Herpes Simplex Virus Immune Response and Uncharacteristic Roles in Other Diseases

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Introduction


By J. Sebastián Chávez Erazo[]

The two viruses HSV-I (Herpes simplex virus 1) and HSV-II (Herpes simplex virus 2) infect humans and cause lifelong genital infections most commonly referred to as “genital herpes”[4]. These viral infections are chronic and most often caused by HSV-II although HSV-1 has recently been connected to increased numbers of anogenital herpetic infections most prominent in men who have sex with men and women[5]. Seroprevalence, the amount of a pathogen in a population, has double the rate in adult females than it does in adult males[6]. Herpes infection has several common clinical manifestations such as cold sores, genital sores/ulcers, encephalitis, and corneal blindness [7]. However, most people who have genital herpes do not present with symptoms, or have very mild symptoms[8]. For this reason, most people who do have genital herpes are not aware that they do[9]. Although a good proportion of people infected with genital herpes are unaware of their status, they continue to shed HSV at all times[10]. For these reasons genital herpes is very prevalent among American and worldwide populations. HSV-II caused genital herpes affects approximately 50 million people in the United States; about one in six people in the age range 14-49 years old in the U.S. is infected with HSV-I or HSV-II and has genital herpes[11]. Worldwide, the number of persons infected with genital herpes is more than half a billion people[12]. Most commonly, antiviral medications such as acyclovir are used to control herpes symptoms[13].While having genital herpes is commonly not life-threatening, genital herpes increases the risk of human immunodeficiency virus (HIV) acquisition/transmission by almost four-fold[14]. The need for a vaccine to prevent HSV-I and HSV-II infection is therefore also relevant to aid in preventing HIV infection[15]. There has been research that suggests a link between HSV-I/HSV-II infection and Alzheimer’s disease development[16]. The basic explanation for their relationship is that a weakened immune system in a geriatric patient would allow for the spread of HSV-1 through the trigeminal nerve or through the olfactory tract to create infection within the brain[17]. The infection by HSV would produce inflammation and cellular changes that lead to Alzheimer’s disease. Specifically, some studies have found that reactivation of HSV infection is possibly responsible for an increased risk of development of Alzheimer’s[18]. Epidemiologic evidence supporting this hypothesis is lacking, however [19]. Still, a growing body of research calls for further investigation into the connection between HSV-1 infection reactivation and Alzheimer’s disease because of the overwhelming proportion of the population harboring HSV-1 since early childhood[20]. HSV reactivation has also been associated with Bell’s palsy, the most common cause of facial paralysis[21]. The cause is possibly attributed to when a latent herpes virus from the ganglia of the cranial nerve is reactivated[22]. The reactivation possibly causes a demyelination of cranial nerves, especially the facial nerve, that would result in unilateral facial paralysis[23]. However, some findings contest a relationship between reactivated HSV and Bell’s palsy and instead support a correlation between other herpes viruses and Bell’s palsy[24]. While reactivation may cause the development of a disease, primary infection could cause severe diseases, especially in immunosuppressed patients[25]. One such example is herpes linked encephalitis in neonatal, gestational, and even postpartum patients(5,6). HSV infection in the central nervous system in these cases can present with symptoms ranging from headache to focal and generalized seizures[26]. These cases are especially dangerous when antiviral-resistant strains of herpes simplex 1 virus arise[27].



Viral Description

Variations of glycoprotein D genital herpes vaccine for human trials.[1].

