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Herpesvirus, DS, Linear, Enveloped Icosahedral (Large, “friend egg appearance”). Hepadnavirus, DS, Circular, Enveloped icosahedral, Pleomorphic/ filamentous. Adenovirus, DS, Linear, Naked Icosahedral. Papovirus – DS, Circular – Naked Icosahedral. Now Papillomavirus & Polyomavirus. Poxvirus, DS, Linear, Multi-enveloped, ovoid brick (Largest virus, can be seen by light microscopy, double enveloped “brick” shape”. Parvovirus, SS, Linear, Naked Icosahedral (Smallest viruses) Naked DNA virus need PAPP (Parvo, Adeno, Papillo, Polyo)
DNA viruses replicate in Cell’s nucleus (except Poxvirus). Intranuclear inclusion = DNA virus. Pox viruses is seen as cytoplasmic inclusions but is so large it isn't RNA viruses. DNA viruses express proteins in a coordinated fashion: 1) Immed, Early(alpha): Regulatory/evasion proteins. 2) Early (beta): Regulatory/Replication Proteins. 3) Late(gamma): Structural (make capsid). In general, viruses encode a DNA polymerase & genomic replication machinery:
Reasons for eradication: No subclinical infection, narrow host range, life-long immunity & virus clearance (ie no carrier state)
Symptoms: Upon initial infection, VarV has an incubation of approx. 12 d followed by synchronous evolution of lesions (VZV lesions are discontinuous).
Lesions 1st appear as mild rash then maculopapules then vesicles then pustules then scabs then scar.
Clinically: 12d incubation. 1-2w for progression above. Small pox virus prefers cooler temps thus found on extremities
Unusually stable virus:chemical or physical agents and adverse pH conditions. Allowing for prolonged survival outside of body and water
Direct cell damage by replication although (much damage is from host cell immunity). Co-infection involving the eye can be used to distinguish flu-like symptoms w/ an conjunctivitis as an Adenovirus. Adenoviral infections can present as: tonsilitis, strep throat, ear infection, Croup, bronchiolitis, pneumonia, viral meningitis, encephalitis, & rarely hemorrhagic cystitis (inflammation of urinary bladder)
Epidemic conjunctivitis – sporadic – acute follicular conjunctivitis. Steroidal suppressant eye drops can make eye look better but pt still shedding virus
Epidemic keratoconjunctivitis – common affliction across all ages. Virus can be passed in swimming pools that do not have enough chlorine
Sporadic acute follicular conjunctivitis – benign conjunctivitis, most common eye infection
Vascularization of sclera & cornea b/c of host immune response. Tx: No licensed antivirals; Ganciclovir in trials. Cidofivir works but is toxic to eye & kidney
Gastroenteritis: Some w/ adenovirus gastroenteritis may shed virus in their stools for months after symptoms. Enteric adenoviruses (types 40 & 41) cause diarrhea in young children; 2nd only to Rotavirus as a major cause of infantile viral diarrhea
Meningoencephalitis: Common among children & immunocompromised pts
Acute hemorrhagic cystitis: disease occurs almost exclusively in male children. Symptoms – urinary frequency, bladder pain, & gross hematuria
Replication gene is required, Cap gene encodes capsid proteins. Hint: Parvus means small (virus is so small it is packaged one strand of DNA). B/c of limited # of genes & size, cells must be in S (synthesis) Phase for replication.
Transmission: Aerosol (Respiratory), Transplacental, highly transmissible, 60% of Adults are seropositive
Needs epithelial cells in the S (synthesis) phase or needs helper virus (Adeno/Herpes virus).
Can also infect erythroid progenitor cells (which are constantly dividing) causes destruction & will destroy endothelial cell of blood vessels (lowers RBC counts)
Infection helper dependent parvovirus DNA integrates into chromosome 19 then Superinfection w/ helper virus then Lytic replication & virion release
Direct cell damage caused by viremia, & humoral immune response against infected cells is implicated in damage of infected tissue. Approx. 60% of population has Ab for Parvovirus B19.
P – Pregnancy associated hydrops fetalis
A – Aplastic Anemia & Arthritis
Arthritis: Joint Pain/Soreness (adults) – Anti-nuclear antibody & rheumatoid factor positive
Immunocompromised host = chronic relapsing anemia.
