Overview

Viruses: RNA or DNA. Have capsid coat, might have lipid envelope. Helical, icosahedral, or complex shape.
Capsid: Protein shell enveloping genetic material.
Classification: By genomes, capsids, or reproductive strategies.
Baltimore Classification System: Viruses are classified by how mRNA is produced by genes, # of strands, + or - nucleic acids, RNA or DNA.
Intracellular trafficking: Ensures molecules target the correct cell area.
Human viruses: Mostly -RNA.
Plant viruses: Mostly +RNA.
Fungal viruses: Mostly dsRNA.
Bacteriophages: Mostly tailed dsDNA.
Algae + protozoan viruses: Mostly large dsDNA.

Influenza

Orthomyxoviridae. Types A, B, C. -ssRNA, enveloped, segmented genome. 8 vRNP (viral ribonucleoprotein segments) in A + B, 7 segments in C. High morbidity and mortality. Must be diagnosed by lab tests.

Nomenclature: Type / Town / # of isolates / Year / Major (type of HA + NA). Example: A SINGAPORE 6 66 H1N1.
Transmission: In humans and swine by respiratory droplets, in birds by fecal-oral.
Symptoms: Fever, headache, sore throat, cough, myalgia, worsen chronic disease, superinfection (bacterial / viral pneumonia), direct rapid progression (severe viral pneumonia).
Seasonal: Because of host resistance (melatonin + Vitamin D), temperature, or changing host behaviour (more time indoors, closer contact).
Genetic drift: Minor HA / NA changes, does not change subtype.
Genetic shift: Major HA / NA changes, can change subtype, from different strains, can cause pandemics.

Types: 16 HA subtypes, 9 NA subtypes. All are in birds. HA 1-3 and NA 1-2 are human flus.

A: Severe, pandemic, gene shift + drift, treat with Rimantidine and Amantadine.
B: Less severe, epidemic, gene drift, above antivirals have no effect.
C: Least severe, gene drift, above antivirals have no effect.

Proteins

Hemagglutinin: Surface protein that helps attach and penetrate. Binds to sialic acid α2,3 in birds and α2,6 in humans.
Neuraminidase: Surface protein that helps release from host cell. Cleaves sialic acid and releases. Prevents clumping so that the virus can spread farther.
M2 protein: Endosome acidity helps M2 release vRNP into the cytoplasm which goes into the nucleus to replicate.
M1 protein: Targeting signals to package RNA. Binds to HA + NA.
NS1: Suppresses immune system's interferons and prevents activation of Protein Kinase R that would inactivate transcription.

Flu

1918 Spanish Flu (H1N1): Low mortality but widespread. From avian source. Scientists used reverse genetics to remove HA + NA and splice harmless strains. HA + polymerase cause lung damage. Resurrection led to antivirals, vaccines, and discovery that most died from bacterial pneumonia (secondary infection).
Avian flu (H5N1): Very pathogenic for waterfowl. Can infect mice withhout adaptation. Rarely infects humans but can have high mortality, and cannot transmit from human to human. Difficult to make a vaccine because it evolves continuously, and 2 clades are circulating. More avian flu exists maybe because farms are flu factories. A human was infected aand treated with antivirals in April 2022.
Swine flu (H1N1): Mild, similar to the flu, has some drug resistance. Filamentous shape. No markers of pathogenicity. Control by hygiene, antivirals, and vaccine (immunoprophylaxis, should not be received if less than 6 months old or have illness with fever). Flu shot (contains 3 inactivated / killed strains). Nasal spray (contains 3 attenuated strains). Quadrivalent (contains 3 strains + another type B virus, egg based or cell / recomb based).

Antivirals

For type A, block viral entry and release: Amantadine, rimantadine. Resistance is a problem. Side effects on nervous system, liver, and kidneys.
For uncomplicated A + B, NA competitive inhibitors: Zanamivir (Relenza), Oseltamivir (Tamiflu), Peramivir (Rapivab, injectable)
Enzyme inhibitors: XOFLUZA (one dose).

Retroviruses

Retroviridae. Diploid +ssRNA with polyA tail +5' cap, tRNA primer binding site, some regions of base pairing. Uses DNA intermediates. Icosahedral, enveloped, has tRNA and enzymes. Avian leukemia virus / Rous Sarcoma chicken tumors were discovered. Can infect vertebrates and plants.

Simple: Only make structural genes (gag, pol, env, maybe src) and do not kill cell.

Alpharetroviruses: Oncogenic. Leukemia and sarcoma. Example: RSV.
Betaretroviruses: Example: MMTV.
Gammaretroviruses: Example: FeLV.

Complex: Make regulatory genes and may kill cell.

Deltaretroviruses: Example: HTLV.
Epsilonretroviruses
Spumaretroviruses
Lentiretroviruses: Example: HIV.

WBCs review

T cells: Lymphocyte from thymus. T helper (CD4. TH1 secretes IFN that activates macrophages, TH2 stimulates T cells and makes B cells become plasma cells that secrete antibodies) or Cytotoxic (CD8, recognize infected cells). Recognize antigen from APCs. Divide rapidly and become memory cells.
Dendritic cells: APCs, can take virus as trojan horse. In blood, lymph(oid tissue), skin, tissue mucosa.

Structural genes and proteins

gag: Capsid proteins MA (matrix), CA (capsid), NC (nucleocapsid).
pol: Polymerase (p6), RT (with RNase H activities), protease (pr, cuts gag and helps maturation), integrase (in).
env: Envelope, glycoproteins / peplomer proteins (gp120 + gp41 = gp160) that attach to receptors, transmembrane protein (TM). Makes it hard to make vaccines.

