Most of us harbour in our body several types of herpes virus—perhaps as many as five—and we provide them with a safe and secluded haven for life, as there are no methods for eliminating or expelling them. Much of the time they are latent, i.e., dormant, and in that state they are probably relatively harmless in most people. However, they can reactivate if the host is stressed or immunosuppressed, and they then replicate, causing damage and death in the host cells via direct viral action and viral-induced inflammation. In some cases though the overall damage is minimal, so that the person appears asymptomatic even though infected. Herpes simplex virus type 1 (HSV1) displays this behaviour in that it infects most people by the age of about 60, and reactivates periodically in the peripheral nervous system (PNS), but causes visible damage (cold sores) in only some 25% of infected people.
We decided to investigate a possible role for HSV1 in Alzheimer's disease (AD) for three main reasons: firstly, the fact that as HSV1 remains in the body lifelong and can reactivate, it has the potential to cause damage later in life, consistent with the late development of AD; secondly, a number of viruses (measles, HIV, JC virus) are known to affect the brain and can cause fatal dementing illness, sometimes years after the initial infection; thirdly, the rare and very serious brain disease herpes simplex encephalitis (HSE), which is caused usually by HSV1, affects the same brain regions as those mainly affected in AD .
It has been known for decades that HSV1 lurks in the PNS of "normal" people. However, whether it could reach the central nervous system too, and reside there was totally unknown. In the 1970s and 1980s, several groups sought viral DNA in brain using solution or in situ hybridisation. The results were inconclusive, with some positive and some negative findings. Using PCR, under very stringent conditions, my group detected HSV1 DNA in brain  (a discovery which elicited cries of shock and outrage from some reviewers), and we later found that about 70% of postmortem brains from elderly people and from AD patients were HSV1 DNA-positive . Subsequently, five other laboratories detected HSV1 DNA in human brains. We then found a strong causal association in AD patients between HSV1 presence in brain and carriage of an APOE-ε4 allele. Our data showed that the association was not artefactual in that AD patients, and those carrying an APOE-ε4, were not more susceptible to HSV1 infection than were controls or carriers of the other APOE alleles. In other words, the virus and APOE-ε4 were a cause, not an effect, of the disease, accounting for about 60% of cases (I stress a cause, as the disease is clearly multifactorial). APOE-ε4 carriage also proved to explain the relatively low proportion of infected people who suffer cold sores, as it is a risk for that disorder as well . In fact, we later discovered that APOE genotype determined susceptibility to infection, or severity of infection damage, in several other diseases of microbial cause .
These findings reflect two key features of herpes and other microbes, of which many people seem unaware, judging by the comments often raised after my talks and by reviewers of my group's grant applications and papers: "How can they think that a virus is involved in AD when they find that a high proportion of elderly people as well as AD patients have HSV1 in brain?" Firstly, being infected with a microbe yet unaffected by it is a common phenomenon, strikingly illustrated by tuberculosis, as the bacterium Mycobacterium tuberculosis infects millions of people yet causes tuberculosis only in some 10%; similarly with HSV1 in the periphery, with cold sores occurring in only some 25% of those infected. Secondly, microbes can cause chronic effects, but are often regarded as causes of acute damage only, after which they fly away—or kill their host; lingering on in the body is not even contemplated.
There is now good though indirect evidence from a number of groups that HSV1 not only resides in most elderly brains but also reactivates there , probably repeatedly, when the immune system is weakened (as in aging), so that damage accumulates gradually, eventually leading to AD. The damage is presumably mild or limited, as otherwise, it would be apparent—the patient would display symptoms of HSE. What then is the connection, if any, between reactivation and AD? One answer is that in HSE, which (in adults) is always caused by HSV1, many who survive show symptoms similar to those of AD: memory loss, personality and behavioural changes, and aphasia, and as mentioned above, HSE damage occurs in the very regions of brain that suffer most damage in AD. Also, HSE occurs occasionally in a "mild" form (probably unrecognised and under-diagnosed), and can be recurrent , just as we suggest takes place during the development of AD. There are several precedents for viruses reactivating in brain when the immune system is weakened, causing vulnerability to an endogenous virus: for example, overt JC virus infection can occur in brain after iatrogenic immunosuppression, giving rise to the very serious disease, progressive multifocal leukoencephalopathy.
From cell culture studies, another HSV1-AD link becomes apparent: infection by the virus causes accumulation of both amyloid-beta and of AD-like tau, the main components respectively of the characteristic amyloid plaques and neurofibrillary tangles of AD brain . Further, in AD brains, the viral DNA is located very specifically within plaques (arguments against an artefactual co-localisation are given in detail in  ). Another major connection is that HSV1 causes synaptic damage, one of the main features of AD .
These data and concepts linking HSV1 to AD are often termed "controversial"—a singularly inappropriate term as it implies that there are arguments pro and con. However, opponents never divulge any scientific cons. A frequent bleat is that there is no evidence for the concept, an odd statement, as there are now over 100 publications directly or indirectly supporting it (with only three that conflict, all published over 12 years ago), and the topic is amply discussed in over 20 recent reviews. One can infer only that opponents either have not accessed the relevant information or have not absorbed it. The opponents are mainly devotees of amyloid-beta or AD-like tau, implicating one or other as the cause of AD, despite the absence of any data revealing what causes their appearance, and despite the fact that the virus-AD concept actually accommodates both proteins. And even the current boost for a major role of amyloid-beta in AD, provided by data indicating that it (or an oligomer) is an anti-microbial peptide [10-14], seems only to tiptoe around the concept that infection is involved. Another comment is "How do we know if HSV1 in brain is a cause or an effect of the disease". The answer was stated almost 20 years ago when the frequency of viral DNA presence in brain was found to be similar in AD patients and elderly normal people . Yet this and the "controversial" mantra are still chanted in response to the word "microbe". It is surprising though, as many people are aware of parallel effects caused by well known viruses such as HIV and measles, specifically dementia, as well as amyloid plaque and/or neurofibrillary tangle formation.
Bacteria have also been implicated strongly in AD, in particular, Spirochaetes  and Chlamydia pneumoniae , so a major question in respect to HSV1 and AD is: does the virus act together with either of these bacteria or is one of them responsible for the disease in those patients who do not have HSV1 in brain and APOE-ε4 carriage? A related question is whether HSV1 acts together with another non-microbial factor, though so far, no such factor has been identified.
As for treatment of the disease, surely the evidence presented warrants usage of an antiviral agent. In fact, studies on cell cultures have shown that various antivirals, which target HSV1 by different mechanisms, not only reduce virus replication greatly, as expected, but also reduce HSV1-induced P-tau almost to zero and HSV1-induced amyloid-beta very substantially [17,18]. Probably the most effective treatment would be an antiviral that inhibits viral DNA replication, together with one that blocks viral entry. However, initial trials would necessarily use only the former type—the standard agent for combating HSE, valacyclovir (VCV), which is very effective and has few side-effects. VCV, though, targets viral replication, and so could not deal with latent virus, but presumably, it would act against new virions produced after viral reactivation.
In summary, the three main problems appear to be: 1) Is there significant damage during latency and if so, how could it be stopped? 2) Could an anti-inflammatory substance be used with VCV to combat virus-induced inflammation? 3) Could methods be devised which monitor viral load and activity in brain during treatment? One can only hope that those of us in the microbe-AD field will not have to wait much longer for acceptance of the relevant concepts, and subsequent provision of resources for answering these questions.
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Last comment on 19 August 2016 by Brian Balin, PhD