R – Rash-meculopapular erythema infectiosum
Diagnosis: Serology, PCR, DNA probe. Rubella is main DDx. Tx: No vaccine, tx symptoms (blood transfusion)
5th disease (erythema infectiosum – common) Rash & arthralgia; “Slapped Face”
Symptoms (7d) = Malaise, Fever, Headache, Chills, Myalgia, Maculopapular Rash
3 Stages = 1) Both Cheeks, 2) Maculopapular on trunk & Limbs (1-4d post cheeks) 3) Periodic Evanescence and recrudescence lasts 1-3w
Ddx for Maculopapular rashes = 1) Measles 2) Step pyogenes 3) Rubella 4) Entero/Echo/Coxackie virus 5) Parvovirus B19 6) Roseolo; HHV6
Structure: Large dsDNA virus. Enveloped
Tropism: Epithelial cells, Multiple Cells, Neurons
Transmission: Sexual, & for VZV = Aerogenically
Pathogenesis: HSV-vesicular exanthema (fever blisters, labialis genitalis); VZV – primary chicken pox reactivated to shingles/zoster
Associated Diseases: Persistent lifelong infection, recurrent, for HSV - Severe disease in neonates & immunocompromised pts)
Diagnosis: Cultivation, Serology (problematic), PCR
Vaccine/Therapy: None (HSV); VZV live attenuated vaccine; Nucleoside Analog Prodrugs for treatment:
Tropism: Epithelial cells, multiple cell types, neurons. Transmission: Contact, Kissing, Sexual
Pathogenesis: HSV-vesicular exanthema (fever blisters, labialis, genitalis). Infect neurons & cause neurological & CNS diseases; Leading cause of infectious corneal blindness. Primary infection/Lytic infection: No detectable Ab. Latent infection: After primary, Viral DNA persists in target cell (typically a cell in an immuno- priveledged site). Patient is OFTEN serologically positive Recurrent infection: Reactivation of latent genome, symptoms @ site of initial infection
From mild to severe, persistent lifelong infection, often recurrent; For Simplex virus can be associated w/ severe disease in neonates + immunocompromised pts
HSV-1: Encephalitis, Pharyngitis, Esophagitis, Tracheobronchitis, Genital, Whitfow
HSV-2:Encephalitis, genital, perianal, Neonatal HSV
Serology isn't good for active HSV infection. Pts typically positive (60-70% of the population is positive for HSV). HSV 1 + HSV 2 can cross react so to tell them apart use the Tzanck Test - Histological determination of HSV-1 & HSV-2 infection (also works for VZV). HSV-1 & HSV-2 are distinguished by IFA/ELISA Ab type specific assays against glycoprotein G. For possible HSV encephalitic cases: do PCR on CSF (Most rapid diagnosis) [replaced the brain biopsy]
Access body via mucosal surfaces/skin breaks. Causes cold sores; sore throat + fever; Rarely pt gets encephalitis. HSV-1 is less frequently a genital infection (if it is then latent in the sacral ganglia & NOT trigeminal). Lesion progression: Tingle, Edematous ulcer, rupture, scab, healing in 1-2w
Leading cause of infectious corneal blindness in developing countries. Disease is virus but damage is from the immune cells
Viral eye infections: HSV-1, HSV-2, VZV, CMV.
1)Trauma – virus is replicating in the epithelium
2) Infections – clouding of the eye is due to T cell proliferation; 3) Inflammation
4) Neovascularization – eye is normally avascular in nature (can’t see through bv
Pt will need corneal transplant even w/ tx w/ anti-viral b/c damage to the eye is T-cell mediated
(25-30% prevalence in the US)
Primary infection = vesicular eruptions on the genitalia. Less frequently found as Herpes Labialis (cold sores)
Transmission: Sexual contact, affects both sexes, once associated w/ Cervical carcinoma (its HPV)
Acquisition-Epidemiology: In US about 50 million ppl have HSV-2: more common in women (approx. 20%)
Extremely dangerous if HSV untreated/not diagnosed rapidly (mother's infection may not be apparent but need to do a C-section! (85% of children will die). No protective immune response so viremia & organ detruction & ulcers throughout
Neurological Complications:In utero (5% of infections); Intrapartum (75-80% of infections) Must make sure mother doesn’t acquire HSV-2 during pregnancy; Post-natal: HSV-1 (asymptomatic mother/father shedding virus & kissing neonate
Divided in 2 goups: Neuronal Herpesviruses = HSV-1, HSV-2, VZV, Herpes B/Monkey B & Leukocytic herpesviruses = beta + gamma herpesviruses, CMV (monocytes), EBV (B cells), HHV6/7/7 (Leukocytes)
Establishment of latency - Primary infection then suppression by immune system. Transport capsid & establish latency w/in cell body of the neurons. Asymptomatic (No virus or virion proteins produced) & Viral DNA resides in sensory cells of the nerve ganglia
Viral DNA exists in genomic form as an episome (Circular) w/in the cell body
Lytic cycle genes are transcriptionally & functionally quiescent (another evasion tactic)
Only a stable intron of HSV RNA is expressed during latency = LAT transcript (fxn unknown)
Upon stressor (sun, stress, hormones) virus replicates & travels down sensory nerve fiber to infect epithelial cells around nose & mouth. Symptoms: Milder form of 1st infection b/c of immune response. Infection of the eye can occur from reactivation & self-inoculation
Over 50% acquire HSV before the age of 6; 33% of seropositive individuals have recurrent infections:
80% don’t know they are infected. Post-pubescent acquisition of this virus can lead to severe disease. Don’t want to get this as a neonate or as a teen
Up to 30% of adults are infected w/ HSV-2 (50 million Americans)
Recurrence: 1/3 have > 8/9 outbreaks a year, 1/3 have 4-7 a year, 1/3 have 2-3 per year
Less severe presentation than the 1st infection. HSV-1 genital infections are less likely to recur/reactivate
Being infected w/ HSV-1 in the genitals is somewhat protective against HSV-2 infections @ the genitals
Co-infections b/c the same groups are at risk.
