Medical Virology PATB 4710
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Date Created: 10/27/15
Jay Truitt and Tom Coates Medical Virology 2006 IntroductionKaposi s Sarcoma and IIHV8 In 1981 the emergence of Kaposi sarcoma KS among young gay men in New York Los Angeles and San Francisco heralded the beginning of the AIDS pandemic Previously KS was recognized as an uncommon malignancy of elderly Mediterranean men African children and Ashkenazi Jews However it soon became the most common neoplasm of AIDS patients Nearly 40 of persons infected with HIV in the mid1980s developed KS and the condition rapidly became associated with the quotface of AIDSquot portrayed in popular lm theater and print media By the end of that decade the number of new KS cases began to decline due to the introduction of antiretroviral therapy ART The widespread use of effective ART in the United States and Western Europe resulted in a 3fold decrease in the incidence of KS as compared with the early years of the HIV epidemic However as other AIDSassociated malignancies declined KS was still left to be the most common AIDSassociated malignancy and continues to be a common af iction among persons with HIV worldwide In 1994 Chang and Moore established that a novel human herpesvirus human herpesvirus8 HHV8 also known as KSassociated herpesvirus was responsible for the development of KS This website includes a review of the virology and molecular biology of herpesviruses and specifically HHV8 and its relationship to the development of KS as well as the clinical presentations pathogenesis diagnostics and treatments as it relates to KS Viral Genome and Structure of Herpesviruses and IIHV8 The name herpes comes from the Greek 39herpein39 39to creep39 these viruses cause chroniclatentrecurrent infections Approximately 100 Herpesviruses have been isolated at least one for most animal species which has been looked at To date there are eight known human Herpesviruses The Herpesvirus family is divided into three subfamilies Alphaherpesvirinae Betaherpesvirinae and Gammaherpesvirinae HHV8 belongs to the Gammaherpesvirinae family which has a restricted host range produces little infectious viral particles and has an association with tumors Specifically HHV8 has a tropism for epithelial and B cells and it is kept under immunological control and only presents a problem during immunosuppression Herpesviruses have large genomes up to 235kbp DNA and are complex viruses containing approximately 35 virion proteins All encode a variety of enzymes involved in nucleic acid metabolism DNA synthesis and protein processing The Herpesviruses are widely separated in terms of genomic sequence and proteins but all are similar in terms of virion structure and genome organization Size 180200nm Envelnpe Present assomatedglycoprotems Te men Protexnr lledregxon between capsxd and envelope Czpsirl Icosahedral gselosnnn dwmeter 162 hexagonal capsomers Cure Toroxdal DNA around protein 75nm dameter Gennme Linear double stranded DNA 1057235ka Rep aunn Assembly Nuclear Cnmmnn ndgmsNone The on the metempsu tegnmt gwum Inf hrqu g ycopr un cornqu I g ycupra39em carnpr m new 199 gt9 Markham Figure 10vera1l structure at a typical herpesvinls Figure 2 A View of the cp J of a typical herpesvirus wwwtulaneeduWWW335Her esviruseshtml 7 quot741 7 A Figure 3 An electron micrograph of negativelystained herpesvirus particles various iso1ates ofa pamcularvirus can vary up to 10 kbps Figure 4 UL Us H 1151 msuknn 1 Us e 121 121 was was Us g H EHV 22 khn IlllquotWH IIHIII w 121 122m 124w 1 Figure 4 Typical gennniis Sequences nrnisn39ni herpesvinlses 1 wwwmlaneedlWWW335HEIE esvirusesintm Tne eonnp1ete mixe8 genome sequence shows that it has sequence sinni1anties to otnei m mi Wm HVS Mm68 and EpsteianarrVn39us Hm4 Tne appioninnate1y 165 kb genome eontains nnu1tip1e 801bpter mmal iepeat units ofhigh guanine and eytosine eontent T1ie1ong uniqu iegion eontains blocks ofconserved genes foundm nnostneipesvnuses inteispeised Witn blocks ofnonrhomologous genes that are speci c for HHWB an t dvimses HHWB pioteins Witn recognizable homology to cellularprotems ine1uo1e eonnp1ennent binding piotein ORF 4 make eytokine ORF K2 iee chemokmes ORF K40K1 K4 1 and ORF K6 i A ni E equot lt3 inteifeion iegu1atoiy factor ORF K9 Drtype eye1in ORF 72 FLICE innibitoiy piotein ORF K13 ee11 adhesionrlike nno1eeu1e OKFK14 Gprotein coupled receptor ORF 74 In addition HHV8 has a number of genes such as ORF K12 encodes the highly expressed transcript kaposin and ORF Kl a transmembrane protein that interacts with immunoreceptor kinases which are likely to play a role in tumorigenesis Functional studies suggest that these pirated genes may help the virus to evade immune responses prevent cell cycle shutdown