herpes

what kind of DNA does the herpes virus family have? are they enveloped?
dsDNA, they are enveloped
does the herpes virus go latent/reactivate?
herpese has the potential for latency and reactivation through immortilization&transformation – they frequently reactivate in compromised hosts
what are the 3 subfamilies of herpes virus? what are they organized according to?
alpha, beta and gamma which are organized according to the genome structure, tissue trophism&latency site, and pathogenesis&disease manifestation
what are the alpha herpes viruses? what are their targets/site of latency?
HSV1,2 (primary target: mucoepithelial cells/site of latency: neurons) and varicella-zoster (primary target: mucoepithelial cells&Tcells/site of latency: neurons), which causes chicken pox
what are the beta herpes viruses?
cytomegalovirus(primary target: monocytes/lymphocytes&epithelial cells/site of latency: monocyte/lymphocyte), human herpes virus 6,7 (primary target: monocytes/lymphocytes&epithelial cells 6: salivary glands&neurons/site of latency: T cells),
what are the gamma herpes viruses?
epstein-barr (primary target: B cells&epithelial cells/site of latency: B cells), and kaposi’s sarcoma herpes virus (primary target: lymphocytes/site of latency: B cells)
how do herpes viruses attach to target cells?
herpes attach via proteoglycans (specifically heparin sulfate), herpes entry mediators (HVEM), but EBC uniquely binds to complement receptors
how do herpes viruses enter and uncoat?
herpes viruses fuse the plasma membrane of target cells and the capsid along with some tegument proteins migrate to the nucleus and uncoating occurs at the nuclear membrane. other proteins and mRNA remain in the cytoplasm
what are the 2 things that can happen when viruses enter cells?
productive infection or latency
how do herpes viruses go into latency?
the genome is maintained as circular, extrachromosomal DNA and minimal viral transcripts & few or now viral proteins are expressed
how do herpes viruses cause productive infections?
productive infection is accomplished via genome replication/viral gene expression in 3 steps: immediate-early (alpha genes), early (beta) genes, and late (gamma) genes
what do immediate-early alpha genes do?
encode alpha proteins: DNA-binding proteins important for regulation of transcription
what do early beta genes do?
encode beta proteins (transcription factors/enzymes) inhibit expression of alpha genes, initiate viral DNA replication, shut down host cell replication, transcription and protein synthesis, initiate expression of late genes and minor structural proteins
what do late gamma genes do?
encode gamma proteins and major structural proteins
how does assembly and release occur with the herpes simplex virus?
the genome is replicated in the nucleus which is also where some structural proteins are brought. the virus buds into the inner nuclear membrane and fuses with the outer nuclear membrane, releasing the nucleocapsid into the cytosol. additional tegmental proteins associated with the nucleocapsid and the virion buds into and exocytic vesicle. the virus is finally released from the cell via exocytosis
what is acyclovir?
a guanosine analogue given to inhibit herpes virus DNA synthesis that is first phosphorylated by viral enzyme thyminidine kinase to give the triphosphate or active form of the drug, (host enzymes can add phosphate 2,3)
why are drugs like acyclovir only active in replicating cells?
b/c host kinases don’t phosphorylate acyclovir well and viral thymidine kinase is only active when viruses are replicating
what does the triphosphate form of acyclovir inhibit DNA synthesis?
it is missing the -OH group that the normal dGTP it competes with has, and without that you get chain termination
which herpes viruses is acyclovir active against?
HSV is most efficient at phosphorylating VZV, and CMV doesn’t encode a thymidine kinase so it has no action agasint CMV
can acyclovir inhibit a latent infection?
no, only productive infection
how can viruses resist acyclovir via thymidine kinase?
the gene encoding thymidine kinase can be lost, (however resistant viruses are less virulent). there can also be a mutation in thymidine kinase that reduces its affinity for acyclovir. neither of these are great problems clinically.
how can viruses resist acyclovir in terms of DNA polymerase? who is this seen in?
a mutation in the DNA polymerase inhibits binding to the acyclovir triphosphate, and this is clinically significant b/c these viruses can retain their virulence. this is seen in immunocompromised hosts w/recurrent HSV necessitating prolonged acyclovir tx
is the herpese DNA polymerase host or virally encoded?
