylation of Tau protein, the main component of neurofibrillary tangles Citation[8–11]: these are the same cellular events associated with the development of AD. Recent results have also demonstrated that the interaction between amyloid precursor protein and the HSV-1 capsid proteins Citation[12] is essential to allow the migration of new viral particles inside infected cells. Moreover, HSV-1 can modulate the host autophagy, inhibiting the homeostatic process involved in turnover/elimination of cytoplasmatic components, damaged organelles and protein aggregates Citation[13]; this mechanism was recently suggested to contribute to deposition of amyloid plaques within the brain. Finally, neuropathology of human HSV-1 acute encephalitis and studies on animal models showed that HSV-1 infection preferentially targets the same brain regions that are altered in AD: the frontal and temporal cortices as well as the hippocampus Citation[14].

The clinical outcome of chronic HSV-1 infection depends on a number of factors, many of which are unknown. Data obtained in the murine model have shown that HSV-1 infection of the brain and the concentration of HSV-1 DNA in CNS during acute, latent and vertical transmission is modulated by the apolipoprotein E ε4 allele (APOE4) Citation[15], a well-known host risk factor for AD. Thus, a complex association of main risk factors (age, gender, APOE and other genotypes) with other nongenetic conditions (immune status, localization of cells that are targeted by HSV-1, viral load and strain) likely determines the outcome of primary infection and the establishing of HSV-1 latency in the CNS. Many important questions remain unresolved: because subclinical reactivations may occur in CNS of immunosuppressed individuals Citation[16], what kind of effects on the host would this have? Could other factors, besides immunosuppression, reactivate the virus in the brain? Could the presence of an inflammatory condition induced by other viral (HHV-6, VZV, EBV, CMV, JCV) or bacterial (Chlamydia pneumonia, Borrelia Burgdorferi) infectious agents play a role on the development and clinical course of AD? Indeed, a recent paper showed that CMV-associated immune dysregulation can induce the reactivation of HSV-1, thus strengthening the idea that different infections modulate inflammation, possibly accelerating immunosenescence Citation[17].

We have recently analyzed possible relationships between HSV-1-specific humoral immunity and cortical damage using a particular MRI technique that allows the in vivo detection of brain changes associated with AD pathology (voxel-based morphometry) Citation[18]. Results obtained in AD patients in the early stage of the disease showed that, although mean HSV-1-specific Ab titers were similar in patients and in age- and sex-matched healthy controls, a significant subgroup of AD patients could be identified that presents very high HSV-1 Ab titers. Notably, a linear correlation was detected between Ab levels and cortical volumes in the right orbitofrontal cortex, the left temporal pole and the right inferior frontal gyrus/temporal pole. This correlation was specific for HSV-1 Ab, as no associations were observed between CMV-specific Ab and brain volumes. These somehow surprisingly results suggest a protective role for (high levels of) anti-HSV-1 IgG toward the degeneration of the same brain areas that are affected by active virus replication during acute infection. Interestingly, recent studies on a well-known murine model of senescence (senescence accelerated mice or SAP) underlined that accelerated senescence correlates with an increased permeability of the brain–blood barrier Citation[19] and an IgG extravasation that primarily occurs in the cortex, hippocampus and hippocampal fissure Citation[20].

What do these results mean? It is possible to hypothesize that, at least in the early stage of AD, HSV-1-specific humoral responses could have a protective role against pathology by reducing viral activity in those brain regions where blood–brain barrier disruptions are present. If this was the case, then our data could be explained as a consequence of a reduced brain deposition of key AD proteins, possibly resulting from a stronger HSV-1-specific humoral response. This hypothesis is consistent with the data showing a correlation between gray matter volumes and AD severity Citation[21]. Thus, HSV-1 Ab could cross the blood–brain barrier and access the CNS because of an increased barrier permeability in the early stage patients enrolled in our study; these (high concentrations of) Ab would reduce HSV-1 activity and impede the consequent degeneration of the temporal and orbitofrontal cortices.

If high titers of Ab, besides preventing HSV-1 replication also impede brain degeneration, then inhibition of viral replication via antiviral agents could be an important therapeutic target. A number of findings seem to support this possibility. To summarize: infusion of intravenous immunoglobulin (IVIg) in mice with HSV-1 encephalitis was shown to prevent death and decrease the number of HSV-1 latently infected trigeminal ganglia Citation[22]; the use of IVIg is associated with a lower risk of AD in retrospective case–control studies Citation[23]; and pilot studies designed to verify the possible usefulness of IVIg in mild forms of AD reported overall stability on neurocognitive scores and trends toward improvement in some areas (WMS logical memory II recall, WMS verbal paired associates and auditory delayed memory test) in IVIg-receiving patients Citation[24,25]. When, on the other hand, Aβ-specific monoclonal Ab were used in AD patients in the attempt to inhibit Aβ aggregation by blocking its production and/or disrupting tangle formation, results were disappointing, as no evident clinical benefit could be detected Citation[26]. Additional recent results obtained in a multicenter placebo-controlled IVIg trial showed no changes in Aβ plasma or cerebrospinal fluid concentrations or in brain areas typically affected in AD Citation[27].

How can these apparently discordant findings be reconciled? IVIg-associated clinical benefit could not be due to the removal of Aβ from the cerebrospinal fluid to the clearance of the senile plaque, but, rather to an immunologically mediated inhibitory activity on infectious agents. This speculation was recently reinforced by in vitro results showing that exposure of HSV-1-infected cell cultures to a commercial preparation of human Ab currently used for IVIg greatly reduces the accumulation of Aβ and P tau, and that this effect is potentiated by acyclovir Citation[28].

Herein, we have summarized evidences pointing to a possible role of HSV-1 in the pathogenesis of AD, these evidences do not yet give us the smoking gun, but we believe that it is plausible that viruses, and in particular HSV-1, play a pivotal role in the pathogenesis of AD. It could be interesting to verify in clinical trials the effect of preventative and/or therapeutic strategies for AD that are based not only on contrasting Aβ formation, but also on agents that hamper viral replication.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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