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Home , Herpesviridae

* Fbz.oM: A C~~~~P~U-@eU~LIFE /h/~lffG~hMs 2 52 DNA : &DNA, Cubic or Helical Symmetry

HERPESVIRIDAE i

Lipomratelm- - earclove Cmpsld eoclorlmg Tegmmert, cornpored of protelms emcoded by double-ntramded : the rlrmr amd s8rrooadimg the moeleocapsid DNA

pen8lralion Cytoplmrm of hott ccll

Cytoplarmic membrmme or Lort cell

Viral DNA replicalion

Envelope

Transport through cytoplarrn and rrleare from call by unknown 2-rnrchanirnr .mk- FIGURE 52 Replication of . Specific in the are'.essential for adsorption on host cell receptors in the cytoplasmic membrane. Envelope and cell membrane fuse and the viral nucleocapsid is released into the cytoplasm. Viral DNA is then uncoated and transported to the nucleus. Early and rnRNA are apparently catalyzed by host enzymes. The resulting early viral enzymes are used in DNA replication. Further RNA transcripts are responsible for synthesis d viral and envelope proteins as well as glycoproteins in the nuclear membrane. The structural proteins enter the nucleus to participate in the assembly of novel viral nucleocapsids. The latter are enveloped by budding through the nuclear membrane and complete viruses are released by unknown mechanisms. (Modified from Pelczar, M.J.,Chan, E.C.S., and Krieg, N.R., Microbiology - Concepts and Applicatiom, McGraw-Hill, New York, Q 1993,428. Reproduced with permission of The McGraw-Hill Companies.) PER I 5 ...... Herpes simple& Virus David Rakel, M.D.

HYSIOLOGY INTEGRATIVE THERAPY

pe~sonalContact Avoiding exposure to persons =Periencing out- breaks of either HSV-1 or HSV-2 infection is war- ranted but does not ensure against contracting the . Use of condoms while limiting the number of sexual partners will help reduce the prew alence of infection. Oral sex should also be avoided because can cause oral lesions, and tially affects these mucous mem- vice versa- shin is thin. Other common dermal at are overly moist or been compromised

assic progression of symp mation, and fol-

**oino=u'ation The patient should be educated on how to prevent to other Parts of the body durinl3 an outlmak For example, after bathing, patting dry with a towel instead of rubbing should be encour- aged, The transmission of vesicular fluid to other parts of the body must be avoided.

\

Trauma to the Skin at higher risk for complications. It is o observe that many more people have 1 HSV is more prone to causing recurrence and primary infection if the skin is traumatized or exposed to ultraviolet radiation. The patient should be encouraged to use sun protection to help prevent recurrence of HSV-1 infection, should avoid trau- potential effects of this virus is a point matic intercourse, and should prevent chapping of dy and invites an integrative therapeu- the lips. Using zinc ointment on the lips not only to reduce the severity of the disease protects against ultraviolet light exposure but may e has occurred. also help to suppress HSV growth. 133 1 34 CHAPTERIS W Herpes Simplex VhInfection

Dorsal root ganglia

Latent viral (may be interated or extrachrornosomal)

Stimulus for reactivation (stress, UV light, etc.)

peripheral sensory nerves

Figure 15- 1. Schematic diagram of herpes simplex and reactivation. W, ultraviolet. prom Whitley RI: . In Goldman L, Bennett JC [eds]: Cecil Textbook of Medicine, 21st ed. Philadelphia, WE3 Saunders, 2001; 1810-1814.)

Table 15- 1. Potential Triggering Factors for recommendation for helping patients reduce recur- Reactivation of Herpes rence of HSV infections, Evidence from in vitro stud- ...... ies supports this approach. The replication of the HSV-1-Spedfic Tmn~ virus requires proteins rich in arginine, and arginine Ultraviolet light itself may be a stimulator of HSV replication. Lysine Immunodeficiency exerts antiviral effects by blocking the activity of Stress, depression, anxiety (chronic) argi~~ine.~Clinical studies show mixed results?' Poor sleep One argument is that inadequate doses of lysine Trauma to mucosa Cold, windy, or dry weather were used. In one study, 52 people with recurring Hot food or lip biting oral and genital HSV infections were assigned to Food allergy receive either L-lysine 1 g 3 times daily or placebo; Fever they also avoided nuts, chocolate, and gelatin (argi- nine-rich foods). After 6 months, 74% of persons Immunodeficiency receiving lysine reported their treatment as either Stress, depression, anxiety (chronic) effective or very effective, versus 28% of those Poor sleep receiving placebo. The mean number of outbreaks Food allergy Trauma to genital mucosa was 3.1 in the lysine group, compared with 4.2 in Menses (usually 5-12 days before onset) those taking pla~ebo.~ There is some concern that taking supplemental lysine for prolonged periods of time may increase the Sleep risk of , possibly by increasing levels of lowdensity lipoprotein^.^ Accordingly, adjusting Poor sleep hygiene can result in fatigue, which may lead to an increased frequency of recurrence. The Table 15-2. Arginine-Containing and Lysine-Rich clinician should specifically inquire about sleep Foods: Dietary Recommendations for Prophylaxis of habits to help the patient make changes that will Herpes Simplex Virus Infection Recurrence result in an improved sleep cycle...... Foods to Avoid Foods to Include (High Arginine Content) (High Lysine Contenf) Nutrition Chocolate Vegetables Peanuts B&S Lysine- and Arginine-Containing Foods Almonds ~ish Cashews Turkey A diet that promotes lysine-rich foods and reduces ~unflowerseeds Chicken arginine-containing foods has become a popular CHA~IS W Herpes Simplex Virus Infection 1 35

the amount of arginine in the diet by reducing the adrenal gland. Overactivity of the adrenals can arginine-rich foods may be the safer approach (see lead to suppression of the immune response and Table 15-2). increase susceptibility to recurrent HSV infection (see Chapter 94, Learning to Meditate).

