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Micro Chapter 41: Alphaherpesviruses: Herpes Simplex Viruses and Varicella-Zoster Virus Herpesviruses are DNA viruses that can establish lifelong latent infections, that can reactivate symptoms throughout life The alpha herpesviruses are herpes simplex 1 and 2 (HSV-1 and -2) and varicella zoster (VZV) Infection with one or more herpesviruses is inevitable for pretty much everyone - Most of us have probably spread HSV-1 by kissing or exchanging saliva HSV-1 can be gotten in childhood or during sex through oral-oral or oral-genital contact Most adults have antibodies to HSV-1 HSV-2 can be gotten oral-oral and oral-genital, but is mainly spread by genital-genital o So HSV-2 gets more common with sex Varicella zoster is gotten mainly through respiration, but you can also get it by touching the blisters or secretions o Varicella zoster is much more contagious than HSV o Adults with no immunity from shots or exposure can have more severe chickenpox disease than kids do o A mild version of chickenpox can happen in vaccinated people since the vaccine isn’t 100% effective, called breakthrough disease Breakthrough disease is contagious and can be spread o Varicella infections are almost always symptomatic, causing chickenpox Most infections with HSV are asymptomatic (1/3 who have it show symptoms) - Asymptomatic people can still spread HSV by shedding from epithelial surfaces from lesions too small to be noticed Herpesviruses are fragile and susceptible to drying and inactivation by heat, mild detergent, and solvents, due to their membrane envelope - So they can’t survive well in the environment, and usually need direct contact with saliva or other secretions from an infected person HSV likes to infect the mucous membranes of the mouth, eye, genitals, respiratory tract, and anus - The first line of defense against HSV is the skin, which normally can’t be penetrated infected by HSV The thick keratin layer of the superficial epidermis prevents access of HSV, but mucous membranes don’t have a thick layer like that, so they’re easier to infect The main way to get chickenpox is by inhaling aerosols of varicella, but you can also get it directly So mucous membranes are the main entry for herpesviruses into us Herpresvirus infection starts by attaching to cells, which it does by using glycoproteins to bind to our heparan sulfate on the cell surface - - - - This isn’t enough to enter the cell, but brings the virus close to other parts of the cell It then binds to a so called “entry receptor” on the host cell, causing fusion of the virus envelope with the cell membrane, which can be either the plasma membrane or an endosome membrane This releases viral stuff into the cell, and the nucleocapsid is taken to the nucleus, where cells that can transcribe herpesvirus DNA, like epithelial cells, will transcribe it to make viral proteins and do viral DNA replication If the cell is latently infected, then the viral genome hangs out in the nucleus as an episome that only transcribes the minimal amount of genes In herpesvirus and varicella, the virus enters nerve cell ending that extend toward the epidermis, and is sent to the nerve cell bodies in peripheral sensory and autonomic ganglia, where the latent infection is established During productive infection (when virus replication is happening), immediate-early genes are transcribed to make proteins to help replicate the viral DNA After DNA synthesis, late genes are expressed to make progeny virions As the new viral nucleocapsids are made int eh nucleus, they bud through the inner nuclear membrane to get a temporary envelope, which they lose then by fusing with the outer nuclear membrane The final viral envelope with all its glycoproteins is gotten by budding ito cytoplasmic vacuoles made from the golgi These vacuoles take the mature virus to the cell surface and release it through exocytosis These new viruses aren’t good at being released from the cell, so they immediately attach to and penetrate adjacent cells o This is why HSV infections are localized and rarely found at many distant sites o HSV rarely spreads systemically, except in newborns or severely immunocompromised people o Varicella though, is very systemic, probably cause it infects & can be carried by WBCs Host defense to herpesviruses: - - Host defense is usually enough to limit the duration and severity of infection, and can prevent symptoms and recurrences Host defense won’t prevent latent infections though, and can’t eliminate the virus, because latently infected cells don’t trigger an immune response At first, herpesviruses induce immediate innate response with neutrophils and NK cells, and within days there are antibodies and T cells o Antibodies don’t do much, because herpesvirus doesn’t spend much time outside the