Persistent Viruses and the Aging Immune System. Part 1: HSV-1, a.k.a. “herpes” or “oral herpes”

This series of articles is focused on common, human viruses which are not completely “cleared” by the immune system, and instead, hang around for the life of the person. There is substantial evidence in the scientific literature that these common, persistent viruses can negatively affect one’s health, and possibly even one’s lifespan. These viruses can “reactivate”, causing symptoms which are usually milder than the initial infection. But the challenge more relevant to living a Long Life is that these viruses have been associated with things like cancer, weakening of the immune system, and Alzheimer’s. In this series of articles, we present and comment on some of the scientific evidence for the harm these viruses can do to healthspan and lifespan, and consider how that harm might be mitigated or eliminated.

Part 1 (this article) will focus on Herpes simplex virus – 1 (“HSV-1” or “oral herpes”). 

Part 1 (this article) will focus on Herpes simplex virus – 1 (“HSV-1” or “oral herpes”). 

Additional articles in this series will discuss other, potentially harmful, persistent viruses, including Herpes simplex virus – 2 (“HSV-2” or “genital herpes”), Cytomegalovirus (“CMV”), and Epstein-Barr Virus (“EBV”). 

The goals of this series are: 

  1. Report what the scientific literature has to say about the long-term effects of each of these viruses, in the context of living a long, healthy life
  2. What the prevalence (also called “seroprevalence”) of each virus is, and how to avoid it
  3. Where to get tested for each 
  4. The prospects for eliminating each virus, either through vaccines or other treatments

Why care about HSV-1?

Long Life Labs focuses on understanding how and why human health deteriorates with age, and learning about and sharing what we can do about it. HSV-1 came up on the Long Life Labs radar because of the apparent association between HSV-1 infection and development of Alzheimer’s Disease. Here is a picture of my PubMed screen right now:

Just a few papers about AD and HSV-1. The search results for this particular query came up with only 11 results. But maybe 11 is enough…..

Because I don’t like to study things in great detail until I’m convinced there is a valuable purpose in doing so, I’m going to jump right into discussing the content of some of these papers, and the relationship scientists have found between HSV-1 and Alzheimer’s. Once we learn whether there is reasonable cause to be concerned about HSV-1 (spoiler alert: in my opinion, there is), I’ll discuss HSV-1 more specifically, and what we might do about it.

HSV-1 and Alzheimer’s Disease

As noted above, the primary concern about HSV-1 from the perspective of Long Life Labs is the apparent association between HSV-1 infection and Alzheimer’s Disease. For example, one article at WebMD discussed some recent research showing that people with antibodies to HSV-1 – a proxy measurement of latent HSV-1 infection – are at nearly double the risk of Alzheimer’s Disease.

I’ll go back to some of the papers I shared a picture of above. The most recent one (which is, thankfully, a free full-text) was published in 2014, and is a literature review. In this paper, HSV-1 and Alzheimer’s disease: more than a hypothesis, they review some pretty concerning observations. For example, here are some quotes (emphases mine):

Herpes simplex type 1 virus is a neurotropic double-stranded DNA virus that primarily infects epithelial cells of oral and nasal mucosa. Here virus undergoes lytic replication; the newly produced viral particles may enter sensory neurons and, by axonal transport, reach the trigeminal ganglion where usually establishes a latent infection. The virus undergoes periodic reactivation cycles in which the newly formed viral particles are transported back to the site of primary infection through the sensory neurons, causing the well-known clinical lesions (i.e., cold sores and blisters). However, the bipolar trigeminal ganglion neurons also project to the trigeminal nuclei located in the brainstem. From here, neurons project to the thalamus to finally reach the sensory cortex. This is the path through which the reactivated virus may reach the central nervous system (CNS), where it may cause acute neurological disorders like encephalitis [herpes simplex encephalitis (HSE)] or a mild, clinically asymptomatic, infection, or establish life-long latent infection (Kastrukoff et al., 1982; Lewandowski et al., 2002; references in Dobson et al., 2003). The weakening of immune system occurring during aging may favor this process. In addition to the neuronal route, HSV-1 may enter the CNS through the blood stream, as demonstrated by Burgos et al. (2002, 2003, 2005). Many experimental evidence, described below, suggest that accumulation of intracellular damage caused by repeated cycles of viral reactivation may concur to neurodegeneration.