Food Allergy Supplements Although there is limited research to back the claim that food allergies trigger recurrences of HSV Vitamin C infection, a trial of an elimination diet should be offered to persons with frequent recurrences (see When used early in the prodrome of an outbreak, Chapter 82, on elimination diets). vitamin C 1000 mg with the addition of 1000 mg bioflavonoids taken 5 times a day for 3 days after recognition of symptoms was found to reduce Good Nutrition healing time in , from 10 days in the placebo group to 4.4 days in the treatment group.'* The most important nutritional factor in preven- tion of HSV infection is a balanced diet with 7 or 8 servings of fruits and vegetables a day, to help Zinc support a healthy immune system. Zinc has been found to inhibit HSV replication in vitro and enhances cell-mediated immunity to help Mind-Body Medicine reduce HSV infection recurrence. Oral compound of 25 mg of zinc with 250 mg of vitamin C was given It has been a common belief that isolated stressful twice a day for 6 weeks, which resulted in either events may lead to recurrent HSV outbreaks, although complete suppression of an outbreak or resolution of research has not supported this association. One HSV-1 eruptions within 24 hours.13 Topical applica- study of 64 people with HSV infection found no corre- tion of a zinc sulfate solution of 0.01% to 0.025% lation between acute stressful events and a later out- concentration has also been found to be helpful in break.' On the other hand, chronic or persistent healing HSV-1 lesions and in inhibiting recurrence.14 stressors have been found to correlate with an Use of zinc and vitamin C supplementation constitu- increased frequency of rec~rrence.~This correlation tes an inexpensive option for the patient with fre- is consistent with findings showing a decrease in HSV quent recurrences. immunity in caregivers of dementia sufferers1' and a Dosage. Zinc 25 mg a day with vitamin C 250 mg a decrease in herpes zoster immunity in persons with day for recurrence prophylaxis. depression." Therapeutic focus should be on helping Precautions. In prescribing zinc supplementation, the patient find a balance of lifestyle demands and on the clinician should be aware that zinc competes learning techniques to reduce day-to-day stress in with copper, calcium, and iron absorption. The persons with frequent recurrences. patient should not take more than the recommended dose and should not take calcium and iron supple- ments with zinc. Doses greater than 50 mg per day have been found to be associated with reduction in serum copper levels. Chronic rather than isolated stress has been found to result in more heequentHSV outbreaks. Lysine

As discussed previously under "Nutrition," lysine Relaxation Exercises exerts antiviral effects by blocking the activity of arginine, which promotes HSV replication. Although Teaching the patient a simple relaxation exercise the results of research are mixed, a trial of 1 g of -'at can be used on a regular basis or when needed lysine daily to prevent recurrences, increased to 1 g 3 ,,r ,,r recurring stressful events can empower the times a day during an outbreak, seems reasonable. patient to learn how to reduce stress (see Chapter Dosage. L-Lysine 1 g daily for prevention, 1 g 3 91, Prescribing Relaxation Techniques). times a day for acute outbreaks. Precautions. Diarrhea and abdominal pain have I been reported in persons taking doses of more than editation 10 g a day. There has been a single case documented of tubulointerstitial nephritis progressing to renal For persons with chronic recurring stress, practice failure.'' Lysine may cause a modest rise in low- f meditation can help to reduce the stimulation of density lipoprotein levels. 136 CHAPTERIS Herpes Simplex VimInfection

Vitamin E Oil been found to enhance the immune function and may be a component of its therapeutic benefit. Topical application of vitamin E oil has been found Dosage. Steep a tea bag, cool, and apply directly to to help reduce the pain of oral herpetic lesions lesions for 20 minutes 1 to 3 times a day. within 8 hours and to result in more rapid healing.16*l7 Dosage. Squeeze the contents of a vitamin E cap Pharmaceuticals sule (d-alpha-tocopherol) onto a cotton swab and apply directly to the lesion every 8 hours as needed. Antiviral medications effective against HSV work Precautions. Local skin reaction is possible but is by inactivating DNA polymerase, which inhibits viral rare. replication. In order for these medications to be effective, they need to be started soon after symp- toms appear because viral replication may end as Botanicals early as 48 hours into an infection. Oral antiviral medications should be used with Lemon Balm caution in persons with underlying kidney disease or when given with other nephrotoxic drugs. As with Lemon balm (Melissa officinalis) is the most any , regular use can result in viral common botanical used for treatment of herpes resistance. infections. Lemon balm ointment consists of a 70:l lemon extract concentrate. The preparation has been found to be helpful for the treatment of active Treatment for Primary Genital Herpes HSV outbreaks. In one large study involving three Infection German hospitals and a dermatology clinic, when lemon balm was used to treat the primary infection a Acyclovir (Zovirax) 200 mg 5 times daily for 10 of HSV-1, not a single recurrence was noted. This days finding suggests that lemon balm may help to pre- a (Famvir) 250 mg 3 times daily for 10 vent recurrences if used during an initial infection. days The cream has also been found to reduce the healing a Valacyclovir (Valtrex) 1 g twice daily for 10 days time for both genital and oral herpes lesions.'' Although more expensive, valacyclovir has the Dosage. 70:l lemon extract cream, applied fairly advantage of reduced frequency of dosing. thickly (1 mm) to herpetic lesions 2 to 4 times a day. Precautions. Toxicology studies have found lemon balm to be safe and suitable for long-term use. Treatment for Episodic Recurrences