Herpes simplex virus 1 and herpes simplex virus 2 are both double stranded DNA viruses[28]. The two strains are virtually identical when observed under a microscope[29]. However, the two strains differ mostly in their preferred site of latency in the human body and in about half of their DNA[30]. Both strains usually target cells of the oral or genital mucosa which lead to the typical ulcerated sores[31]. Extreme symptoms include corneal blindness and encephalitis as well as possible links to Alzheimer’s and Bell’s palsy[32]. Like other viruses, HSV-I and HSV-II exist in lytic or lysogenic cycles. During lytic infection, the viruses actively replicate uncontrollably in epithelial cells which results in cell destruction, leading to the sores and irritations typically associated with oral/genital herpes[33]. Often, these viruses will also exist in lysogenic states, where they establish latent infection in nerve cells of the body[34]. This latency is established commonly in lumbosacral dorsal root ganglia for HSV infections that affect the genital region[35]. Herpes simplex virus 1 and herpes simplex virus 2 structure is composed of the relatively large double stranded circularized genome, surrounded by an icosahedral nucleocapsid which is also surrounded by a lipid envelope[36]. The HSV-1 genome is very large and encodes over 70 gene products with terminal repeating sequences[37]. The space around the capsid and the lipid envelope is labeled the tegument and contains about 15 different proteins encoded by the virus itself while also containing proteins from whichever previous host it had[38]. The lipid envelope contains several types of envelope proteins used to attach and infect possible host cells on different receptor molecules. HSV-1 and HSV-2 attachment is made possible by its envelope proteins and is followed by entry of the intact capsid into the human cell cytoplasm and ultimately down a microtubule scaffold into the nucleus through a pore complex[39]. Before entering the nucleus, the virus’s host shutoff factors degrade host cell mRNA in order to halt host protein production. After entry into the nucleus, the herpes genome’s expression of mRNA either moves toward the lytic or lysogenic state by encoding proteins for infection cycle or synthesis of LAT proteins to maintain latency[40]. If the virus moves towards infection, the mRNA made for the lytic cycle is transported out of the nucleus for translation followed by re-entry of the new proteins in to the nucleus for packaging within capsids along with replicated progeny genomes[41]. The main viral enzymes used for circular DNA replication include DNA polymerase, single stranded binding protein, and a proofreading endonuclease along with aid from host cell enzymes[42]. The rolling circle method is used for DNA replication whereby the double stranded genome is snipped at one point and replication begins with the intact DNA strand as the leading strand. Translated envelope proteins move from the endoplasmic reticulum membrane to the nuclear membrane; completed capsules with replicated viral genomes and late stage proteins acquire their envelope from the outer nuclear membrane, undergo secondary envelopment through the endoplasmic reticulum, and ultimately move to fusion with the cell membrane which results in exocytosis of new virus particles[43]. If LAT proteins are made and the virus enters a state of latency, other processes become necessary. The infection of cells which will harbor the virus for long periods of time becomes necessary, which is why HSV-1 and HSV-II has evolved to infect the ganglia and neurons[44]. The virus will also regulate itself to suppress lytic replication through use of host proteins that inactivate lytic cycle genes, as well as regulate the host cell to prevent programmed cell death, apoptosis[45]. Diagnosis of HSV-I/HSV-II infection is usually taken care of through cell culture or PCR due to the common asymptomatic presentations of infection[46]. PCR and nucleic acid amplification methods are more reliable tests than viral culture since it has better sensitivity and less of a chance of resulting in a false positive test result[47]. For the diagnosis of HSV infections targeting the central nervous system, such as encephalitis and neonatal herpes, PCR is the test of choice[48]. Because of some type specific antibodies of HSV that exist, such as HSV specific glycoprotein G1 (HSV-1) and glycoprotein G2 (HSV-2), there are somewhat accurate (80%-98% specific) type-specific HSV serologic assays that will allow for diagnosis of one viral type against another[49]. Repeated testing is indicated for persons who may be experiencing early stages of infection since false negative values for these tests may be more frequent during early acute HSV infection. All patients with any episodes of genital herpes should receive antiviral therapy, usually in the form of acyclovir/valacyclovir/famciclovir in varying dosages depending on the individual and reaction to infection[50]. For recurrent episodes of gential lesions with HSV infection, antiviral medication is given to shorten the time period of breakout or ease the symptoms; use of these medications also decreases risk of viral transmission[51].


HSV Vaccine

Copies of HSV-2 186 delta Kpn genomes in dorsal root ganglia of mice 30 days after exposure. Mock group has no vaccine, SQ is subcutaneous injection and IM is intramuscular injection.[2].