Yes: this paragraph is explaining how the latent HSV-1 virus may (or does – I’m not sure about the weight of the evidence for this yet) lie latent in the brain, where it periodically reactivates, which could cause problems.

Here are additional concerning quotes, this time about how HSV-1 DNA has been found in the brain of Alzheimer’s patients:

Jamieson et al. (1992) and Itzhaki et al. (1997) reported that a high proportion (about 60%) of brains of elderly people contained latent HSV-1 DNA, especially in the CNS regions critically involved in AD. When present in AD brains, HSV-1 DNA was primarily located within amyloid plaques (Wozniak et al., 2009a). Whether or not the virus contributes to activation of pro-neurodegenerative pathways may largely depend on several host factors, including genetic predisposition, as described in greater detail below. Many infectious agents whose pathogenetic role has been established in other CNS diseases (e.g., varicella zoster virus, causing meningitis or encephalitis; Epstein–Barr virus, associated to both multiple sclerosis and CNS lymphoma; human herpes virus 6, associated to seizure in children) may infect subjects without producing evident clinical signs.

I’ll stop here for now, for the sake of brevity.

Now that I hopefully have your interest, I’m going to leave you to read as much of the above-quoted paper as you care to. I’ll now go on to discuss HSV-1, what it is, its symptoms, how to test for it, and what might be done about it.

What is HSV-1?

Picture of 2nd day of HSV-1 “breakout” or “active infection”. This is the primary symptom of an active HSV-1 infection. From the Wikipedia article on “Herpes simplex” (picture referenced 5/20/2015).

HSV-1 goes by quite a few names. It is also known as:

  • “herpex simplex virus – 1”
  • “oral herpes”
  • “herpes labialis”
  • “mouth herpes”
  • “herpes”
  • Names for its main symptom (shown above) include: “mouth ulcers”, “oral ulcers”, “canker sores”, or “cold sores”

The introductory paragraphs of the Wikipedia article on “Herpes simplex virus” are one of the better summary descriptions of the virus I could find:

Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), also known as human herpesvirus 1 and 2 (HHV-1 and HHV-2), are two members of the herpesvirus family, Herpesviridae, that infect humans. Both HSV-1 (which produces most cold sores) and HSV-2 (which produces most genital herpes) are ubiquitous and contagious. They can be spread when an infected person is producing and shedding the virus. Herpes simplex can be spread through contact with saliva, such as sharing drinks.

Symptoms of herpes simplex virus infection include watery blisters in the skin or mucous membranes of the mouth, lips or genitals. Lesions heal with a scab characteristic of herpetic disease. Sometimes, the viruses cause very mild or atypical symptoms during outbreaks. However, as neurotropic and neuroinvasive viruses, HSV-1 and -2 persist in the body by becoming latent and hiding from the immune system in the cell bodies of neurons. After the initial or primary infection, some infected people experience sporadic episodes of viral reactivation or outbreaks. In an outbreak, the virus in a nerve cell becomes active and is transported via the neuron’s axon to the skin, where virus replication and shedding occur and cause new sores. It is one of the most common sexually transmitted infections.

Exciting.

How do you get HSV-1?

I searched around to find a detailed, scientifically-reliable description of how HSV-1 transmission works (e.g WebMD, herpes.org, etc.). Some of these sites seems to really “dumb down” explaining these things sometimes. So again, I present a quote from the Wikipedia article on “Herpes simplex virus” (emphases mine; Wikipedia references removed):

HSV-1 and -2 are transmitted by contact with an infected area of the skin during re-activations of the virus. 

HSV-1 is often acquired orally during childhood. It may also be sexually transmitted, including contact with saliva, such as kissing and mouth-to-genital contact (oral sex). HSV-2 is primarily a sexually transmitted infection but rates of HSV-1 genital infections are increasing.

Herpes simplex viruses can affect areas of skin exposed to contact with an infected person. An example of this is herpetic whitlow which is a herpes infection on the fingers. This was a common affliction of dental surgeons prior to the routine use of gloves when conducting treatment on patients.

How many people have HSV-1?

Before talking about how common HSV-1 is, let’s first consider how one is considered “HSV-1 positive”. This is important, because based on this, there are some important scientific caveats about these test results to consider.