and interrupt activation of apoptotic pathways This strategy has been referred to as quotmolecular piracyquot of host cell genes Like many complex DNA viruses HHV8 encodes a number of immunomodulatory factors Viral Infection CycleHerpesviruses and HHV8 1 l The virion attaches to host cell with the envelope glycoprotein onto heparan sulfate moieties of cellular proteoglycans Another viral glycoprotein is believed to bind to a secondary cellular receptor Figure 5 steps 1 2 The viral envelope fuses to the plasma membrane in a pHindependent fashion such that the nucleocapsid enters the cytoplasm Three glycoproteins are instrumental for this phenomenonFigure 5 steps 2 4 The capsid travels along the cytoskeleton to a nuclear pore where the viral DNA is released The linear genome enters the nucleus and circularizes Figure 5 steps 5 8 Once in the nucleus the viral DNA is transcribed into mRNA by cellular RNA polymerase II In herpesviruses viral gene expression is tightly regulated and divided into 3 kinetic classes of expression a A tegument protein associates with 2 celluar proteins and the complex transactivates transcription of HSV39s five immediateearly IE or alpha genes IE genes generally encode regulatory proteins Figure 5 steps 9 10 b An IE protein initiates transcription of the early E or beta genes These gene products are enzymes needed to increase the pool of nucleotides and for viral replication Figure 5 steps 11 13 c Lastly late L or gamma genes are activated for production of viral structural proteins Figure 5 steps 14 18 After transcription in the nucleus all mRNA transcripts are translated into protein in the cytoplasm Subsequently the proteins can go to the nucleus stay in the cytoplasm or become a part of the membrane bilayer Figure 5 steps 5 18 Capsid proteins assemble in the nucleus to form empty capsids Fulllength viral DNA is packaged to form nucleocapsids The nucleocapsids associate with segments of the nuclear membrane where tegument and glycosylated envelope proteins have bound This association triggers envelopement by budding through the nuclear membrane Figure 5 steps 18 19 Enveloped virions accumulate in the endoplasmic reticulum ER Figure 5 steps 19 21 Mature virions are released by exocytosis and Virusspecific proteins are also found on the plasma membrane of infected cells Figure 5 steps 22 23 Figure 5 Infection cycle of a typical herpesvirus Principles of Virology Flint DNA re lication and ackin Her esviruses and HHV S The mechanism of DNA packaging in herpesviruses is expected to resemble that in dsDNA bacteriophage because of similarities in the mechanism of capsid formation and because of the existence in the HSVl genome of genes encoding homologs of bacteriophage packaging proteins The mechanism of bacteriophage DNA packaging is therefore described brie y below The starting materials for bacteriophage DNA packaging are lquot Newly replicated phage DNA a multigenome concatemer in Which individual viral genomes are linked in a headtotail fashion Figure 6 step 1 The phage procapsid contains at one site a portal ring through Which DNA enters the capsid Figure 6 step 2 9 3 The phageencoded terrninase an enzyme with multiple functions in the packaging process Packaging begins when the terrninasse makes a double strand cut in the concatemer DNA The terminaseDNA end complex then docks onto the procapsid by way of the portal complex as shown to the left in steps 1 and 2 The cut creates one end of the progeny virus genome and cutting may occur at a speci c nucleotide sequence eg the cosN in the case ofphage lambda A er cutting DNA begins to enter the procapsid and continues until terrninase makes a second cut in the concatemer DNA The second cut may occur at a second pac site or a er a head lll of DNA has been injected As DNA is entering the procapsid is transformed into its mature icosahedral morphology Once the last DNA end has entered the capsid the portal is closed and the capsid is stabilized by addition of head completion Broteins Figure 6 steps 35 NA Packaging 1n dsDNABacteriophage mm W J mummim 39 39 ZDack DNA ama mcapsid pm 0 M III391 Pimp 1 3 1quot pm 4 momma mum J Can 5 Blackpuml ardstnbihzemmd Figure 6 DNA replication and packing of a typical herpesvirus Viral Latent Infection Herpesviruses and HHV 8 The speci c mechanism of the establishment the maintenance of and the reactivation from latency remains poorly understood The only detectable viral transcript in herpesvirus latently infected cells is the latency associated transcripts LATs The most abundant LAT is 20 kb long What is know is the rst 7 steps as in shown in Figure 7 are similar to the infection cycle of a typical herpesvirus However normal viral transcription is blocked or becomes leaky And as a result