virally
what are some other nuceloside analogues designed to stop DNA synthesis of herpes?
valacyclovir, which is hydrolyzed in the liver & intestines. penciclovir, which is the same as acyclovir, but it does not cause chain termination and is available for topical use. farniciclovir, which is deacetylated and oxidized to penciclovir. trifluridine, which is phosphorylated by host cell enzymes and inhibits both viral & host DNA – therefore it is not used systemically (only used topically)
what is ganciclovir? what is it active against?
ganciclovir is a guanocine analogue that is active against CMV
what is valganciclovir?
a drug that is hydrolyzed to ganciclovir by intestinal and hepatic esterases
what is the mechanism of action for ganciclovir? does it have activity against other herpes viruses?
ganciclovir is phosphorylated by protein kinase phosphotransferase (UL97) which is encoded by CMV, however host enzymes can also use ganciclovir, leading to some toxicity (though it does inhibit viral DNA polymerase preferentially over host DNA polymerase). ganciclovir completely inhibits the incorporation of dGTP into DNA, leading to chain termination. it does have activity against other herpes viruses (CMV, HSV, VZV, EBV, HHV 6,8)
how can resistance be made against ganciclovir?
point mutations in the UL97 gene can lead to inability to phosphorylate the drug and a mutation in the CMV DNA polymerase can lead to less affinity for ganciclovir triphosphate
what is cidofovir?
a cytidine analogue that already has the 1st phosphate, (2,3rd can be added by host enzymes), so the active drug is present in both infected and uninfected cells. it does have a higher affinity for viral DNA polymerases than host however. it competes with dCTP for incorporation into DNA
what is cidofovir used for?
cidofovir can be used for CMV (retinovirus), HSV-1,2, EBV, HHV-6,8, adenovirus (experimentally) and HPV
how can there be resistance to cidofovir?
mutations in the DNA polymerase.
can acyclovir-resistant HSV (due to mutations in thyminidine kinase) be treated with cidofovir?
yes
what is foscarnet? what does it bind to?
a pyrophosphate analogue that prevents cleavage of pyrophosphate from dNTPs, stopping DNA synthesis. it can bind to herpes virus DNA polymerases as well as HIV reverse trascriptase. it does have a higher affinity for viral polymerases than host polymerases
when is foscarnet used?
foscarnet is used for ganiciclovir and cidofovir resistant CMV
what diseases do the alpha herpes viruses cause?
HSV-1)primary:oral herpes/gingivostomatitis/genital herpes (10-20%)recurrent:cold sores, fever blisters. HSV-2)primary:genital herpes 80-90% secondary:genital lesions VZV)primary:chickenpox/varicells secondary: shingles/zoster
can HSV cause encephalitis?
yes
can HSV-2 cause oral and neonatal herpes infections?
yes
what is herpetic whitlow caused by?
HSV-1,2 on the finger
what causes herpes gladiatorum?
HSV-1 on the skin
what do the lesions for HSV and VZV appear as? are the infectious?
clear vesivles on erythematous base that start as pustules->ulcers->crusted lesions. the fluid in the lesions do contain infectious virus
how is oral herpes (HSV-1) transmitted?
the virus is transmitted through saliva and remains localized at the oral mucosa. it enters the neurons at the site of infection and travels via retrograde transport to the trigeminal ganglion where it establishes a latent infection
is the initially HSV-1 infection usually worse than reactivated one?
yes, however it can also be asympomatic
what is the pattern of transmission for genital herpes (HSV-2)?
it is sexually transmitted and remains localized at the genital mucosa. it enters neurons at the site of infection and travels via retrograde transport to the sacral ganglion where it establishes a latent infection
can HSV-2 be shedding even if it doesn’t appear as large lesions?
yes, micolesions can shed even when there are no apparent symptoms
how is VZV transmitted?
through respiratory droplets that are breathed in, taken to lymphatics which brings the virus to the liver, spleen, reticuloendothelial system, T cells causing viremia (fever, malaise, headache) and macules->papules->vesicles->pustules->crusts on the skin, and finally latency in neurons
what is a major difference between HSV and VZV?