Vaccine’s for HSV-I and HSV-2 have been attempted to be synthesized since the 1920’s with the same outcomes: no vaccine sufficient for large commercial production due to safety/efficiency[52]. Different approaches have been taken toward creating a successful vaccine. One such approach involves including a virus that is inactivated or replication defective that may be called disabled infectious single cycle virus[53]. Trials for these vaccines have yielded good results for seronegative individuals who are not infected with either genital herpes virus but show no boost in immune response for seropositive individuals[54]. Another approach to an HSV vaccine comes in the form of live virus vaccines that are replication competent, though these vaccine trials sometimes go awry due to viruses that are not attenuated well or that produce local reactions and adverse systemic side effects[55]. Further on, a vaccine featuring viral DNA with no viral vector has been attempted with the idea that dendritic cells would present antigenic genes to T cells for an adaptive immune response[56]. However, there were too many viral epitopes in these trials which resulted in competitions among each either that yielded decreased efficacy[57]. Recombinant protein based subunit vaccines have also been attempted where HSV-I and HSV-II common envelope glycoproteins gB and gD are key to vaccine production[58]. These vaccines had limited effects on men compared to women in trials and also had small effects on seropositive women though they activate both humoral and cell mediated adaptive immune responses. The importance of gender in producing a working vaccine has been highlighted with these studies[59]. Other research includes the use of virus like particles (VLPs), lipopeptide vaccines, and adenoviral vectors. Two approaches most at interest today include the use of asymptomatic epitopes from tegument or envelope proteins of the virus as well as the engineering of live attenuated virus lacking immune-evasive genes/putative neurovirulence genes[60]. Research specific to multiple epitope containing vaccines aims to focus on uncovering optimal designs for multiple epitope vaccines[61]. Two notable problems that HSV vaccine research faces are: the unknown reason for the lack of effect of past vaccine trials and the lack of understanding in why some seropositive individuals are more or less likely to have clinically typical herpes symptoms[62]. Multiple recent studies do include promising results that move us closer to obtaining a vaccine ready and sufficient for widespread use. With the goal of utilizing a vaccine that reduces latent infection and reactivation in seropositive individuals, one study used an animal model to introduce HSVdl5-29 attenuated virus[63]. Through the use of a specific ELISA for protein 8 antibodies and a qPCR assay, it was observed that immunization reduced latent infection, viral shedding, seroconversion, and disease in mice models[64]. This immunization was nonspecific to subcutaneous or intramuscular routes of delivery[65]. Within the field of recombinant protein based subunit vaccines, there is increased interest in vaccine formulations regarding specific concentrations of glycoproteins for use as antigens and what chemicals components are introduced along with them. Such studies concern themselves with different antigen doses, different aluminum salts used in the vaccine, different preservatives, as well as with volumes of vaccine used[66]. One such study investigated the differences between five vaccine formulations with concentrations varying at 20, 40, and 80 ug of glycoprotein D-2t among other conditions and found the smallest concentrations paired with varying types of preservative to be most effective in stimulating immune responses[67]. This is interesting due to a lack of observation in dose-related increase of immune response in humans. Within the field of vaccine research, new characterization of HSV type in genital infection has been found. In one sample of individuals, genital herpes was caused by HSV-1 at a proportion of 60%, an observation that is consistent with a shift in American epidemiology of infection[68]. Another recent and surprising find in HSV vaccine research has been the correlation with protection against HSV-1 genital infection and antibodies rather than T-cells[69]. Further research aims to replicate results as well as to assess the role of important antibodies for infection protection[70]. Possible roles for those antibodies include restriction of plaque size as marker of intra-cell spread, neutralization of entry of virus, antibody dependent cytotoxicity, and lysing of virus infecting cells through antibody dependent cellular cytotoxicity[71].


Herpes and Alzheimer's/Encephalitis

A coronal T2-weighted MR image showing altered signals in temporal lobes consistent with encephalitis in a patient positive for HSV type 1.[3].