cells o The antibodies can prevent primary disease though, which is why we can make a varicella vaccine The ability to mount a good enough immune response to herpseviruses changes with age o o o The immune cells are maturing for the first month of life, so herpesvirus infections in the first month can be devastating, neonatal infections are often fatal After 1 month old and up to we’re old, we tolerate the virus well Reactivation of varicella zoster happens more as we get older due to senescence of antiviral immune responses Damage from herpesviruses – pics page 424, table page 421 - - Both HSV and varicella destroy the epithelial cells they replicate in in the skin and mucous membranes, causing blisters that rupture, leaving shallow gray-white ulcers with an erythematous base As virus replication and spread get contained by immune response, the epithelium fully regenerates HSV lesions are usually localized, with spread of virus restricted to regional nerves o During primary disease, there can be sequential crops of lesions, resulting from reseeding of adjacent epithelial sites by neurons infected during earlier waves of epithelial replication o Inflammation or damage of the nerves can happen in the acute phase of disease, causing symptoms of itching, tingling, burning, or pain o Feeling these same symptoms later, called a prodrome, can indicate that a recurrent lesion is about to develop o Things that can trigger the reactivation of latent HSV are sunburn, systemic infections, immune impairment, emotional stress, and menstruation o Reactivated HSV travels down the axon process to infect mucocutaneous epithelial cells o Page 425 – events in HSV infection o Where HSV enters determines the manifestations of disease Corneal infections cause immune responses that damage the cornea irreparably and cause blindness, making you need a corneal transplant to get vision back Genital herpes can progress to meningitis, or affect autonomics for urination and defecation HSV-1 can pass from peripheral nerves to the CNS to cause life-threatening encephalitis, characterized by a strongly progressive and destructive inflammation that’s localized and unilateral HSV-1 encephalitis is rare, but accounts for most cases of sporadic disease Newborns are very susceptible to HSV infections that spread or cause neuro disease, and if they survive they often are developmentally impaired People with low cell mediated immunity can have HSV spread a lot o Chickenpox is a systemic disease with mucocutaneous lesions, caused by varicella zoster Cells of the lymphatic system are infected in the respiratory tract o o The spread of virus infected WBCs throughout the lymphatic system induces cytokine responses that cause fever, malaise, and headache In secondary viremia, circulating WBCs transmit the virus ot epithelial cells of the skin and mucosa, causing characteristic chickenpox lesions Latent infection is established in peripheral ganglia, and then they recover with no further symptoms Along with chickenpox lesions, kids can have cerebellar ataxia, immunocompromised can have encephalitis Shingles zoster lesions are similar blisters to the chickenpox ones, but they’re clustered along the dermatome innervated by the nerve that varicella was reactivated from The neurosymptoms are mainly pain, and are more severe Page 426 – course of varicella infection You usually can diagnose HSV or varicella from history and inspection, but you can also scrape the lesion for polymerase chain reaction (PCR) - HSV shows cytopathic effect, where if you take sample and put on a set of cells, it will lyse each cell, causing plaques that don’t stain o It wipes out only adjacent cells, and not the whole set Drugs for herpesviruses are usually nucleoside analogs - - Acyclovir – guanosine analog that is used only by the herpesvirus enzymes and not cell enzymes, and then incorporated into viral DNA as a chain-terminating nucleotide o So acyclovir is active in herpesvirus-infected cells, but has no toxicity for uninfected cells o Acyclovir is a prodrug that needs thymidine kinase to become active Other antiherpesvirus drugs include penciclovir, valacyclovir, and famciclovir These drugs can only treat symptoms, and can’t cure the infection, because they don’t prevent entry into neurons and so can’t get rid of latent infections Long term use of acyclovir can suppress recurrent infections There are no vaccines for HSV, but there is a vaccine for varicella - A live attenuated vacricella zoster vaccine prevents chickenpox in normal and some immunocomprommised people The vaccine virus establishes latent infection just like normal virus does, and reactivation can lead to mild cases of shingles Latency associated transcripts (LATs) – micro RNAs that keep the virus from erupting - When you remove the LATs, you have a herpes eruption