HSV-2 is an important co-factor for HIV acquisition. Almost ½ of HIV transmission can be contributed to HSV-2 infection. Believed that persistent inflammation against subclinical recurrence of HSV-2 leads to high lvls of HIV infection
HSV-2 damages the mucosal barrier & attracts CD4+ T cells (target of HIV) to the site making HIV infection more likely
Often in pts w/ high Ab titers (an indicator of continuous reactivation/replication in neurons)
Virus is transported from peripheral nerves to olfactory bulb then into brain.
Classically HSV-1 affects the Temporal lobe: focal neurological signs + edema
Ddx – Brain abscess, tumor, intracerebral hemorrhage
Tx – I.V. Acyclovir can reduce morbidity + mortality w/ early diagnosis
Structure: Large dsDNA virus, enveloped
Tropism: Epithelial cells, T cells, Neurons
Transmission: Aerogenic transmission w/ communicability highest just prior to rash onset; virus rarely isolated from crusted lesions. 90% communicability rate
Associated Diseases: Disseminated Chicken pox on primary infection & Shingles w/in an isolated dermatome on reactivation: Post-herpetic neuralgia
Upper respiratory tract then regional lymph nodes to primary viremia. Enters reticuloendothelial systems + initiated secondary viremia & finally infection of T cells and skin.
1 virus but 2 diseases (Herpes Varicells/Chicken pox + Herpes Zoster/Shingles) Shingles = Usually unilateral recurrence/reactivation
Infections in seasonal epidemics Contracted from an infected individual (90% transmissibility)
Systemic infection results in generalized, vesicular rash. Crops of vesicular lesion on neck + trunk, highly pruritic, high fever. Usually no scarring from virus but can scar from bacterial superinfection.
Complications of VZV infections = Pneumonia, Severe infection in immunocompromised, Bacterial superinfection (eg group A strep). DO NOT TX kids w/ Asirin or siacylated
Asymptomatic w/ no virus or virion proteins produced. Viral DNA resides in the cells of the dorsal root ganglia
Virus travels down the sensory nerve fiber, infects epithelial cells innervated by fiber. Usually a single dermatome (Extremely painful if on face)
Infections: Unilateral, single dermatome, painful vesicular eruptions typically head or upper trunk
Severe systemic infections are seen in immune suppressed individuals
Complication of Shingles
Very painful, lasts for months after Shingles resoles, doesn’t respond to antivirals, likely due to the nerve damage from zoster outbreaks. Must manage psychological state, suicide common
Tic douloureux - even more painful if on face
VZV vaccine given as multivalent MMRV
Live attenuated vaccine (Rarely a mild rash)
2 doses; given as post-exposure prophylaxis if administered w/in 3d of exposure.
Zostavax: vaccine for shingles, live attenuated vaccine for adult > 60yo (much higher titer of virus in this ie not for children). Stimulates cell immunity (b/c of high dose). Lessens probability of post-herpetic neuralgia (given after shingles) Zosravax contraindicated in immunosuppresed
Drug activity relies on activation by viral Thymidine kinase (TK)
TK phosphorylated prodrug, then cellular kinases phosphorylate again to activate drug (3phosphates)
Important: 1) Activated by a viral gene 2) Causes inhibition of DNA chain replication + inhibits DNA polymerase
Acyclovir used against HSV-1, HSV-1, VZV
Mechanism of Action: Incorporation of acyclovir-triphosphate into elongating viral DNA chain terminates virus genomic replication; Also inhibits viral DNA polymerase by competing w/ dGTP
Mechanism of Drug resistance: Alter or mutate the viral Thymidine Kinase or viral DNA polymerase
Resistance to Acyclovir = resistant to derivatives (Secondary antivirals – Valacyclovir + Famciclovir)
Some DNA polymerase mutations can make the virus resistant to both Acyclovir Foscarnet/Cidofovir
A cytosine nucleoside analog: phosphorylation “activation” not dependent on viral enzymes
Uses: CMV*, HSV-1, HSV-2, VZV, EBV, HHV-6, Adenovirus, & HPV lesions
Side effects: Nephrotoxicity (major reason generally not used but sometimes it’s the only choice! Nephrotoxicity can be prevented w/ Probenecid [a gout medication]) Nephrotoxic b/c Cidofovir induces apoptosis of renal tubular epithelium
Resistance = mutation in DNA polymerase
Inorganic pyrophosphate, inhibits viral DNA polymerase, RNA polymerase, & HIV RT
No need phosphorylatation from viral protein (good!)