A vaccine effective in resulting in sterilizing immunity would have far reaching consequences beyond typical clinical presentations of genital herpes and their associated social troubles. HSV-1 and HSV-2 have uncharacteristic roles in common medical diseases and complications. Herpes simplex virus 1 and herpes simplex virus 2 have complex roles that are not well understood/confirmed in Alzheimer’s disease as well as better documented roles in postpartum/neonatal encephalitis. While no definitive conclusions have been made regarding Alzheimer’s disease and a possible herpes simplex virus etiology, the construct has been found to be highly attractive to understand development of disease[72]. In Alzheimer’s patient’s brains, abnormally phosphorylated tau, a faulty human protein, spreads through neurons almost as a virus and there are increasing studies and arguments regarding the role of HSV instead of phosphorylated tau in AD[73]. A hypothesis for this etiology is that HSV-1 spreads through branches of the trigeminal nerve to the meninges or through the olfactory tract to create brain infection[74]. The presence of HSV-1 is then thought to create conditions/responses known to be associated with Alzheimer’s disease[75]. Herpes simplex 1 is thought to create inflammation and cellular changes in the brain such as amyloid beta production and tau hyperphosphorylation that lead to Alzheimer’s disease[76]. There has been a proposed link between reactivation of herpes simplex infection in humans already seropositive for HSV-1 and AD. One ongoing longitudinal, prospective cohort study regarding memory function in the adult life span found no link between presence of anti-HSV IgG antibodies and risk of AD but did find a significant link between anti-HSV IgM and risk of AD[77]. The link with HSV IgM is notable because it is known sign of reactivated infection[78]. Acute HSV infection in neonates and pregnant women may cause herpes encephalitis through infection of cerebrospinal fluid and the swelling could lead to seizure activity as well as necrotic changes(5, 6). The consequences associated with herpes encephalitis are growing as well with a reported case of postpartum herpes encephalitis[79]. Such a case is rare since the presentation of herpes encephalitis is usually associated with women during pregnancy and preeclampsia[80]. Drug resistance is an issue that almost no pathogenic microbe fails to present and HSV is no exception. Newborns with weak immune systems are especially susceptible to herpes encephalitis if exposed and a recent case of acyclovir-resistant herpes simplex virus 1 strain causing necrotic changes of the bilateral temporal lobes of a newborn was confirmed to be related to newborn’s mother’s HSV-1 and HSV-2 latent infection through direct immunofluorescent antibody assay[81]. As the medical results of HSV-1 and HSV-2 infection broaden, further research into understanding the differences between the two, their potential cause of uncharacteristic disease, and creating a vaccine becomes increasingly necessary.


References

[1] "Chentoufi, A. A., et al. “Toward a rational design of an asymptomatic clinical Herpes vaccine: the old, the new, and the unknown,” Clinical and Developmental Immunology. Article ID 187585, 16 pages, 2012. ".

[2] "Diaz, M. F., Knipe, D. M., “Protections from genital herpes disease, seroconversion and latent infection in a non-lethal murine genital infection model by immunization with an HSV-2 replication-defective mutant virus,” Virology 488, 61-67, 2015.".

[3] "Lövheim, H., et. al. “Reactivated herpes simplex infection increases the risk of Alzheimer’s disease,” Alzheimer’s and Dementia 11, 593-599, 2015.".

[4] "Ball, M. J., et. al. “Intracerebral propagation of Alzheimer’s disease: strengthening evidence of a herpes simplex virus etiology,” Alzheimer’s and Dementia, 9, 169-175, 2013. ".

[5] "Dikici, S., et. al. “Postpartum herpes encephalitis that apply with status epilepticus: case report,” Am J Clin Obstet Gynecol 2(4):185-188, 2015. ".

[6] "Kakiuchi, S., et. al. “Neonatal herpes encephalitis caused by a virologically confirmed acyclovir-resistant herpes simplex virus 1 strain,” Journal of Clinical Microbiology, Volume 51, 356-359, 2013.".

[7] "Turriziani, O., et. al. “Early collection of saliva specimens from Bell’s Palsy patients: quantitative analysis of HHV-6, HSV-1, and VZV,” Journal of Medical Virology, 86:1752-1758, 2014. ".

[8] "Greco, A., Gallo, A., Marinelli, C., Macri, G.F., and de Vincentiis, M. “Bell’s palsy and autoimmunity,” Elsevier Autoimmunity Reviews 12:323-328, 2012.".

[9] "Leroux-Roels, G., et. al. “Immunogenicity and safety of different formulations of an adjuvanted glycoprotein D genital herpes vaccine in healthy adults, a double-blind randomized trial,” Human Vaccines and Immunotherapeutics 9:6, 1254-1262, 2013.".

[10] "Vogel, K., Thomann, S., Vogel, B., Shuster, P., and Schmidt, B. “Both plasmacytoid dendritic cells and monocytes stimulate natural killer cells early during human herpes simplex virus type 1 infections,” Immunology, 143, 588-600, 2014. ".

[11] "Awasthi, S., and Friedman, H. M. “A paradigm shift: vaccine-induced antibodies as an immune correlate of protection against herpes simplex virus type 1 genital herpes,” The Journal of Infectious Diseases 209, 813-815, 2014.".

[12] . "Centers for Disease Control and Prevention: Genital Herpes. ".

[13] "Slonczewski, J. L., Foster, J. W. “Microbiology an evolving science,” New York, W.W. Norton & Company, Inc., 2014.".












Authored for BIOL 238 Microbiology, taught by Joan Slonczewski, 2016, Kenyon College.