herpes latencyassociated RNAs are transcribed spliced and a 2kb LAT in the formed and transported to cytoplasm This molecule is translated to LAT proteins which are hypothesized that it may affect the viral replicative cycle by limiting the expression of certain immediate early IE or a gene products of infectedcells m Z k gt LAT mRNA l l LAT pmins39l Figure 7 Viral latent infection of a typical herpesvirus Principles of Virology Flint Pathogenesis A sarcoma is de ned as a cancer that develops in connective tissues such as cartilage bone fat muscle blood vessels or brous tissues related to tendons or ligaments Kaposi sarcoma KS was named for Dr Moritz Kaposi who rst described it in 1872 Until recently Kaposi s Sarcoma was a rare disease that affected mostly elderly Italian and Jewish men In the last couple of decades however most KS cases have developed in association with HIV infection and AIDS especially among homosexual men With new treatments the number of cases of AIDSrelated Kaposi s Sarcoma has decreased around 85 to 90 This disease typically causes tumors to develop in the tissues below the skin surface or in the mucous membranes of the mouth nose or anus These lesions abnormal tissue areas appear as raised blotches or lumps that may be purple brown or red Sometimes the disease causes painful swelling especially in the legs groin area or skin around the eyes Intraoral Kaposi s sarcoma lesion with overlyingcandidiasis WWW Mb ulOWa edu Although the skin lesions ost may be disfiguring they usually are not life threatening or disabling In most es the lesions cause no further s mptoms In some the lesions may be painful especially ifthey cause swelling ofnearby unatfected skin Ks does become life threatening when it is in the lungs liver or gastrointestinal tract This can cause major symptoms Ks in the gastrointestinal tract for example can cause bleeding I quot 39 39 in 39 mt 39 39 sputum quotL l r st They all dine 39 r 39 39 to be atfected how aggressively the cancer grows and spreads risk factors and other personal characteristics ofpatien s Classic Kaposi Sarcoma classic Kaposi sarcoma was first described in Jewish men ofEastem European origin or among elderly men ofMediterranean heritage primarily Italian classic Ks is quite rare even 39 L L 39 A r 39 39 lesions on the hands and arms and legs ankles or the soles ofthe feet The lesions slowly get bigger new lesions may develop over the course oflo to 15 years pressure from the lesions can block lymph vessels causing swelling that may be painful Lesions can also develop L 39 39 I mnh node A I L 39 L L 4 although they rarely cause lifethreatening symptoms African Endemic Kaposi Sarcoma African or endemic Kaposi sarcoma is a form of the disease that develops in people living in Equatorial Africa This disease is fairly common it accounts for 9 of all the cancers seen among Ugandan men In many cases this disease is identical to classic KS although it usually develops at a much younger age Both African and Classic Kaposi Sarcoma affect many more men than women Typically African KS causes skin lesions that do not produce symptoms and do not spread to other parts of the body However more aggressive cases do occur and some skin tumors may penetrate the underlying bone Another form of the disease strikes children before puberty affecting 3 times as many boys as girls and usually involves the lymph nodes and other organs In most cases it leads to death within 3 years Trans lantRelated Ac uired Ka osi Sarcoma Transplantrelated or acquired Kaposi sarcoma develops in people whose immune systems have been suppressed after an organ transplant Usually a transplant patient must take drugs to prevent the immune system from rejecting the newly transplanted organ Because these drugs weaken the body s natural immune defenses other diseases or infections can take hold Kaposi sarcoma is 150 to 200 times more likely to develop in transplant patients than in the general population Often transplantrelated KS affects only the skin In some cases though the disease can spread to the mucous membranes or other organs AIDSRelated Epidemic Kaposi Sarcoma AIDSrelated or epidemic Kaposi sarcoma develops in people who are infected with Human Immunodeficiency Virus HIV Early in the AIDS epidemic doctors began to see an unusual and sudden appearance of this form of KS This led them to realize a new disease had emerged Acquired immune deficiency syndrome AIDS results from infection by HIV This virus destroys certain cells of the immune system making the body unable to fight infections caused by certain other viruses bacteria and parasites Certain cancers are also more likely to develop in people whose immune systems have been damaged A person infected with HIV that is being HIVpositive