Uses: HSV, VZV, CMV, HHV-6, HBV, & HIV
Side effects: this drug inhibits DNA replication so it can have major side effects. Hypo/Hypercalcemia & Phosphatemia; Renal failure, Genital Ulcers
Tropism: Epithelial cells, neurons, CNS. Transmission: Needle,scratch, bite, spit Pathogenesis: Incubation 5-30d; Replication @ entry site. 1st systemic infection - prodrone “flu-like symptoms'. Early neurological = Paresthesias, disorientation, Dysphagia. Late neurological: Progressive paralysis; Encepho-myelitis, Coma, Death. (75-80% Fatality) Severe neurological disorders for survivors; Diagnosis: Cultivation; PCR, HISTOLOGY, test animal. Vaccine/Therapy: None. Post exposure: Wound cleaning, prophylactic Acyclovir (via IV)/ Gancyclovir
Symptoms: Chronic fatigue (weeks), Sore throat/ Swollen tonsils w/exudate, Chills/fever, loss of appetite, nausea/occasional vomiting.
Recommended to avoid contact sports during & 2w after infection subside
more prone to severe CMV disease such as pneumonitis, retinitis, colitis, & encephalopathy.
Reactivation or reinfection w/ CMV is usually asymptomatic except in immunocompromised pts
Diagnosis of CMV cannot be made solely on clinical grounds, need labs (sample urine, saliva, blood, tissue, amniotic fluid, BAL. CMV = labile virus & can grow in fibroblasts cells (MRC-5) & produces “giant cell” CPE. Virus growth is slow (2w for results). CMV causes large Cytomegaly (enlargement of cell) Pronuclear inclusions “owl eyes” on histo. (Culture or PCR (id CMV DNA in leukocytes, serum, plasma, etc) & CMV RNA in peripheral leukocytes diagnosis CMV infection. DEAFF (Detection of Early Antigen Fluorescent foci) – Detects IMMEDIATE (w/in 1st few hrs) early protein & pp65 antigenimia assay.
An inflammation of the eye’s retina that can lead to blindness
Associated w/ cotton wool spots and bloody lesions (“Ketchup + mustard” appearance)
Fomivirsen (brand name Vitravene) is the 1st antisense drug. Administered as an intraocular injection
2m after transplant get a Nonproductive cough, dyspnea on exertion. CXR showes profuse, mixed interstitial alveolar infiltrates. Pts w/ CMV pneumonitis rapidly develop respiratory failure & 85% will be dead w/in 2-3w. LEADING cause of mortality after allograft transplantation
Strategies to control CMV infection: Selection of CMV seronegative graft/blood donor. B/c body will attack the graft. If only option is seropositive:
Ganciclovir tx, but Ganciclovir & steroids prevent anti-CMV immunity from forming
Structure: large dsDNA virus, enveloped
Tropism: T lymphocytes, B lymphocytes, Neurons, HHV-6 integrates in DNA & can be inherited (most viruses cannot be inherited, rare even for HHV-6)
Transmission: Saliva (HHV-6B, but not HHV-6A) blood; Sexually (HHV-6A); Breast milk (HHV-7)
Associated Diseases: Ubiquitous childhood disease: Roseola infantum (aka 6th disease) Rarely febrile seizures & encephalitis; possible link w. MS & myocarditis
Primary infection: Exanthem subitum (generalized “sudden” rash on body Aka Roseola infantum (rose rash of infants) – 6th disease (6th rash causing childhood disease) + 3d fever. = 20% of all ER visits for infants w/ fever in US. Usually children > 2yo, w/ sudden high fever (can have febrile convulsions) & while child seems to recover a red rash appears) caused by HHV-6A/B + HHV-7, Rash begins on trunk, spreading to legs + neck. Rash is not itchy & may last 1-2d. Ddx = VZV (typically itchy ulcerative pruritic rash).
Wide range of clinical courses (mild or deadly in <6m
100% of pts w/ ATLL are seropositive for HTLV-1. 1-4% of infected individuals develop cancer
Histology: Mulilobular Nuclei w/ Condensed chromatin“Flower Cell” (T cell).
HTLV-1 is a retro virus (integrated into the T cell genome). Cancer occurs 20-30y post infection w/ HTLV-1
Most viruses we treat Lytic/Acute stage (b/c symptoms); Gammaherpes virus issues arise during latency (MOST serious disease w/ gamma are assoc. w/ latency). Structure: Large dsDNA virus, enveloped. Small # of viral genes drive cell proliferation causing activation of cell signaling pathways, inhibition of checkpoints, blocking of apoptotic pathways. EBV has > 100 gene.