Licorice Root Research has shown only a minimal benefit with treatment of recurrences with antiviral medications, and some experts may question the need for epise Licorice (Glycyrhiza glabra) is well known for its dic treatment. Best results are obtained if the drug is anti-inflammatory properties and has also been started at the prodrome of the recurrence, when the found to be of benefit in inhibiting both the growth patient notices itching, burning, or erythema. and cytopathic effects of HSV." Topical application of licorice root preparations is an option to help a Acyclovir (Zovirax) 800 mg twice daily for 5 days reduce duration of outbreaks and severity of oral a Famciclovir (Famvir) 125 mg twice daily for 5 days herpes lesions. Valacyclovir (Valtrex) 500 mg twice daily for 5 days Dosage. Apply tincture of licorice with a cotton swab, or drop directly onto the lesions, three times a day until resolution. Pharmaceutical Prophylaxis Precautions. Local allergic reaction may be seen with topical application. Prophylaxis is generally reserved for persons who have more than 6 outbreaks in a year. For patients with frequent recurrences, the practitioner should Tea Bags look holistically at other potential factors such as chronic stress, suboptimal nutrition, and decrease in A folk remedy that has been found to be an perceived level of well-being before simply prescrib- inexpensive and easy-to-prepare treatment for oral ing prophylactic antiviral medication. If pharmaceu- HSV lesions is to steep an ordinary tea bag (prefer- tical prophylaxis is started, therapy should be ably Earl Gray tea), cool, and then apply to lesions. discontinued once a year to see whether continua* This measure is thought to speed healing and to tion is necessary, and the patient should be encour- prevent recurrence, although there are no studies aged to titrate down to the lowest effective dose. to support this. Tea contains catechins that have Short-term prophylactic therapy for oral herp CHAPTERIS Herpes Simplex Virus Infection 1 37 bas been shown to reduce severity but not recur- and coconut oil. It has been found to destroy the rence following ultraviolet light exposure in skiers.20 fatty coating of certain viruses that allows them to

I ---- 1--2- ---A ---- ,Ann -- --A -I-:r-- adhere to cells, causing infection. It is thought to help protect breast-feeding infants from viral infec- tion. Monolaurin is currently being studied for its 3x1 I g once aauy potential use in treating infections due to lipid- coated viruses including HIV. There is a lack of I In a small pilot study, aspirin was found to reduce evidence to recommend its use at this time, but ! rate of active infection by nearly 50%.2 This patients have reported clinical benefit from this xpensive therapy may prove fruitful if more inexpensive therapy.- - kbage. A,t the first sign of infection, the should take 1800 to 3600 Img (6 to 12 300-1 sules) daily for 4 days and thc en reduce the tn 17nn mrr C) tn A Lmdr ranciil~c\ Aa KnnVVV LV IMVV ll.6 \M &V 7 VVV2nn ll.6 bUpUUIWJ U-lJ UIALAI lesions have resolved. Precautions. Animals fed monolaurin in amounts UP to 25% of their diet showed no signs of harm after weeks.23 Human studies are limited.

Homeopathy

her Therapies to Consider Homeopathic remedies are given until resolution of lesions occurs. Examples of remedies used for nolaurin genital HSV infection are sepia, graphite, rhus (tox- icodendron), and dulcamara. Hylands #27 is a Bonolaurin (Laricidin) is a monoglycerol ester of common homeopathic remedy for oral HSV infec- uic acid, a saturated fatty acid found in breast milk tion.

- THERAPEUTICREVIEW

mg and vitamin C 250 mg a day

phylactic therapy is reserved for persons who have not responded to a holistic mpeutic approach and who experience more than 6 outbreaks in a year. 138 CHAPTERIS .Herpes Simplex Virus Infection

??ERAPEVTICREVIEIY continued Acute Treatment of HSV Infection Supplements L-Lysine 1 g 3 times a day until resolution 0 Topical vitamin E oil: Apply oil from capsule to oral HSV lesion 3 times a day. Botanicals Lemon balm (70:l lemon extract cream): Apply to herpetic outbreak 2 to 4 times a day. Licorice root tincture: Apply to lesions 3 times daily until resolution. Tea bag: Steep tea bag, cool, and apply directly to om1 lesions for 20 minutes 1 to 3 times a day. Pharmaceuticals For primary infection: Acyclovir (Zouirax) 200 mg 5 times daily for 10 days Famciclovir (Famvir) 250 mg 3 times daily for 10 days Valacyclovir (Valtrex) I g twice daily for 10 days Efficacy of treating episodic recurrences remains to be established, but the following can be tried: Acyclovir (Zouirax) 800 mg twice daily for 5 days