The most common test (from my study) for HSV-1 “positivity” is called “seropositivity”. This is where a person’s blood is tested for anti-HSV-1 antibodies. These kinds of antibodies are made in response to an infection, for the purpose of maintaining immunologic “memory” against that specific infectious agent. These stay in a person’s body for years, decades, or even the rest of a person’s life. This persistence is an important aspect of how immunization enables one to have a persistent resistance to an infectious agent (e.g. it is common for one to only ever have a “chickenpox” infection once. After recovery, most people are “immune” to subsequent infections). Immunization – this immunological “memory” – can also be acquired through vaccination.

So, the main test for HSV-1 status is to test to see whether a person has persistent, anti-HSV-1 antibodies. If they have these antibodies, it is assumed by apparently many clinicians and scientists:

  1. The person has been infected before with HSV-1,
  2. HSV-1 can not be cleared by anyone, ever (a tenuous assumption, I suspect), therefore:
  3. The person is “positive” for HSV-1, and thus,
  4. The person will periodically have sub-clinical infections or “viral reactivation” episodes, during which they will shed virus from their body fluids (including saliva, semen, and vaginal fluid). The person may or may not have the usual “cold sores” or “ulcers” normally associated with viral activation.
  5. This asymptomatic viral shedding may be an important method of virus transmission in humans, because both infected and uninfected individuals can’t determine when extra caution should be used to avoid transmission to a sexual partner (for sexual acts) or loved ones (for kissing).

Medline has a good article describing this blood test for herpes simplex (both HSV-1 and HSV-2, the latter using this  method as well), here.

Now, onto the prevalence of HSV-1.

Using the testing method I described above, it has been estimated (presumably through some kind of somewhat-random sampling and testing) that greater than 50% of people in the U.S. and Europe will test positive for HSV-1. There is a book available on the NIH “Bookshelf” called “Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis.“, which well-describes seroprevalence of HSV-1. Here is a quote (emphases mine):

Herpes simplex viruses are among the most ubiquitous of human infections. The frequency of HSV infection has been measured by testing various populations for the presence of antibody, as both virus and the immune response are thought to persist after infection for the life of the host…..HSV-1 is the more prevalent virus, with 65% of persons in the United States having antibodies to HSV-1 (Xu et al., 2002). The epidemiology in Europe is similar, with at least half of the population seropositive for HSV-1. In the developing world, HSV-1 is almost universal, and usually acquired from intimate contact with family in early childhood (Whitley et al., 1998). After childhood, the HSV-1 prevalence rates increase minimally with age. Rates of HSV-1 infection are similar for men and women. In the United States, African-Americans and Asians have higher rates of HSV-1 infection than whites. The majority of infections are oral, although most are asymptomatic. Some data suggest that in developed countries, acquisition of HSV-1 is delayed from early childhood to adolescence or young adulthood (Hashido et al., 1999; Mertz et al., 2003).

So, there you have it. It’s pretty common – perhaps one of the most common human viruses there are. I don’t know about you, but it makes me, for one, think very differently about this whole concept of “kissing” that humans are so fond of.

HSV-1 and other possible harm

So far, I’ve only discussed HSV-1 having a possible role in the development of Alzheimer’s Disease. However, because HSV-1 apparently persists (in one’s brain!) for one’s lifetime, there is a possibility that it contributes to the development of some other health problems with age. This hypothesis of mine (and probably others) comes from the observation that a different, apparently persistent virus – cytomegalovirus (CMV) – appears to impair the immune system during aging. I will be reviewing CMV and relevance to health preservation during aging here at the Long Life Blog.

Since HSV-1 is also apparently persistent (not cleared by the immune system) once a person is infected (just like CMV), I wonder if HSV-1 might contribute to some of the same immunological problems in aging as CMV does. I did a brief search of the scientific literature on this topic.

I found just one relevant study, done in mice, and the results are concerning: “Life-long persistent viral infection alters the naïve T-cell pool, impairing CD8 T-cell immunity in late life” (2012). In the abstract, the authors report (emphases mine):

To address the causal impact of life-long persistent viral infection on immune homeostasis and defense, we infected young mice systemically with HSV-1, MCMV or both viruses, and studied their T-cell homeostasis and function. Herpesvirus+ mice exhibited increased all-cause mortality compared to controls. Upon Listeria-OVA infection, 23 month-old animals that had experienced life-long herpesvirus infections showed impaired bacterial control and CD8 T-cell function, along with distinct alterations in the T-cell repertoire both before and after Listeria challenge, compared to age-matched, herpesvirus-free controls. Herpesvirus infection was associated with reduced naïve CD8 T-cell precursors, above the loss attributable to aging.