EBV Tropism: B-lymphocytes, Epithelaial cells (95% of humans are EBV+). KSHV Tropism: Endothelial, epithelial, & B cells (Very small % of ppl who are non-HIV+ are infected)
Disease is caused by unregulated proliferation of the infected cells, assoc. w/ immunosuppression
Primary epithelial infection - B cell infection - B cell transformation - primary CTL response (keeping B cells in check) - Memory B cell quiescence - Reactivation = Lytic infection transferring back to epithelium - CTL response + renew B cell prolif.
LMP1 – activates NFkB and AP-1 pathways w/out Viral protein ligand (ie no CD40/CD40L)
EBNA2 – activates pathway w/out ligand (normal = Notch activation)
EBNA3/1 – Stop apoptosis, EBV+ cell don’t die (Most plasma apoptose)
From mild to severe, persistent lifelong infection, assoc. w/ severe disease in immunocompromised pts (AIDS defining malignancies)
Together w/ Kaposi’s sarcoma, EBV-positive lymphomas were the earliest AIDS-defining malignancies
Diseases are mostly associated w/ latency (small subset of viral genes expressed – differs from HSV w/ transcript
Defined as white patch/plaque, firmly attached to oral mucosa, vary from smooth/flat to hairy. Found all over mouth. Caused by epithelial hyperplasia – in AIDS/ Immunocompromised (Precancerous lesion). Most common viral oral disease of HIV+. Virus is shed but it's in latent phase w/in the Epithelium. Symptoms = mild pain (or painless), dysesthesia, alteration of taste, lesions resemble Candidiasis/Thrush except it CANNOT be scraped off the tongue. Other Ddx: = HPV condyloma
Uncommon in US (1:100,000); Very common in China/Taiwan (18% of all cancers)
Commonly begins in the Squamous cells lining the nasopharynx
Difficult to diagnose: early symptoms may include - lump in neck from swollen lymph node, bloody saliva/nasal discharge, nasal congestion, Hearing loss, ear infection, headache
Infection post-pubescence; EBV mononucleosis ie “Kissing Disease” (14-25yoa) Symptoms = same as b4
Is it EBV or CMV. If there are heterophile Ab (Ab against random ish that isn’t EBV) = EBV mononucleosis. B/c EBV is a mitogen of B lymphocytes. Pts produce horse/bovine/sheep Ab. Monospot (Horse RBC)/ Bunnell (Sheep) test. Issue is test isn't positive during 4-6w incubation period (prior to the onset of symptoms) or after infection is cleared even though virus persists in cells
Definition: reactive atypical lymphocyte w/ distinctive morphology commonly associated w/ viral infections (not only seen in EBV infection). Not seen normal circulating blood. These cells are generally enlarged, cytoplasm is abundant and sometimes basophilic (or gray) vacuoles are also often present. During active EBV infection, B cells increase to 50-60% of total WBC (normal is 10%). Of 50-60%, 10% of those = “atypical lymphocytes “ (5% Downey cells 95% atypical T cells)
Acute mono = rest, Acetominophen; Chronic mono = corticosteroid (Prednisone)
Prednisone suppressed IL-1a production from neutrophils (fxn = B cell proliferation). Helps reduce lymph node & tonsillar swelling; Sometimes helpful for chronic mono.
Burkitt lymphoma [1st human tumor virus id’ed], post-transplant lymphomas, Hodgkin’s disease, CNS assoc. Lymphomas, AIDS assoc/ lymphomas, Primary Effusion Lymphomas.
CNS Lymphomas (100% EBV +). Immunoblastic lymphomas (100% EBV+) – suppression of T cells in HIV, bone marrow transplant, & renal transplant. Burkitt’s Lymphoma (80% EBV+) hit&run possible. Primary effusion lymphoma (EBV/KSHV double positive). Hodgkin’s disease (50% EBV +) mainly pediatric (70%). EBV DNA in Reed-Sternberg cells. EBV Hodgkin’s disease is more aggressive
HAART & Lymphoma - lymphoma incidence rising due to HAART-dependent increase in life-span in AIDS pts.
Presentation = black/purple popular nodules on skin, also on mucous membranes. Multicentric neoplasm of multiple vascular nodules.
Characterized by highly vascularized red spindle cells. Therapy = 1) HAART 2) Radiation 3) Cryosurgery 4) IFN-a
KSHV +, about 80% are KSHV/EBV double ++
Prognosis is poor b/c resistant to therapy
Diagnosis: Serology (can be problematic), PCR, Monospot test
CHOP/CHOMP: Cyclophosphamide – damaged DNA by alkylation to block DNA replication. Hydroxydaunorubicin – intercalated in DNA, reduce gene expression, damage DNA. Oncovin – interferes w/ tubulin (blocks mitosis) Prednisone – decreases IL-1a (reduce B cell prolif.) CHOMP= M - Methotrexate
CD20 – found on immature B cells & highly expressed in B cell lymphoma.