References 10. Glaser R, KiecoltGlaser JK: Chronic stress modulates virus-specific immune response to latent herpes simp 1. Wald A, Zeh J, Selke S, et al: Reactivation of genital herpes virus type 1. Ann Behav Med 19:78-82,1997. simplex virus type 2 infection in asymptomatic seropositive 11. Irwin M, Costlow C, Williams H, et al: Cellular immunity persons. N Engl J Med 342:844-850,2000. varicella-zoster virus in patients with major depresslo6 2. Mertz GI: Epidemiology of genital herpes infection. Infect Dis Infect Dis 178 (Suppl 1):S104-S108.1998. Clin North &n 73825-E9, 1993. 3. Griffith R Debnn D. Nelson J: Relation antagonism to he&& simplex growth in tissue <ure.- he rent herpes labialis. Oral Surg 45:56-62,.1978. mot6erapy 27:209-213, 1981. - 4. MGiovanna J. Blank H: Failure of lvsine in fi~eauentlv recurrent herpes simpl'ex infection. Arch ~Grmatol120:48-5i, 1984. post-herpetic with low ioncentratiofi 5. McCune MA, Perry HO, Muller Sk' Treatment of recurrent zinc sulphate solution. Br J Dermatol 104:191-213, 1981. 4 herms simplex infections with L-lvslne monohvdrochlorite. 15. Lo JC, et al: Fanconi's syndrome and tubulointerstitial ned cutis 34368-373, 1984. 6. Griffith RS. Walsh DE. Mvrmel KH: Success in frequently recurrent herpes simplex infectioh. ~ermatd; 16. Fink M. irk J: Treatment of hemsimplex by alpha gica l?5:183-190, 1987. - 7. Sanchez A: Nutr RE Int 28:497. 1983. 8. Rand KH, Hoon EF, Massey Jk, et al: Daily stress and recur- rtindvosto&atitis in an adult. N Y State ~eiJ 44:j824 rence of genital herpes simplex Arch 1niem Med 150:1889- 1893.1990. 9. ohe en F, Kemeny ME, Kearney KA, et al: Persistent stress as a dried &r&t from Melissa officinalis: khytomkd 1:25:31, d predictor of genital herpes- recurrence. Arch Intern Med 159:2430-2436,1999. Hcrpcsviruscs

McEwcn. B. 5. (1998). Protective and damaging effects of proteins and cr~~~-toluuluin plants. PhyJioL Plrmt. saess mediators. N. Eng. j. Md338, 171-179. 103, 437-441. Morano, K. A.. Liu. P. C. C., and Thiele, D. J. (1998). Protein Sanders, B. M. (1993). Stress proteins in aquatic organisms: chaperones and the heat shock =porn in Sacchmomyccs An environmental pequctive. Cnt. Rev. TmrioL 23, cncvisioc. Cum. Opin. Microbiol. 1, 197-203. 49-75. Narkrhaus, F. (1999). Negative regulation of bacterial heat Schoffl, F., Prandl, R., and Rcindl, A. (1998). Regulation shock . Mol. Microbiol. 31, 1-8. of the heat shock response. Plant Physiol. 117. 1135- Neidhardt, F. C.. VanBogelen. R A.. and Vaughn. V. (1984). 1141. The genetics and regulation of heat shock proteins. Annr Singer. M.. and Lurdquist. S. (1998). Multiple effects of mha- Rm.Gmt. 18. 295-329. lose on protein folding in vim and in vivo. Mol. Cell Piper, P. (1997). The yeast heat shock response. In Teast 1,639-638. Stress RCS~O~~KS''(S. Hohmann and W. H. Mager, Eds.), Stratal&,C. A, and Chrousos, G. P. (1995). Neurocndocrin- pp. 75-99, Chapman & Hall. New Yo& ology and pathophysiology of the s~assystem. Ann. Piper, P. (1998). Differential role of Hsps and uchalox in N. Y. Acad Sci. 771, 1~18. stre& tolerance. Trends MicroMol. 6,434. Watson, K. (1990). Microbial snew proteins. Adv. Microbial bbchat. A., Weiss, D., and Lurie, S. (1998). The heat shock PhySiOL 31, 183-223.

David A. Padgett and John F. Sheridan The Ohio Statc Univmity

I. Introduction qtic)form most of the time with very linlc viral replica- 11. Virology tivt my.ALo Chupctaired by intamittcnt h-ups 111. Immunobiology and Rccumnt Distve of dinid discP#. N. Sues and Htrpcsvirus Reactivation rurrwIndPda thc capsid and the enclod nudeic V. Conclusion acid.