VZV disseminates, HSV remains localized
what is herpes stromal keratitis? what does it cause?
an autoimmune disease of the eye where the viral protein contains the same sequence as the protein in corneal cells and the viral antibody binds to corneal cells. this causes clouding of the eye, progressing to blindness. it is a leading cause of infectious blindness in developed countries
what is herpetic whitlow? how does it happen?
HSV enters through breaks in the skin on the fingers. it can happen to healthcare professionals treating pts with HSV or a child w/HSV who sucks his thumb
what is herpetic gladiatorum?
HSV enters through breaks in skin; often seen w/wrestlers
what eczema herpeticum?
pts with eczema get HSV transmitted through the resultant breaks in skin
how can encephalitis be caused by HSV? what are the symptoms?
HSV-1 is the leading viral cause of sporadic encephalitis. the symptoms include influenza-like symptoms along with lethargy, confusion, seizures & coma. HSV-2 rarely causes encephalitis except in cases of neonatal herpes, but it can cause meningitis
what is the primary concern with HSV-2 infected mothers giving birth?
primary infections place the baby at highest risk for neonatal herpes. if the mother has already had a primary infection and is just experiencing a re-infection, then she already has antibodies to it that have been passed onto the fetus. the primary infection can however be asymptomatic. transmission can also occur through nursing or nosocomially.
what are the symptoms of neonatal herpes?
lesions on the skin, eyes, and mouth. if the virus stays localized there and doesn’t disseminate = low mortality. however, if the virus disseminates, encephalitis, pneumonitis, hepatitis, cardiovascular involvement and meningoencephalitis can occur = high risk of mortality
what is a complication of VZV that occurs in 20-30% of adults?
varicella pneumonia, a possibly fatal complication
how does latency occur with HSV? what is expressed while HSV is latent?
the capsid travels up the axon to the nucleus, where a low level of replication is possible and the genome is maintained (nonintegrated). LATs are expressed during this time from a single promoter and do not encode viral protein, just regulatory miRNA
what do LATs do that are expressed by latent HSV?
this miRNA inhibits translation of mRNA affecting signaling pathways and blocking apoptosis <- possible vector for treating latent HSV infections
are viral proteins expressed during HSV latency? can T cells detect infected cells with laten virus? is VZV latency similar to HSV?
viral transcripts, but not viral proteins are expressed during HSV latency. T cells cannot differentiate cells infected with latent virus. VZV latency is similar to HSV, (but with VZV there are some detectable proteins/RNAs during latency)
what can trigger HSV reactivation?
UV radiation, fever, emotional/physical stress, menstruation, spicy/acidic food, immunosuppression (HIV, chemotherapy)
what must first happen for HSV reactivation to occur?
a low level of productive infection in the neurons, then the infectious virus travels down the axon to the site of initial infection and triggers a productive infection in nearby permissive cells. however, the host should be able to clear the infection more quickly.
how does reactivation compare between HSV and VZV?
HSV reactivation is cold sores/genital lesions at the site of primary infection. VZV reactivation is in the form of shingles (zoster) at the site where the virus entered the neuron. with HSV, reactivation can occur multiple times, but only 1 episode with VZV. probability of HSV reactivation decreases with age, while VZV reactivation risk increases with age
how is cytomegalovirus (a beta herpes virus), transmitted?
CMV is transmitted through exposure to contaminated saliva, blood transfusions, sexual transmission, organ transplants, in utero, at birth, and during nursing
where does CMV productive infection occur?
fibroblasts, epithelial cells, macrophages and others. however infection in the kidneys & heart is generally asymptomatic. if CMV infects ductal epithelial cells, the virus will be excreted in body fluids
where does CMV latent infection occur? when does reactivation occur?
monocytes, stromal cells of the bone marrow and others. reactivation is frequent, but only disease-causing in hosts (can then lead to serious disease)
what are the 2 ways that CMV infections can manifest themselves?
in a normal host CMV is asymptomatic, though mononucleosis is possible. in the baby of a seronegative mother (primary infection), cytomegalic inclusion disease is possible, and AIDs/immunosuppressed pts, multisite symptomatic disease can manifest itself
what is the most common viral cause of congenital disease? how is transmitted?