(Mechanism: direct apoptosis, NK mediated apoptosis, Complement Activation
Polyomaviridae = SV 40 – Vacuolating virus simian virus (LgT + Polio Vaccine). JC virus – Progressive Multifocal Leukoencephalo- pathy (70% similar DNA to SV40). BK virus – Hemorrhagic systitis (80%) similar to JC virus. Merkel cell Virus – New id, Merkel Cell Carcinoma. Similarities btwn the 2 = DS, circular, DNA Small, non-enveloped virus w/ icosahedral. Differences btwn 2: Polyoma viruses: Large T (LgT) transforming protein. Papilloma viruses: E6 + E7 Transforming proteins
JC virus = Progressive Multifocalencephalopathy (PML) – demyelinating disorder, fatal in AIDS pts
BK virus = Hemorrhagic cystitis, organ transplant pts
Commonalities = Both viral infection occur during childhood. Relapse occurs during severe immune suppression. Remain latent in the kidney (BK & Archetype JC), while disease causing variant of JC remains latent in lymphocytes + brain
Archtype JC virus doesn’t progress to disease
Structure: Small dsDNA virus, circular, non-enveloped.
Tropism: Epithelial cells; Neurons; Oligodendrocytes; Astrocytes
Vaccine/Therapy: No vaccine, possible Tx w/ Ribavirin & Cidofovir
Associated Disease: Progressive Multifocal Leukoencephalopathy
Demyelination + abundant Foamy Macrophages but relative preservation of axons. Viral inclusions fill enlarged oligodendroglial nuclei
Clinically: Insidious onset of weakness, impaired speech + vision, mental slowness. Due to oligodendrocytes destruction. Progress to cognitive deterioration, paralysis blindness, sensory abnormalities, & death. Diagnosis: Suggestive CT/MRI changes – PML lesions in subcortical white matter, no contrast enhancement or mass effect. Biopsy w/ pathology, immunostaining, EM/PCR for JC virus in CSF.
A LOT of monoclonal Ab drugs have a common side effect of PML
Hemorrhagic cystitis = diffuse inflammation the bladder (dysuria, hematuria, & hemorrhage) Associated w/ BK virus but can be associated w/ Adenovirus. Presentation: usually bone marrow transplant pts. 50% BMT pts shed BK virus in high lvls. Correlation btwn symptoms, virus, but unclear pathology. High lvls of virus being shed = greater symptoms. Diagnosis: Viral culture, pathology, EM, ELISA, PCR. Tx: none are great. Cidofivir can decrease viruria (but nephrotoxic). Leflunomide can work (immunosuppressive & antiviral)
Diagnosis of BK-virus associated nephropathy (BKVAN) require a combination of clinical + laboratory findings.
Gold standard = id of characteristic viral inclusions from the graft
Typical inclusion in Renal Epithelial Cells – Nuclear enlargement w/ “smudgy” / “ground-glass” appearance. Clearing in cytoplasm + viral inclusions in the nucleus
Rare, aggressive skin tumor usually in older Caucasians. Located on head + neck. Rare but incidence has tripled in the last 15y – 80% of MCC have MC virus. Presentation: Older white male living an “exciting” life w/ lots of sun exposure
Pathogenesis: Sometimes MCC is a Neuroendocrine carcinoma of skin, arising from uncontrolled growth of Merkel cells in skin. 40 times less common than melanoma. Has lethal potential ie need aggressive tx. Other Risk Factors for MCC:
Being immunocompromised (eg Chronic lymphocytic leukemia or HIV or immuno-suppressive drugs), > 50yoa,
MCC tumors express CK-20 & MCV LgT
Tx – based on stage of disease
Surgical excision of primary lesion, Lymph node surgery, Radiation Therapy, Chemotherapy
HPV types 1, 2 = Plantar + Common warts
HPV types 6,11 = Condylomata & Laryngeal warts
HPV Types 16,18 = Anogenital malignancies
HPV Epidemiology Cutaneous
Plantar – types 1,2 = in adolescents + young adults
Common – types 2,1 = school aged kids (50%)
Flat – 3,10 = least common wart, Verrucous wart
Other: 7 = warts of Butcher’s, Meat packers, Fish Handlers
Risk factors: Predominant = sexual behavior, sexual intercourse @ an early age, being female, smoking, oral contraceptive use, uncircumcised partners
Overall HPV prevalence is 42.5% in US females
HPV Anogenital Warts – usually Types 6,11 (+ oral warts). Prevalence increased in past 30y. Regression of warts in 20% of cases. HIV can exacerbate condition. Warts found on shaft of penis, vulva, or around anus. Genital warts more common in men. These genotypes can also lead to oral warts
Pre-school aged children – possibly via vertical transmission
Presents w/ hoarseness or change in cry. Can lead to stridor & rarely death
Occurs in adolescents & adults via orogenital contact
Can lead to death in AIDS pts
2nd most common malignancy of women worldwide; 35% mortality (Death b/c of local invasion, not distant metastasis). Preceded by many years of persistent high risk HPV infection
Premalignant lesions develop early after infection
# of cases has declined in US over past 40y due to the Pap smear. High risk HPV preferentially infects the transition zone @ the squamo-columnar junction btwm endo/ecto cervix
Sometimes virus linearizes/integrate itself into host cell - Once this occurs pt isn't shedding virus but Association w/ integration of HPV DNA & neoplastic changes & premalignant conditions
E6 + E7 only expressed in high risk HPV types once genome integrates into host DNA (upregulation of E6 + E7 proteins) All HPV genomes have E6 + E7 proteins, however only “high-risk” types have mutated versions of E6 + E7 making proteins more malignant (increased carcinogenesis)
E6 blocks p53 telomerase and E7 inhibits pRb.