GLOSSARY I. INTRODUCTION

capsid The protein coat or shell that contnins the nuckk The Herpesviridae represent a large group of vi- acid genome of the vinn panicle. ruses that are pathogenic for many vertebrates. Tk cupsomme Represents the individual morphologicd units (or name is derived from the Greek word Uhcrpcinn sides) on the surkcc of thc apsid. meaning "to creepn such as the chronic, latent, and cnvclopr The lipui-comaining outer mcmh that sur- rcamcnt infections associated with hupesvlrws. rounds the entire vinn ppRidC Thc aivclope arises frma a buddmg of mature hapawus pPrdchs *ugh the nu- Disuws resulting from infection with member of clear membrurr. the hupejvinwsMtywi~ac~'tothevirus. i Lcosohtdmn Geometric shape with 20 equal sides or apso- Sevd mcmbcrs of the fnrmly cam lifelong infec- meres (similar to n soccer ban). The hqpvinw capsid b cions in humans that arc characterized by pcEiods of an icosohedroa quirscarcc followed by reactivation and exprcdon t hM infqth he virus persists in an quiescent (occult &' of dinid symptoms. The pattern of infection de- Hypcsviruscs pends on the portal of enuy or site of infection and bounded by a unique long (UL)and a unique short the immune status of the host. In neonates and im- (US) region. These repeats allow some members of munocompromised individual, primary infection by the family to undergo genomic rearrangement of herpes simplex virus (HSV), for example, results in their unique re&ons, giving rise to differentgenomic severe infection that can lead to . Resolu- isomers. Because of the high incidence of re- tion of the primary infection in healthy individuals arrangement, spontaneous deletions occur, and de- is accompanied by the establishment-of latency. For fective viral particles are common. Thus, there is HSV, the development of latency means that virions little DNA homology among different herpesvi~ses reside "quietly" in neural tissues without causing except for herpes simplex virus types 1 and 2, which disease. Periodic reactivation of the latent virus is show 50% sequence homology, and herpesvirus 6 frequently accompanied by clinical symptoms and and 7, which share 30-50% homology. Digestion of the development of herpetic lesions. Other members the genome with restriction endonucleases yields a of the family have been associated with mononucleo- characteristic fragment pattern specific for each fam- sis, lyrnphoproliferative disease, lymphomas, and ily member. This allows for rapid epidemiologic trac- Kaposi's sarcoma. ing of a given strain. The genome of the typical herpesvirus is large and encodes for at least 100 different proteins, many of which (>35) are struc- tural in nature. Several virus-specific enzymes, in- 11. VIROLOGY cluding DNA polymerase and , are - synthesized in infected cells, but no virus-specific A. Characteristic Structure enzymes are incorporated into the mature virus par- Herpesviruses are large DNA viruses. The diverse ticle. members of the family share similar architectural details and are morphologically indistinguishable. C. Subclassification Each member has a double-stranded DNA toroid core (DNA spooled around a cylinder of protein) that is Over 100 different herpesvirus have been identi- encapsulated within an icosahedral capsid. The cap fied, including eight human isolates. The entire fam- sid is composed of 162 capsomeres and is itself within ily of herpesviruses is subdivided into three sub- a lipid envelope. This envelope is formed from the classes based on modes of replication and nuclear membrane of an infected cell from which sequence similarity. progeny viruses bud. Within this nuclear-lipid enve- lope are virus-encoded glycoproteins or "spikes" 1. Alphaherpesviruses have a broad host range; about 8 nm long. An additional feature of the herpes- they replicate rapidly in many types of cells. Al- virus family is a tegument, which is an amorphous, though these are highly lyuc viruses, members of asymmetrical structure located between the capsid this subclass can establish latency in and and envelope. The entire virion measures 120-200 glial cells. This group includes human herpes sim- type nm and the naked capsid is approximately 100 nm plex virus 1 and type 2 (HSV-1 and HSV--2). in diameter. human varicella-zoster virus (VZV), and bovine her- pesvirus type-1 (BHV-1 ). 2. Betaherpesvirus have a restricted host range B. Characteristic Genome and grow slowly in tissue culture. Infection typically causes cells to swell. These members can establish The genome of herpesviruses is double-stranded latency in hematopoietic progenitor cells and can linear DNA with a molecular weight of 95-150 X 106 cause persistent infections of epithelial and glandular or 120-230 kbp. Herpesviruses have a characteristic cells. Includes human and murine arrangement of their DNA sequences; their (CMV), , and human herpesvi- have terminal and internal repeat sequences that are rus 7. Hcrpcsviruscs