does not necessarily have AIDS The virus can be present in the body for a long time typically many years before causing any major illness The disease known as AIDS begins when the virus has seriously damaged the immune system which results in certain types of infections and other medical complications Certain diseases occur so often in people with AIDS that they are considered AIDS defining conditions 7 that is their presence in a person infected with HIV is a clear sign that fullblown AIDS has developed The Centers for Disease Control and Prevention has identified certain cancers as AIDSdefining diseases Kaposi sarcoma lymphoma especially nonHodgkin lymphoma and primary central nervous system lymphoma anal cancer and an er cervlcal cancer Many other klnds of cancer may be more llkely to develop ln people p ofcourse p p of cancer In most cases epldemlc KS causes wrdespread leslons that erupt at many places on the tract lung llver and spleen Kaposl s Sarcoma leslons ona paumt sback http hrstory nlh govmmnoWnWordsdocspaggmd htrnl In contrast clasle KS usually affects only one or a fevv areas ofskln most often the lovver legs h Pr l L symptoms especlally lthelr leslons only develop on the skln However many reven those wth no skln eslons e have svollen ymph nodes unexplalned fever or welght loss Ev entually ln almost all patrents epldemlc KS spreads throughout the body h b developmg Diagg o s Medical history and physical exam Your doctor will take your medical history to learn about any past illnesses operations your sexual history and other possible exposures to KSHV and HIV The doctor will ask you about symptoms and about any skin tumors you have noticed The doctor will examine your skin thoroughly as well as give you a complete physical exam Sometimes KS lesions develop inside the rectum the part of the large intestine just inside the anus A doctor may be able to detect such lesions during an exam with a gloved finger Skin lesions in patienm who are HIV positive or who engage in high risk sexual activity are of especially serious concern Biopsy Skin lesions caused by KS can resemble other kinds of skin disorders in ammation bacterial or fungal infections nonHodgkin lymphoma or a benign tumor of the blood vessels hemangioma For that reason the doctor will want to take a small sample of tissue biopsy from the lesion and send it to a lab to be analyzed Under a microscope KS cells usually have a distinctive shape and pattern of arrangement Sometimes though early lesions may not reveal the characteristic cell patterns necessary to positively diagnose KS For skin lesions the doctor will usually perform a punch biopsy which removes a small round piece of tissue usually about l6inch in diameter Or the doctor may remove the entire lesion in a procedure called an excisional biopsy Imaging studies The most important imaging study in KS is the chest xray This can tell ifKS is in the lungs Tl Chest Xray of Kaposi s Sarcoma in the lungs Endoscopy In an endoscopy procedure the doctor uses a thin flexible lighted tube called an endoscope to look into your lower intestine or your stomach for lesions This is done while you are sedated It is also possible to biopsy these lesions using small surgical instrumenm operated through the endoscope Bronchoscopy In this procedure a doctor looks into the breathing tubes of the lungs with a thin exible instrument The patient is put to sleep with light anesthesia This procedure is usually done if you are coughing up blood If the doctor sees a KS lesion it will be biopsied Sometimes AIDSrelated KS affects other organs such as the liver spleen heart or bone marrow but in just about all cases the disease can be diagnosed from biopsies of other tissues such as skin lungs or intestines Treatment Treatment for AIDSrelated KS often signi cantly relieves the pain and discomfort that accompany the lesions However it is important to be aware that treatment will not produce a cure and there is little evidence showing that treatment for AIDSrelated KS prolongs life Perhaps the most important part of treatment is to treat the underlying AIDS with modern antiAIDS drug combinations called Highly Active Anti Retroviral Therapy HAART Treatment directed at the KS can then be added Local treatment Patients with about 25 or fewer small skin or mouth lesions may be treated with local therapies such as liquid nitrogen or alitretinoin gel Because local treatment does not result in a cure the most important goals are to improve appearance and reduce the social isolation AIDS can cause Local lesions sometimes improve with injections of vinblastine a chemotherapy drug directly into the KS lesion This method known as intralesional chemotherapy is an especially good choice for lesions that develop