L1 – another protein that is part of HPV capsid (target of Vaccines & PCR for diagnostics).
p16 is inversely proportional to RB levels. (HPV inhibits RB aka “the brakes” on cell proliferation)
Normally p16 stimulates pRB indicating that the cell needs to stop proliferating. p16 lvls rise b/c the cell continues to try to stimulate RB (Cancer is turning the brakes “off”
RB normally suppresses p16
HPV genome linearize & integrates into the host cell DNA, initiates expression of E6 + E7
E6 of high-risk HPV types binds degrades tumor suppressor gene p53
E7 of high risk HPV types binds and inhibits fxn of tumor suppressor Rb
*E6/7 of low risk types do NOT bind/degrade/suppress p53/Rb. High risk infection - uncontrolled cell cycle - proliferation - cancer
Most clinics use Liquid Papsmears (Thinprep) = Preserves cell morphology & can genotype HPV DNA. Classic papsmear stain has several dyes
1. Haematoxylin Nuclear stain – imparts yellow color to glycogen 2. Orange keratin counterstain – staining keratinizing squamous cell carcinoma
Normal cervix has no keratin layer & outermost cells have small dense nucleus 3. Azure Eosin Y – stains superficial epithelial squamous cells, nucleoli, RBCs, cilia 4. Light green yellow dye – stains other cells
Abnormal: Dyskaryosis, microvascularization, perinuclear clearing. Dyskaryosis = 2 nuclei w/in 1 cell. This is not syncytia. 1 cell trying to divide into 2 cells but unable to do so. Besides, syncytia occurs w/ enveloped viruses (HPV is non-enveloped)
Abnormal pap shows changes consistent w/ HPV + Mild dysplasia. Note the irregular perinuclear cyctoplasmis clearing, nuclear enlargement, cytoplasmic microvacuoles
Classification of Histological finings (CIN)
1. CIN 1 : Mild dysplasia; includes condyloma (anogenital warts) (CIN 1 usually clears w/out tx)
2. CIN 2: Moderate dysplasia
3. CIN 3 : Severe dysplasia; includes CIS (in situ)
Colposcopy - Acetic acid is used to visualize abnormal epithelium (enlarged nuclei reflect light)
Advantages: Less labor intensive, not operator dependent, regulations are less burdensome. Disadvantages: Cannot detect non-HPV cervical cancers (10%), Target of PCR amplification is L1 protein (often disrupted during virus integration), No STIs detection or, glandular neoplasms (Endocervical or endometrial lesions)
Loss of L1 – once HPV DNA is integrated no longer shedding virus particles so L1 (capsid forming protein) is not essential but w/out L1 you can’t detect HPV w/ Roche test
Oral Cancer: HPV status of tumor is greatest determinant of life or death after Dx of advanced oropharynx cancer HPV + pts have 60% reduction in death after diagnosis when compared to HPV negative pts b/c the HPV + Pts are MORE responsive to TX! Most HPV associated oral cancers are HPV 16 associated. HPV vaccines protect against these types!
