Herpes simplex virus and Alzheimer’s disease

herpesvirusAlois Alzheimer was the first to propose that an infection might play a role in the disease named after him. Herpes simplex virus type 1 (HSV-1) has been most frequently linked to Alzheimer’s Disease (AD), and a clinical trial is in progress to determine if antivirals ameliorate its development. What is the evidence that HSV-1 is involved in AD?

HSV-1 is acquired early in life when the virus is introduced onto a mucosal surface, typically from a family member. The virus replicates productively in epithelial cells, spreads through tissue, and may cause a characteristic cold sore on the lips. The virus enters sensory neuron axons and is transported to the cell body in a peripheral ganglion. There it establishes a latent infection in the neuronal cell nucleus. The viral genome is present but silenced except for the production of a single viral RNA. Reactivation caused by conditions such as stress or ultraviolet light (think sunlight) cause the virus to reactivate. New infectious viral particles travel down the nerve to mucosal tissues, possibly causing a cold sore. Virus is shed from mucosal tissues and may infect others. Sometimes virus goes the wrong way along the nerve and enters the central nervous system, causing encephalitis, a very serious infection of the brain. Those who recover might harbor latent viral genomes in the brain.

There are two types of herpes simplex viruses, type 1 and type 2. HSV-1 mainly causes oral herpes, and HSV-2 genital herpes.

Results of a number of independent studies suggest a role for HSV-1 in AD. Viral DNA can be found in the brains of both AD and normal individuals, although infectious virus has never been demonstrated. In one study, antibodies to the virus were detected in cerebrospinal fluid of AD patients and normal controls. However, such antibodies do not prove that infectious virus is present; they could be induced by viral proteins.

HSV-1 infection appears to induce the accumulation of amyloid-beta both in cells in culture and in mice. The deposition of amyloid-beta in the brain, forming plaques, is a key feature of AD. Evidence is emerging that amyloid-beta is an antimicrobial peptide induced in response to infection. Amyloid-beta can block HSV-1 infection in cells and in mice. In addition, HSV-1 DNA localizes with amyloid plaques in the AD brain.

Epidemiological studies indicate a link between HSV-1 infection and the development of AD. But if over 85% of the human population is seropositive for HSV-1, why would it cause AD in only a subset? It has been suggested that a specific allele of the gene encoding apolipoprotein E, called epsilon 4, may be a culprit. Carriers of this allele are more likely to develop AD than those with other isoforms of ApoE. The combination of HSV-1 DNA in the brain and ApoE-E4 confers a high risk of developing AD. Curiously, ApoE-E4 increases the frequency of HSV oral lesions without viral shedding. The mechanism for the increased susceptibility to AD is unknown, but has been suggested to involve more frequent reactivation of HSV-1 in the brain followed by deposition of amyloid-beta, tissue damage, and inflammation.

HSV-1 infections may be treated with a number of antiviral compounds such as valacyclovir. A study was done in Taiwan to assess whether administration of such antiviral compounds can effect the development of senile dementia (SD) of which AD is the main cause. This study was conducted by mining the National Health Insurance Research Database, in which nearly all of the country’s population is enrolled. The incidence of senile dementia was studied from 2000-2010 in 8,362 subjects aged 50 years or over who were diagnosed with HSV-1 or HSV-2 infections, and in 25,086 age- and gender-matched individuals with no HSV infection. The risk of developing SD in the HSV infected group was 2.56-fold greater than in uninfected controls. This effect was mainly observed in HSV-1 infected individuals.

Some of the HSV-infected patients (N = 7, 215) were treated with one of a number of antivirals, including acyclovir and valacyclovir. These individuals had nearly a 10 fold decrease in the incidence of SD compared with those who were untreated (N = 1,147). Over the next 10 years, 419 (5.80%) developed dementia in the antiviral treated group, while 325 (28.33%) of the untreated group developed dementia.

A clinical trial is now in progress to determine if treating patients with early onset AD with the anti-HSV drug valacyclovir affects the development of the disease. Notwithstanding the results of the Taiwan study, I am not convinced that an interventional treatment will impact AD. My concerns and comments on the HSV-1 etiology of AD are as follows:

  • Infectious HSV has not been demonstrated in the human CNS. The antibody studies cited above are limited in scope and do not prove the presence of virus. Antibodies could be made in response to viral proteins, not infectious virus.
  • The Taiwan study showed an effect of antiviral on AD development, but this observation was not correlated with reduction of viral loads. The drug might have other effects, and other confounding variables might be present in the treatment group.
  • The HSV antivirals are used to treat acute infections, e.g. a cold sore or encephalitis. They will not remove latent genomes from nerve cells. It is not clear that there is actively replicating virus in AD patients. Even if infectious virus is present, viral DNA will remain after treatment. Does this mean that AD would return after antivirals have been stopped?
  • Instead of hypothesizing the presence of infectious virus in the brain, an alternative is that HSV-1 abortively reactivates in the brain, without the presence of infectious virus. The viral proteins could stimulate amyloid-beta production and deposition, leading to inflammation and AD. The catch is that antivirals would have no effect on this process because they inhibit viral DNA synthesis, a late event in the infectious cycle.
  • Patients who have HSV in the brain – herpes encephalitis – are very sick. I have a difficult time believing that so many people have HSV reactivation in the brain without developing encephalitis.
  • Antivirals like valacyclovir inhibit the viral DNA polymerase, which is produced later in the infectious cycle. It will have no effect on the earlier production of viral proteins that could be involved in AD. It might be useful to develop an antiviral that acts early in the viral reproduction cycle. A candidate target is the viral protein VP16, which is needed to initiate the transcription of the immediate early genes, required for all subsequent macromolecular synthesis.