3. Gammaherpesvirus have a restricted host Herpesvirus DNA is synthesized by a rolling circle, range. These members can replicate in epithelial cells or concatameric, mechanism that appears seemingly and establish long-term latency in lymphocytes. In endless. Huge amounts of viral DNA are transcribed addition, some of these viruses can transform or im- throughout the replicative cycle by cellular RNA mortalize their host cell. Includes Epstein-Barr virus polymeraie 11. The length of the replication cycle (EBV) and Kaposi's sarcoma-associated human her- varies from about 18 h for herpes simplex virus to pes virus (also called human herpesvirus type 8). over 70 h for cytomegalovinis. Although host cell polymerases are required for viral DNA replication, D. Virus Replication many virus-derived cofactors are involved. This dis- tinguishes the herpesviruses from other nuclear DNA Viruses are obligate intracellular parasites; as such, viruses in that they encode a large number of en- members of the Herpesviridae must interact with a zymes involved in DNA synthesis. The newly synthe- host cell for survival. These viruses recognize poten- sized viral DNA is packaged into preformed empty tial host cells through specific interactions between a nucleocapsids in the . host cell receptor and a viral membrane . Maturation occurs by budding of nucleocapsids Some herpesviruses bind to host cell surface glyco- through the inner nuclear membrane. Enveloped vi- saminoglycanssuch as heparan sulfate. Other herpes- ral particles are then released from the cell through viruses recognize immunoglobulin supergene family tubular structures that are continuous with the out- members; EBV recognizes a specific complement re- side of the cell or from vacuoles that release their ceptor and human recognizes &- contents at the surface of the cell. Cells infected microglobulin, whereas W-1binds to a member of productively with herpesvirus are invariably killed. the tumor necrosis factorhewe growth factor (TNFI NGF) receptor family. In addition to these common E. Overview of Caused receptors, other glycoproteins have also been impli- by Herpesviridae cated in herpesvirus recognition of host target cells. After binding, the virus enters the host cell by As there are over 100 different types of herpesvi- fusion with the cell membrane. The capsid is trans- ruses, it is not surprising that they can cause a wide ported through the cytoplasm to a nuclear pore. variety of diseases. As their subclassification into a, Once inside the nucleus, uncoating occurs and the /3, and y herpesviruses suggests, primary infection viral DNA forms a circle immediately upon 'release and possible latency may involve different cell types from the capsid. Host macromolecular synthesis is and present a widely different set of symptoms and shut off early in infection; normal cellular DNA and clinical disease. protein synthesis virtually stop as viral replication begins. 1. Herpes Simplex Viruses Expression of the viral genome is regulated tightly HSV are extremely widespread in the human popu- and ordered sequentially in a cascade fashion. Imme- lation and &bit an ability to replicate in many host diate early are expressed, yielding a proteins tissues. They also infect other animals. There are two (those that are produced in the absence of prior virus main forms of the herpes simplex viruses: type 1 and gene expression). a Proteins permit expression of type 2. Both viruses grow rapidly and are extremely the early set of genes, which are translated into 4 cytolytic. Typically, these viruses infect epithelial proteins (those that are expressed before DNA repli- cells found in mucosal tissue and establish latent cation). Viral DNA replication begins and late tran- infections in peripheral neurons. HSV-1 has been scripts are produced that give rise to y proteins (those classically associated with oropharyngeal lesions that are expressed after DNA synthesis). Many of characterized by recurrent fever . HSV-1 is the a and /3 proteins are enzymes or DNA-binding spread by contact, usually involving infected saliva. . proteins, whereas many of the y proteins .are struc- HSV-2 has been associated with recurrent genital tural in nature. herpes and is usually transmitted sexually or from maternal genital infection to a newborn. Both viruses ferative disorders in immunocompromised individu- can cause neurologic disease with HSV-1 being the als. EBV is commonly transmitted by infected saliva leading cause of sporadic encephalitis in the United (hence the nicknaMe "the kissing disease"). Primary States. Both HSV-1 and HSV-2 can cause severe pri- infection involves epithelial cells of the oropharynx mary infections in newborns. and parotid gland. Viral shedding occurs for weeks Latent infection followed by recurrent disease is to months after infection. Following replication in the hallmark of these viruses. HSV-1 and HSV-2 re- epithelial cells, EBV infects B cells and quickly be- side in latently infected ganglia in a nonreplicating comes latent. Continuous or immortalized cells lines state with only a few viral genes being expressed; are produced when EBV transforms human .B lym- the infectious virus cannot be isolated during latency. phocytes. EBV blinds to the through the C3d Persistence of the viral genome within a latently in- component of the complement cascade (CRZ or fected cell lasts for the lifetime of the host. Following CD21). a reactivating stimulus, the virus follows axons back to the peripheral site and replication proceeds in 4. Cytomegalovirus the epithelial cells. Spontaneous reactivation occurs CMV or human herpesvirus 5 infects respiratory despite HSV-specific immunity. More than 80% of epithelial cells or epithelial cells within salivary the human population harbors HSV-1 in a latent glands or the kidneys. CMV is an important cause form, but only a small proportion experience reacti- of congenital defects and mental retardation in more vation. The molecular basis for reactivation is not than 5000 infants in the United States per year. CMV completely understood. Herpes simplex viruses are is the largest herpesvirus with a genome of approxi- also called human herpesviruses 1 and 2. mately 240 kbp. Infection is characterized by massive enlargement of infected cells. Primary CMV infec- 2. Varicella-Zoster Virus tions in immunocompromised hosts are more severe VZV or human herpesvirus 3 is highly contagious than in normal hosts. and a very common virus. The typical route of infec- tion is the mucosa of the upper respiratory tract. After primary replication in the mucosal epithelium, 5. Human Herpesvirus 6 and Human the virus enters the circulation and eventually local- Herpesvirus 7 izes to the skin where it causes two distinct syn- These viruses were first recognized in 1986 and dromes. Upon primary infection, usually in children, 1990, respectively. Both viruses were isolated from it causes chicken pox (also called varicella), which cultures of peripheral blood mononuclear cells (T is characterized clinically by a generalized vesicular lymphocytes). Currently, their association with any eruption of the skin and mucous membranes. How- known human disease has not been established. ever, VZV subsequently establish& a latent infection These two viruses share significant sequence homol- and,.on reactivation, the virus causes (also ogy however, they are antigenically and immunologi- called zoster). Shingles is a sporadic, incapacitating cally distinct. disease of adults or immunocompromised individu-

als that is clinically characterized by a that is 6. 'Human Herpesvirus 8 , limited in distribution to the skin innervated by a This virus is also known as Kaposi's sarcoma-asso- single sensory ganglion. The lesions are similar to ciated herpesvirus and was originally isolated in varicella. 1'995. It is present in all forms of Kaposi's sarcoma and in primary effusion lymphomas. HHV-8 ex- 3. Epstein-Burr Virus presses a number of cellular regulatory genes that EBV or human herpesvirus 4 causes infectious the virus appears to have pirated from mammalian mononucleosis (heterophile test-positive) and is a cells as a way of defeating host defense mechanisms. factor in the development of nasopharyngeal carci- This virus represents the first known human member noma, Burkitt's lymphoma, and other lyrnphoproli- of the genus Rhadinovim. Herpesviruses