VLP (virus-like particle vaccine). Merck – Gardasil – quadrivalent 6,11,16,18 . Produced in recombinant yeast & absorbed w/ adjuvant amorphous Aluminum Hydroxyphposphate sulfate. Pts still infected w/ HPV but 100% did NOT get cervical cancer. Vaccines based on L1 capsid protein. Capsid varies w/ each HPV genotype so can't protect against all 120 HPV types. HPV 16,18,45 are found in 94% of all cervical cancers (18 + 45 are invasive/ aggressive). Merck has new vaccine w/ addition of 31,33,45,52,58.
dsDNA, enveloped, pleomorphic, smallest of the enveloped animal viruses. REPLICATES USING A REVERSE TRANSCRIPTASE. ONLY DNA VIRUS THAT USES AN RT. Virus replicates through an RNA intermediate (In the Cytoplasm!) Viruses uses host’s RNA polymerase. Pleomorphism – can be filamentous or capsid. Filamentous structure = HBsAg which is not infectious but outnumber virions 1000:1, "Decoy"
Birth:Vertical transmission. Pregnant mothers can pass HBV to neonates during child birth – especially HBeAg + mothers
Blood: IV drug users (sharing of needles), health care workers (accidental needle sticks), Tattoo/Acupuncture
Sexual Contact: Unprotected sex w/ infected partner whose semen, vaginal secretions, blood, saliva, enter your body. Also sharing personal items à razor, toothbrush, clippers HBV is surprisingly resistant for an enveloped virus
Symptoms w/ HBV (& HCV) develop due to Cell-mediated immune response that is primarily CTL response against the infected cells rather than the virus causing harm to the cells (cytopathic effect)
Acute symptoms overlap production of S & E antigen. This is followed by sustained Anti-HBeAb response, & an anti-HBcAb (IgM then IgG). Antigen is detected about 4w after exposure and peaks @ 12w post-exposure. Symptoms develop when HBeAg gets to a high titer. HBeAg = Diagnostic of Acute infection.
Much later Anti-HBsAb (32w post-exposure) are detected à protective and can = resolved infection + lifelong protection from HBV
Serology: Pts develop chronic disease b/c never develop Ab to HBs. Typically HBeAg is only present for 12-24w but in chronic disease is detectable 4 years. Eventually pt may or not develop HBeAb. Anti-HBcAg Ab is a marker for a pt who has been infected w/ HBV @ some time
Integrated HBV DNA is found in 75% of pts near the myc gene. EBV also integrates near the myc gene. Being positive for HBsAg (& titer) ↑↑ risk of HCC by 100x (takes 30+ y to develop cancer) Risk greatest when + for HBeAg & HBsAg. 2 Main Mechanisms of HCC Development. HBV = chronic inflammation (destroys hepatocytes) & subsequently regeneration (cell division) of damaged liver that = cancer formation. Or X-gene = weak tumorigenic, activates proteins. NFkB, Ras, JNK, Jak-STAY, Srckinase, ERK pathway, binds CREB
If antibodies against E are detected at high levels, then there is a risk of mother to child transmission.
Hepatitis panel (ELISA): Present HepB surface antigen (HBsAg) = current infection
Present Ab (HBcAb) = currently are or have been infected. PCR: Detection of E antigen – determines severity of liver infection
Liver Fxn tests: Initial diagnosis may be on clinical symptoms and liver fxn test (ALT)
Histology: “Ground-glass” appearance of hepatocytes. HBsAg expression causes observed cytoplasmic abnormalities (ie ground-glass). Only in chronic infections
Vaccination works extremely well as a preventative strategy
Subunit vaccines produced in yeast engineered to express HBsAg (contraindicated if allergic to yeast)
When the mother is HBsAg+, the vaccine is given w/ HBV IVIG for passive immunization to infant
Health care workers, lab workers, and hemophiliacs should be vaccinated (3 dose vaccine)
RT inhibitors & Interferon; Hep B Ig
Passive immunization w/ HB IVIG should occur immediately after exposure = IFN-a or pegylated IFNa may also help
Nucleotide analogs that inhibit RT are great
- Lamivudine (Epivir) – resistance is emerging
- Others: Adefovir dipivoxial (Hepsera), Entecavir, Telbivudine
Tx for HCC = tx cancer not virus; Surgery, chemo, transplant
Structure: Enveloped, satellite virus, circular --ssRNA genome. DEPENDENT ON HBV for generating infectious viruses, b/c HDV has HBsAg on its capsid surface but have gene for HBsAg. Thus needs integrated HBV DNA in the same cell to generate HBsAg. Replicates in nucleus using the hosts RNA polymerase II - to make more RNA (RNA to RNA) which is odd b/c this RNA polII normally makes RNA to DNA. Has 1 open reading frame & 2 proteins = small & large delta antigens
Co-infection w/ HBV + HDV = more likely to develop cirrhosis + HCC than superinfection.
Transmission: Parenteral, IV drug use, Sexually (but less efficient than HBV)
Vaccine/Therapy: HBV vaccine, Therapy = eliminate HBV
Diagnosis: Presence of Delat antigen in liver (or blood but if in blood usually pre-clinical)
Acute Disease: Brief appearance of delta antigen in the blood but typically occurs before symptoms. Brief anti-delta IgM produced but never into IgG
Chronic disease: Delta antigen persists in liver (found on biopsy, (FF: no biopsy for acute disease))
Pt will have high anti-delta IgG titers. HDV RNA is detectable w/ PCR long term
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