in the mouth Often treatments are given every 3 weeks for a total of 2 or 3 treatments Because the drug is injected into the lesion instead of into a vein it does not spread throughout the body and does not cause side effects in organs and tissues such as the bone marrow or digestive system The other drug that can be injected into the lesion is sodium tetradecyl sulfate In many cases local KS tumors of the skin mouth or anus improve significantly when treated with lowdose external beam radiation therapy radiation treatments administered using a machine positioned outside the body Depending on the specific clinical situation beams of photons or electrons may be used Doctors always try to deliver the smallest amount of radiation needed to do the job Sometimes only a single session is prescribed Another common technique is to give small doses of radiation frequently over a period of weeks At some treatment centers doctors may give 10 to 20 doses over several weeks In general use of radiation may cause less scarring or skin disfiguration than surgery Unfortunately KS lesions are often widespread throughout the body Even as lesions in the irradiated area are getting smaller a new lesion often appears elsewhere in the body For this reason lowdose radiation therapy of the entire skin surface is sometimes used As a rule doctors use radiation therapy to relieve symptoms or treat highly visible lesions although some patients who also have lesions in their internal organs have also improved with this treatment Patients with more than 25 KS skin or mouth lesions a lot of swelling around the lesions or lung or gastrointestinal lesions may do best with systemic chemotherapy Response rates range from about 30 to 85 depending on various factors such as the stage of the KS and the presence of other AIDSrelated illnesses Recently it was discovered that placing the active molecules of certain drugs into liposomes protective globules made of fats increases their effectiveness and reduces many side effects Drugs delivered in this way tend to concentrate in KS lesions and are gradually released Two liposomalencapsulated forms of the cancer drugs doxorubicin and daunorubicin are now available These have become the firstline systemic treatment Paclitaxel Taxol produces partial or complete responses in more than 50 of patients with AIDSrelated KS The drug seems particularly effective in reducing swelling quickly A recent report found that the antileukemia drug imatinib helped 5 out of the 10 patients treated This may pave the way for combination therapy that includes this drug Also antiviral therapy with a drug called foscamet Foscavir appears to help treat KS The Center for Disease Control and Prevention has reported that people with AIDS who were treated with foscamet for any reason were 70 less likely to develop KS than those not treated with the drug Other chemotherapy drugs given to treat KS are bleomycin etoposide vinblastine and vincristine and combinations of these drugs are frequently used Depending on the results and the onset of certain side effects doctors may change regimens from time to time Biological treatment has been given using certain kinds of interferons Interferons work by preventing viruses from reproducing and by activating immune system cells that attack and destroy the virus Between 25 and 50 of patients improve when given high doses of these drugs The best success rates occur in patients who do not have opportunistic infections and those who have a relatively healthy immune system The most common side effects of interferon therapy are u like symptoms fever pain and weakness There is also research underway to determine whether better results occur when interferon is used in combination with chemotherapy drugs Prevention There is no known method for preventing Kaposi s Sarcoma though taking measures to avoid infection with HIV would prevent the majority of cases found in the United States This means practicing safe seX and avoiding using contaminated needles as is common among intravenous drug users Improved HIV testing in blood banks has now virtually eliminated blood transfusions as a source of HIV transmission References TheBodycom The Complete HIVAIDS Resource httpWWWthebodycomtreatkaposishtml U39S39 National Library 0f MediCine and The National Institutes of Health httpwww nlm nih 1quot u htm American Cancer Society httpwww cancer on J hum inde asn The AIDS InfoNet httpWWW 391 39 r or factsheet detail nhn Ifqnumber511 The National Cancer Institute httpwwwcancergovcancertopicstypesAIDS EMedicinecom article by Ari D Fishman MD httpwww 139 39 J tunic1218 htm EMedicinecom article by Robert A Schwartz MPH httpwww 139 39 onm dermtnnio 70 htm
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