CMV inclusion disease, which is usually the result of the mother’s primary infection during pregnancy (can cross placenta). if there is a reactivation during pregnancy, the maternal antibody should be protective (even if the baby is infected, it should be healthy)
what are symptoms of cytomegalic inclusion disease? how is it diagnosed?
symptoms of CMV affect the CNS and RES including: microcephaly, intracerabral calcification, hepatosplenomegaly, and rash – all/any of which can lead to hearing loss, visual impairment, and mental redardation (mental retardation: most common consequence of congenital CMV infection). it is diganosed by isolating the virus from the infants urine during the first week of life
what is perinatal infection with CMV? who is at risk for this? how is it diagnosed?
transmission occurs during birth, breastfeeding or transfusions. it is usually asymptomatic, but the infant will shed virus for an extended period of time. the newborn of a seronegative mother is at risk for clinical disease if exposed to CMV, (can result in pneumonia/hepatitis). it can be diagnosed at 3-4 wks through the infant’s urine.
how does CMV function as an opportunistic pathogen? what are the most common symptoms? can it affect organ transplants?
immunocompromised individuals are at risk for serious disseminated disease if infected with CMV. the most common symptoms are pneumonia and encephalitis, but retinitis, colitis, or esophagitis are common manifestations in AIDs pts. it can also be responsible for the failure of kidney transplants.
who has huma herpesvirus 6,7 (beta herpes viruses)? where do they replicate? where are they latent?
they are ubiquitous and primary infection usually occurs early in childhood. they replicate in salivary glands and latently affect T cells and monocytes
what are HHV 6,7 associated with clinically?
they could be associated with exanthem subitum (HHV 6) and may contribute to morbidity in AIDs or following transplants
what is the progression of exanthem subitum/rosecola infantum?
an infant is infected with HHV6, incubation occurs for 4-7 days, a high fever for 4 days, the fever breaks/rash appears, and then recovery w/out complications.
where does the epstein-barr virus (gammaherpes virus) bind? where is this expressed?
to complement receptors CR2 or CD21 (C3b receptor) expressed on B cells and epithelial cells of the oropharynx and nasopharynx. MHC class II molecules are used as co-receptors
what EBV antigens are associated with a productive infection? are there other viral products detectable besides antigens?
early antigen (EA), viral capsid antigen (VCA), and membrane antigen (MA). a transcription activator protein called “zebra” is also detectable which activates immediate early genes and sends the virus through the lytic cycle. zebra is not expressed in latent or immortalizing infections
what antigens are expressed during non-productive EBV B cell infection? when are these seen?
EB nuclear antigens (EBNAs 1,2,3A,3B,3C), latent proteins (LP), latent membrane proteins (LMP 1,2 – have oncogene-like activity), and 2 small EB encoded RNA molecules (EBER). non-productive antigens are seen during latency, immortalization or tranformation infections.
what happens with EBV during latency? where does it occur?
EBV’s non-integrated plasmid like genome replicates during cell division in memory B cells (in the presences of T cells). only EBNA and LMP-1 are expressed and a low level of viral protein expression minimizes potential to trigger the immune response.
how are B cells immortalized by EBV? are immortalized cells transformed?
B cell growth is stimulated by B cell mitogen which prevents apoptosis. EBNA and LPsa are involved as DNA binding proteins. immortalized cells are not necessarily transformed cells.
what do B cells immortalized by EBV do? what happens to them?
B cells immortalized by EBV are stimulated to divide and secrete antibody (polyclonal activation – not necessarily for EBV), as well as heterophile antibodies (which can be screened for (IgM that recognizes antigens on animal RBCs). EBV immortalized B cells are eliminated by CD8 T cells (activation and proliferation of T cells = mononucleosis)
what is infectious mononucleosis?
a consequence of the T cell response to EBV infected B cells. mononuclear cells increase, (60-70% of total WBC), and large/atypical cells called Downey cells compose 30%
how long is the incubation perioid for mono? what are clinical symptoms? what is the duration?