It was done in mice, about which I am somewhat skeptical (regarding its applicability to humans). But to report a clear difference in the HSV-1-infected mice over an aged control group is, in my opinion, something to pay attention to.

Conclusion: HSV-1 infection might also degrade one’s immune system during aging, making it worse than just old-age alone. 

Kissing?

One consideration I’d like to explore is this: if these viruses infect people for their entire lives, and they’re so common, then is it really worth thinking much about? For example, HSV-1  has infected approximately 60% of people in the United States. It is supposed (at least by me) that most people acquire it by kissing. Yeah…..kissing. Have you ever kissed someone? Right. So, everyone is at risk, and even if they don’t have HSV-1 (yet), there’s a good chance they’ll get it eventually if they continue kissing without adequate testing and/or precautions.

Yet, someone discovers they do not have HSV-1 , will they want to never kiss anyone again, until they’re potential kissing-partner is tested for HSV-1?

Well: you’ll have to decide that for yourself. Sucking face seems pretty risky to me; then again, I’ve also studied CMV and its apparent negative effects on the immune system, and it is also transmitted by kissing.

There is a fascinating paper  published in 2010 suggesting that the cultural phenomenon of kissing might have evolved to “inoculate” females with CMV early on in a sexual relationship, so they can begin to have an immunological response to CMV before they get pregnant and give birth. This is relevant because CMV is most common congenital viral infection, which can cause deafness and mental retardation, among others birth defects – probably not good for the “survival of the offspring”.

But I’ve gotten carried away about CMV. I’ll talk more about that in my article about CMV.

Back to HSV-1 and kissing: at the very least, you might strongly consider not kissing babies. These cute little creatures have poor immune systems, and slobbering all over them (particularly their eyes and mouth) could get them infected with HSV-1 (and CMV). Each of these viruses are included in what’s called the “TORCH” complex – a set of possible congenital or perinatal infections that newborns may be screened for, due to their increased risk for them.

Are you really going to slobber your HSV-1 and CMV all over this poor kid?

Is HSV-1 truly “persistent”?

An interesting observation that made me quite excited is that there is some (unfortunately) very limited evidence that humans may actually clear (i.e. destroy completely) HSV-1.

In the study “T Cell Immunity to Herpes Simplex Viruses in Seronegative Subjects: Silent Infection or Acquired Immunity?” , published in 2003, the authors basically tested subjects’ T-cells (a type of immune cell), and these cells’ ability to kill HSV-1. Six out of twenty-four (6/24) subjects had T-cells that could specifically target and kill HSV-1. This means they must have been subjected to HSV-1 before, right? And if they had, they must have anti-HSV-1 antibodies, right? Well, no. Despite testing for HSV-1 antibodies or previous HSV-1 infection, the authors couldn’t find any evidence of HSV-1 infection. Interpretation: these 6/24 might have totally killed-off any trace of HSV-1, or possibly been somehow resistant to the initial infection.

A quote from the abstract (emphases mine):

During the course of investigating T cell responses to HSV among volunteers entering trials of investigational genital herpes vaccines, 6 of the 24 immunocompetent subjects with no prior history of oral/labial or genital herpes possessed HSV-specific T cell immunity but, by multiple determinants of even the most sensitive serological assays, remained seronegative to HSV-1 and -2. Of these six immune seronegative (IS; HSV-seronegative with HSV-specific T cell responses) subjects, two had transient HSV-specific T cell responses, while four had CD4+ and CD8+ T cell responses directed at HSV that persisted for up to 4 years…..

…..Oral and genital mucosal secretions were sampled and tested for the presence of infectious HSV and HSV DNA. No evidence of HSV was detected in >1500 samples obtained from these IS subjects. The identification of persistent T cell responses to HSV in seronegative subjects is a novel finding in the herpesvirus field and suggests either undetected infection or acquired immunity in the absence of infection.

They tested over 1,500 samples from these 6 subjects, and never found evidence of HSV! 