7. binding proteins. Many /3 proteins are required for The B virus is highly pathogenic for humans, al- replicative function. y proteins are also called late though transmissibility of the virus from its normal proteins as they are produced after DNA replication host to humans is limited. Typically, B virus infects has begun. These late proteins are mostly structural Old World monkeys and is enzootic in rhesus, cyno- in nature, forming the capsid and envelope glycopro- molgus, and other monkeys. B virus infec- teins. The majority of proteins that constitute the tions in the natural host seldom cause overt disease. mature virion are y proteins. but latency is established and B virus is easily reacti- vated under stressful conditions. Infection of humans usually results from monkey bites and is associated 111. IMMUNOBIOLOGY AND with a high rate of mortality due to an acute, as- RECURRENT DISEASE cending and encephalomyelitis. The course or natural history of a herpes viral infection is influenced by the site of viral entry and F. Herpesvirus Proteins host defenses. Primary infection with a herpes virus Herpesviruses differ widely in their protein expresi induces both innate and adaptive immune responses, sion. HSV type 1 encodes approximately 72 proteins which result in the termination of viral replication (which is average for most herpesviruses, although and cessation of clinical symptoms. However, unlike over 100 proteins are not uncommon). acute viral infections in which a successful immune response leads to elimination of the virus, infection 1. Structural Proteins with herpesviruses frequently leads to latency and The mature virus particle typically contains about thus the opportunity for episodic recurrent disease.