30-day long incubation period. symptoms include: fatigue, fever, pharyngitis, enlarged lymph nodes & spleen, possible signs of hepatitis, rash if treated with amoxicillin. the acute phase lasts 2-4 weeks, but low-grade fever and malaise may last months
what are the clinical symptoms to look for in mono? what is positive lab data?
fever, lymphadenopathy/hepatosplenomegaly, pharyngitis, malaise&fatigue, and virus in saliva. positive lab data: atypical lymphocytes and heterophile antibody titer serologic data: anti-EA, anti-VCA early, and IgG, anti-EBNA later
can EBV be reactivated?
the virus is latent in memory B cells and can reactivate if activated, it is common in tonsils/oropharynx (where virus is shed), and reactivation is asymptomatic
how is mono diagnosed?
observance of circulating WBCs (also downey cells – large atypical T cells), detection of heterophile antibodies, (via monospot test, EIA from end of 1st week ->several months), nucleic acid hybridization, immnofluorescent dectecion of viral antigens, and serology
what is acute EBV infection confirmed by? why is EBNA antibody not seen until later in the infection?
IgM to VCA, but no EBNA antibody. towards the end of the acute phase, increased antibody titer to VCA/EA may occur. EBNA antibody requires lysis of infected cells, which occurs as T cells clear the infection, a process associated with resolution of the infection.
what does detection of both VCA and EBNA antibodies detect?
previous infection
when are heterophile antibodies seen with EBV infection?
acute phase
when are VCA-IgM antibodies seen with EBV infection?
acute phase
when are VCA-IgG antibodies seen with EBV infection?
at every phase
when are EA antibodies seen with EBV infection?
late acute and reactivation (or any of the EBV-associated diseases)
when are EBNA antibodies seen with EBV infection?
at every phase except acute
what is burkitt’s lymphoma? what is associated with the tumors?
a monoclonal B cell lymphoma of the jaw and face. it is most prevalent in children and young adults in africa, (malaria is though to be a cofactor by inducing a kind of immunosuppression). EBNA-1 and EBV DNA are associated with tumors and the tumor cells contain chromosomal translocations that place the C-myc next to an active promoter
what is X-linked lymphoproliferative disease?
this occurs in individuals with congenital deficiencies in T cell function, thus they are unable to clear activated B cells and a polyclonal leukemia-like B cell proliferative disease results
how can EBV affect AIDs pts?
people lacking T cells cannot control polyclonal B cell activation by EBV. this can lead to leukemia-like B cell proliferative disease & lymphomas. transplant recipents and AIDs pts are at risk from both primary exposure and reactivation of the virus
what is hodgkin lymphoma? how is EBV related to it?
HL is a lymphoid neoplasm of B-cell origin, and the neoplastic cells are called Reed-Sternberg cells which EBV genomes are associated with in 3 of the 5 HL subsets
can EBV be associated with nasopharyngeal cancer?
yes, EBV DNA is associateed with cancer cells in epithelial cells lining the nasopharynx (which is most prevalent in chinese males)
what is hairy oral leukoplakia?
lesions in the mouth caused by a productive EBV infection of epithelial cells
what AIDs defining illness is associated with human herpesvirus 8? how is this herpes virus transmitted? what cells does it infect?
HHV 8/KSHV has been linked to tumor cells in Kaposi sarcoma, an AIDs defining illness. HHV 8 is sexually transmitted and infects B cells, vascular endothelial cells, perivascular spindle cells and others
what stages of kaposi sarcoma are associated with KSHV? is KSHV associated with both AIDs and non-AIDs related kaposi sarcoma?
all stages of kaposi sarcoma are associated with KSHV. KSHV sequences are also associated with both AIDs and non-AIDs related KS
what cellular proteins with a specific function do KSHV proteins express homology with?
KSHV proteins share homology to cellular proteins that promote growth and inhibit apoptosis
is it likely that someone infected with both HIV and KSHV will develop KS?
17% of co-infected will develop KS
what is an association between KSHV and the prostate gland?
KSHV sequences have been associtaed with abnormal tissue from prostate glands and the infection is thought to be latent in glandular epithelial cells of prostat glands (virus could be shed in prostate secretions)
what kinds of lymphomas have been associated with KSHV?
KSHV sequences have been associated with body cavity-based lymphomas, a rare form of AIDs-related B cell lymphomas
what is multicentric castleman’s disease?
a lymphoproliferative disease that can be associated with KSHV
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