To me, that’s pretty exciting. If there is a way to facilitate or enhance clearance of HSV-1 in human subjects, we could get the benefits associated with doing so (e.g. avoiding increased risk of Alzheimer’s, and possibly preserving the immune system of 60%+ of the human population)….PLUS – possibly being relevant for enhancing the clearance of CMV, (another allegedly “un-clearable” virus) thereby removing the immunity-degrading effects it appears to have.

Testing for HSV-1

I haven’t found very many companies that will test for HSV-1. Planned Parenthood apparently will test for it (see the “FIND A HEALTH CENTER” link), though I don’t have any experience using Planned Parenthood – perhaps someone can confirm in the comments that they’ll test for HSV-1?

The website STDCheck.com sells an HSV-1 test for only $79 – I think that’s pretty reasonable. I’ve ordered blood tests from them before, and they seem reliable. I don’t know anything about their lab, equipment, protocols, etc., except that the sample was taken at Quest Diagnostics, which is a little reassuring.

HSV-1 or HSV-2?

As is often the case with biology, all of this gets a little more complicated. As I’ve discussed above, HSV-1 usually shows symptoms in and around someone’s mouth. HSV-2, also known as “genital herpes”, most commonly shows symptoms – you’ve guessed it – around one’s genitals.

But apparently, HSV-1 (the “oral” version) can infect the genital area (likely from oral sex), and HSV-2 (the “genital” version) can also infect the area around the mouth (again, from oral sex). This “area switching” seems to have a pretty low prevalence. For example, Wald et al. reported in ‘Oral shedding of herpes simplex virus 2.’ (2004) (emphasis mine):

Objectives: Herpes simplex virus (HSV) 1 and HSV-2 reactivate preferentially in the oral and genital area, respectively. We aimed to define frequency and characteristics associated with oral shedding of HSV-2.

ResultsOf 1388 people meeting the entry criteria, 44 (3.2%) had HSV-2 isolated at least once from their mouths.

Conclusions: Oral reactivation of HSV-2 as defined by viral isolation is uncommon and usually occurs in the setting of first episode of genital HSV-2 or during genital recurrence of HSV-2.

The prevalence of HSV-2 viral shedding from the mouth of just 3.2% is pretty low. But just know that it happens.

If you have HSV-1, what can you do about it?

If one discovers they are infected with HSV-1 (either through a lab test, or from the appearance of painful cold sores that take up to a few weeks to heal), a sense of helplessness can be depressing. If this virus persists for one’s life, and could cause serious harm (such as accelerate the development of Alzheimer’s Disease), this is rightly concerning.

I have some hope that the article I discussed above – about people losing their HSV-1 seropositivity – might be onto something promising. Perhaps humans can and do clear HSV-1, but perhaps this process needs to have the right conditions to occur.

Keep in mind I’m really just making reasonable guesses with the following suggestions. I’m not highly confident these things will work to help clear HSV-1. But if I were trying to clear a heretofore considered “un-clearable” virus, I’d take very good care of my immune system. Doing this could ensure the immune system is consistently working its best to kill and remove things in your body that you don’t want there.

For myself, to keep my immune system working as best as I could, I’d consider (and I actually do) things like:

Avoid sleep deprivation. Further reading:

Don’t over-exercise (e.g. marathons). Further reading:

Get regular exercise

Eat yogurt

One might also consider the use of antivirals, which appear to lower viral loads of these “persistent” viruses. But I don’t know much about the mechanism of action and side-effects of those (if any), so I would do much more research for myself before seriously considering those.

If you’d like to learn about how the body fights and clears and active infection of HSV-1 (and therefore, learn about how one might enhance this process, specifically), you might start studying this free full-text article: Immunological control of herpes simplex virus infections.

Finally, you might be interested in following or even somehow supporting HSV-1 vaccine development. Here is one interesting link that was current as of writing this article (May, 2015):

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Maximus Peto is a longevity scientist focused on the biology of aging, health, nutrition, exercise, lifestyle, and longevity. In his scientific research, he has scanned 160,000+ scientific articles, read 8,000+ scientific abstracts, and studied 1,500+ full-text scientific publications. Maximus has worked with several leading organizations in aging and longevity, including the SENS Research Foundation, the Methuselah Foundation, and the Life Extension Foundation. He shares his knowledge of keeping people alive and healthy at Long Life Labs.