20 proteins, of which many are capsid proteins. A , single major capsid protein (-150 kDa) constitutes A. Innate Immunity the pentons and hexons of the icosohedron. Several other minor capsid proteins (VP19,VP22a, VP23, All are born with a genetically inherited VP24, and VP26) play roles in packaging of the DNA resistance to infectious microbes that is termed in- and the toroid core, although their functions are nate or natural resistance. Expression of natural re- largely unclear. In the envelope of the virus are eight sistance does not require previous exposure to the major virus glycoproteins, some of which form viral antigen (as does the adaptive immune re- "spikes." These proteins are immunodorninant and sponse). The primary function of natural resistance offer targets for virus-specific neutralizing anti- during a viral infection is to restrict the early spread bodies. of the virus prior to the induction of virus-specific T- and B-cell responses. Experimental studies have 2. Nonstructural Proteins demonstrated that cellular components of natural These proteins are subclassified into three groups resistance are activated following infection with depending on the time during viral replication that HSV-1. Macrophages, natural killer (NK) cells, and they are expressed. a proteins, or immediate-early luller cells mediating antibody-dependent cellular proteins, are produced prior to viral DNA synthesis. cytotoxicity (ADCC) all have a role in restricting the Each of these proteins has regulatory roles that take early spread of the virus. Infection by members of over the macromolecular machinery of the host cell the Herpesviridae is also accompanied by the expres- and thus enable production of subsequent proteins. sion of genes encoding the , which impart /3 proteins are also called early proteins. Their pro- resistance to uninfected cells surrounding an infected duction follows that of the a,but the expression of cell. These natural resistance mechanisms are very /3 proteins does not require DNA synthesis either. important in the early phase of an HSV infection Among the proteins in this group are the DNA poly- as this virus has been shown to downregulate the merase, DNA helicase, and DNA synthesis origin- expression of HLA class 1 molecules (which limits recognition of infected cells by CD8' T cells). Loss sion of the latent viral genome. The balance between of HI4 class I molecules. however, targets the cell positive and negative transcription factors deter- for elimination by NK cells, thus limiting spread of mines whether tire genome will be reactivated, and the virus. this process is mediated by numerous hormonal and growth factor signals. These signals may result from many different stimuli. Psychologcal stress, physical B. Adaptive Immunity trauma, W irradiation from a sunburn, or hormonal fluctuations of the menstrual cycle have all been Most infections with members of the Herpesviridae associated with reactivation of latent virus. result in the induction of virus-specific humoral (an- The period of time that the reactivated virus gets tibody) and cell-mediated immune responses. Immu- to replicate, and thus cause clinical symptoms, is nological memory also follows primary infection; mediated immunologically (and represents the sec- however, neither the successful termination of virus ond step in the process). Healthy adults generally replication during primary infection nor the estab- limit clinical symptoms during a recurrence to a cou- lishment of immunological memory prevents reacti- ple of days or less, whereas individuals with dimin- vation of latent virus and the development of recur- ished cell-mediated immunity, as seen in the ac- rent lesions. Clearly, a primary infection with HSV, quired immunodeficiency syndrome (AIDS), often whether asymptomatic or symptomatic, results in the develop severe disease that lasts much longer. production of virus-specific antibodies (both binding and neutralizing). These antibodies play multiple roles in mediating resolution of the primary infection IV. STRESS AND through direct viral neutralization, viral lysis (in HERPESVIRUS REACTIVATION combination with complement), and lysis of infected cells by an ADCC mechanism. Virus-specific T cells The capacity of latent herpesviruses to reactivate are also very important during infection; individuals and replicate is essential for completion.of the viral with cell-mediatated immunodeficiency suffer severe life cycle. During the latent phase of herpesvirus herpetic disease. Detailed sequential biopsy studies infection, virus gene expression is highly restricted; of the pattern of cell acquisition and cytokine gene only latency-associated transcripts (I4Ts) are ex- expression have shown at 24-48 h that herpetic le- pressed. Reactivation of herpesvirus from ganglia re- sions contain CD4' T cells expressing a broad range sults in the appearance of infectious virus at the site of cytokines (including IL-2, -y, IL-12, of the initial primary infection. However, the genetic IL-4, IL-5, IL-10, and IL-13). Clearance of virus from elements that determine reactivation have not been the lesions correlates with the presence of CD8' T identified thoroughly. The limited knowledge of the cells with virus-specific cytolytic activity. molecular pathogenesis of herpesvirus latency and reactivation was generated from studies in laboratory C. Recurrent Disease animals, including mice, guinea pigs, and rabbits. In these models, reactivating stimuli range from me- Whether the time to reactivation of latent virus is chanical and pharmacological to immunological al- weeks to months (as is the case for HSV) or years terations of cells and surrounding tissues. It is to decades (as is the case for VZV), it is clear that thought that the altered expression of cellular !actors immune memory, which results from the resolution in the host cell leads to the induction of herpesvirus of a primary infection with these viruses, offers little gene expression, resulting in reactivation. Accord- or no protection against recurrent diseases. The de- ingly, it is commonly thought that psychological velopment of recrudescent lesions is a two-step pro- stress may be one of the contributing factors to reacti- cess. The first step occurs at the cellular/molecular vation of herpesvirus. level and involves the regulation of viral and host The impact of psychological stress on immune transcription factors influencing the state of expres- function is well. documented in the literature, sup- Herpesviruses porting the hypothesis that both physical and psy- portant biologcal knowledge remains unknown chological stressors can have an impact on the patho- concerning reactivation. physiology of disease. Accordingly, there are numerous studies in humans documenting the reac- tivation of HSV-1 and HSV-2 with psychological V. CONCLUSION stress. Several studies have shown that the reactiva- tion of latent HSV infections was more frequent in The herpesviruses represent a diverse group of viruses that have evolved unique relationships with individuals who experienced traumatic life events, their hosts. Members of this viral group have been such as the death of a family member, the stress of interpersonal problems, or work-related difficulties. associated with diverse disease manifestations rang- Similar relationships between psychosocial stress and ing from malignant transformation to latency and reactivation of other herpesviruses, including EBV reactivation. Herpes infections occur from the cradle and VZV, have also been reported. It is thought that (neonatal HSV encephalitis) to the grave (shingles VZV the physiologic alterations that ensue during stress caused by reactivation of in the later decades alter the cellular microenvironment and serve as re- of life). They affect healthy individuals (CMV, mono- activators of latent herpes infections. nucleosis) and immunodeficient individuals (human In mammals, stressors typically activate a specific herpes virus type 8, Kaposi's sarcoma in AIDS). Reac- set of core stress responses, including the hypothala- tivation of the latent members of the herpesvirus mic-pituitary-adrenal (HPA) axis and sympathetic family has been associated with multiple fonns of UV nervous system (SNS). Activation of the HPA axis stress (from physical stressors such as irradiation results in increases in glucocorticoids such as corti- to psychological stress such as social conflict). How- sol, and activation of the SNS results in increases in ever, detailed knowledge of molecular steps that trig- circulating and tissue levels of catecholamines such ger reactivation is lacking. Furthermore, the inability as epinephrine.. Each of these alterations in the host to contain these viruses with the traditional ap- physiology has been linked to herpes reactivation. proaches of vaccination and/or drug treatment makes For example, a model for in vivo reactivation has research on the development of new prevention and been established in the rabbit with the eye as the site treatment strategies a high priority for Herpesviridae. for shedding. Epinephrine induces reactivation and recovery of mature infectious virus in the tears. In See Also the Following Articles this model, it was found that expression of LATs CANCER;CYTOKINES; HlV INFECTION/AIDS;HPA AXIS; IM- was required for reactivation; however, its role in MUNE RESPONSE reactivation is unknown. Glucocorticoids have also been implicated in Bibliography reactivation. For example, in the presence of antivi- ral drugs, primary cell cultures established from Brooks, G. F., Butel, J. S., and Omston, L. N. (1995). Herpes- latently infected uigeminal ganglia provide viruses. In "Jawetz,Melnick and Adelbergs's Medical Micro- a model to test reactivation in vitro. Glucocorticoids biology," 20th ed., pp. 358-380. Appleton and Lange, Nor- such as cortisol or dexamethasone can drive viral walk. CT. replication in these latently established ganglion Fields, B. N., Knipe, D. M., and Howley, P. M. (Ed.) (1996). "Fields Virology," 3rd cd. Lippincott-Raven, Philadelphia. cultures. Other stressors, such as the protein syn- Neipel F., Albrecht. J. C.. and Fleckenstein B. (1998). Human thesis inhibitor cyclophosphamide, W irradiation, herpesvirus 8: The first . J. Natl. Cancer Inst. and transient hyperthermia, can also cause recru- 23, 73-77. descence. However, in no model are the events Row, B. T. (Ed.) (1992). Herpes simplex virus. In "- that occur between stress and production of infec- esis. Immunobiology and Control." Springer-Verlag, New tious HSV-1 completely understood. Therefore, im- York.