I understand that AD affects many families who would very much like to have an intervention for the disease, and are anxious to see this trial clinical proceed. Nevertheless, I do not feel that this trial is warranted based on the existing data. Additional studies are needed to understand the mechanistic connection between HSV-1 infection and AD, and specifically to clarify whether infectious virus, or viral proteins are involved.

{ 3 comments… add one }
  • Kariem Ezzat 9 November 2018, 10:49 am

    Dear Dr. Racaniello,
    Amazing summary as usual. I agree with you that “Additional studies are needed to understand the mechanistic connection between HSV-1 infection and AD”. In this regard, we have a paper in bioRxiv (https://www.biorxiv.org/content/early/2018/09/10/246785 , also under review) where we describe a mechanism that could be taking place. Amyloid aggregation is a nucleation-dependent phase transition phenomenon, from soluble peptides to fibrils. Similar to other nucleation-dependent phenomena (such as crystallization for example), a molecular assembly of a critical size (nucleus) needs to be formed for the phase transition to take place. Such phenomena are well described within the framework of the classical nucleation theory, where the process of nucleation represents the energy barrier that the system has to overcome to transform from a supersaturated metastable phase to a more stable phase, amyloid fibrils in this case. That is why amyloid aggregation kinetics follow a sigmoidal curve, with a lag phase in the beginning until the process of nucleation occurs, followed by a rapid growth or elongation phase, again very similar to crystallization.

    The spontaneous self-assembly of this critical nucleus is called homogeneous nucleation (HON), and is usually a rare and slow process because such assembly is thermodynamically unfavorable. That is why it is more common in nature (and in industrial technology) to induce the process of phase transition on a catalytic surface or interface, which is called heterogeneous nucleation (HEN). The surface acts a scaffold that facilitates the assembly of the nucleus, which logarithmically lowers the nucleation energy barrier and accelerates the process of phase transition, usually eradicating the lag phase completely from the kinetics.

    In our paper, we demonstrate that viruses can act as catalytic nanosurfaces that facilitate the process of HEN of amyloid fibrils. We show that two different viruses (RSV and HSV-1) are able to catalyze and dramatically accelerate the kinetics of aggregation of two different amyloidogenic peptides (IAPP fragment and Aβ42). We also show that HSV-1 intracranial infection can dramatically accelerate and quantitatively increase amyloid accumulation in Alzheimer’s disease animal models.

    While our findings still do not prove disease causality, they offer a plausible direct mechanistic link where viruses can physically act as catalytic surfaces for amyloid aggregation. Furthermore, we present our results within a more general framework termed “the viral protein corona”, which is a term borrowed from nanotechnology to describe the interaction of nanoparticles with extracellular fluids. Since viruses and nanoparticles are not very different in the extracellular environment, we studied the extracellular interactome or the “protein corona” of viruses including RSV and HSV-1. We found, similar to what is reported in the nanotechnology literature, that both viruses accumulate an extensive and distinctive layer of host factors on their surface. These different viral coronae affect both viral infectivity and immune cell activation depending on the source and the species of the biological fluid they interacted with before encountering the cells. We believe it would be important to study the protein coronae of other viruses too and see how they are affected by their pre-cellular microenvironmental interactions.

    Finally, on your point that “Patients who have HSV in the brain – herpes encephalitis – are very sick. I have a difficult time believing that so many people have HSV reactivation in the brain without developing encephalitis.” It may be that the virus through its corona interactions has evolved to induce these amyloids that somehow enhance its infectivity without inducing a full-blown immune response. It has been shown before that amyloids in the semen for example can enhance HIV infectivity by several logs (Munch. et al 2007).

    I would also be very grateful if you have a general look at our paper for a critical feedback.

    All the best,

    Kariem Ezzat, PhD
    Researcher in Immunovirology
    Department of Molecular Biosciences
    The Wenner-Gren Institute
    Stockholm University, Sweden
    E-mail: kariem.ezzat@su.se

  • Kariem Ezzat 12 November 2018, 9:10 am

    Hi again,
    I posted a link to a slightly older version of our paper, here is the link to the most updated version: https://www.biorxiv.org/content/early/2018/11/09/246785

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