Regulatory genes and proteins

tat: Transactivator. Extends transcription, binds to TAR (transactivating response region) to phosphorylate RNA poly II.
rev: Activates nuclear export of unspliced RNA with RRE. Binds to RRE (unspliced or singly spliced) in env.

Accessory genes + oncogene products

vif: Viral infectivity factor. Needed for continual replication and transmission.
vpr: Viral protein replication. Assembly and release of virus, gets viral DNA into nucleus. Promotes G2/M arrest, infects macrophages.
vpu: Viral protein u. Promotes budding and release by enhancing Tetherin. Lowers CD4, surrounds nucleus.
nef: Negative factor. Lowers CD4, makes HIV and SIV more pathogenic. Regulatory.

Genome regions

R: Repeated on both ends. Transcription start site, polyA, TAR.
U5: Unique to 5'. Primer binding site for tRNA / replication.
PBS: Primer binding site.
Psi / DLs: Packaging signal / Dimer linkage site.
U3: Unique to 3'. Transcription factors Sp1, TATA, NF-kB.
PP: Polypurine site.

Cycle

Binding / absorption (bind to receptors)
Fusion / penetration (release viral core into cytoplasm)
RT (+RNA -> -ssDNA -> +dsDNA)
Transport (+dsDNA in cytoplasm -> nucleus)
Integration
Transcription / translation
Assembly
Budding / Release (from plasma membrane)
Maturation (HIV protease cleaves gag / gag/pol polyproteins into individual proteins)

HIV

Lentiretroviridae. Diploid +ssRNA, enveloped. Structural, regulatory, and accessory genes. Long incubation period (30 years), Causes AIDS and Kaposi's Sarcoma. Lowers T cells and increases opportunistic infections.

Discovery

HTLV-1: Deltaretrovirus. Same as ATLV. Human T cell lymphoma virus, infects CD4 and causes leukemia.
HTLV-2: Infects CD8 and causes a less aggressive leukemia.
HTLV-3 + HTLV-4
HIV: "Gallo's virus" / HTLV-III in early 1980s America. Originated from primates. Lower T cell count and opportunistic infections. Later known as LAV in France. Both later called HIV-I
HIV-2: Slower and less infectous. Mostly in W Africa.

mRNA splicing

30 alternative mRNAs, many polycistronic (many ORFs, single gene product is cleaved into different products).

Unspliced (9-kb): Produce (structural) gag / gag/pol proteins. From late transcription + translation.
Incomplete / singly (4-kb): Encode (envelope + acc) env, vif, vpr, or vpu.
Fully / doubly (2-kb): Encode (regulatory + acc) tat, rev, nef. From early transcription + translation.

Disease

Transmission: By body fluids and prenatally. Must overcome physical barrier by abrasions, ulcers, inflammation, or using dendritic cells as trojan horse.
Latency: Genes are not expressed, T cells not activated.
Infection: Brain (HIV dementia), gut (wasting), heart (cardiomyopathy).
Measure progression: By CD4 count and blood viral load.
Opportunistic infections: CMV, Mycobacterium, Pneumocystis pneumonia, toxoplasmosis of brain, Kaposi's Sarcoma, thrush, yeast, TB, syphillis.
Avoids immune system: By going latent, antigenic changes, fusion of T cells to form syncytium or polykaryocyte, destroying immune system.
Kills: By massive production, gp binding to CD4, forming cyncytia, apoptosis, lysing cells by complement system, by AIDS in 2 years without treatment.
Therapy: AZT, combination therapy, protease / RT / first entry inhibitor. Might be toxic or cause resistance. Difficult to target.

Cycle

Acute infection: increasing viral load, can be rapid / slow / longterm nonprogressive.
Seroconversion: developing antibodies.
Asymptomatic: immune system controls virus, mononucleosis symptoms may develop.
Symptomatic: physical signs.
AIDS: opportunistic infections, end stage.

Natural immunity

Deficient viruses: Less nef or vpr.
CCR5 polymorphism: 1% of Caucasians have this base pair mutation.
CXCR4 3' UTR mutation: 1% of Caucasians have this point mutation that delays disease / death.

Statistics

Living with HIV: 37.7 million. 1/2 women.
Newly infected: 1.5 million.
Deaths in 2020: 680k.

Togaviruses

+ssRNA. Most are arboviruses (arthropod borne). Infection of mosquitoes causes a persistent infection, not cytopathic.

Alphavirus: Sindbis, Semliki Forest, Ross River. Infect birds and mammals. Most transmitted by mosquitoes. 11kb.

Rubivirus: Rubella virus. "German measles". Not transmitted by mosquitoes. 9kb.

Virion

Shape: Spherical, nucleocapsid with icosahedral symmetry in envelope with same symmetry.
Envelope: Glycoproteins E1 and E2 in 240 heterodimers. 240 capsid protein copies.
Genome: +ssRNA, linear, 5' methylated cap with 4 nonstructural proteins (nsP1-4, 2 proteins cleaved by viral protease) translated from + genome RNA. 3' poly A tail with 5 structural proteins (1 capsid protein, 3 envelope proteins, 1 hydrophobic protein) translated from - mRNA. In Sindbis, P1234 is made only after a reathrough of the stop codon, usually only translates P123.
Viral entry: By low pH induced fusion in vesicles through receptor-mediated endocytosis. E2 glycoprotein binds to cell receptor (Laminin receptor in rodents and primates. Heparin sulfate can be used in viruses that have mutations in E2.).

Nonstructural proteins

nsP1: Membrane anchor, capping + methylatiobn, regulate - strand.
nsP2: Protease, RNA helicase domain, capping.
nsP3: Phosphoprotein, - strand synthesis.
nsP4: RNA dependent RNA polymerase.
Antigenome: Synthesis catalyzed by P123 and nsP4.

Structural proteins

Process: Cleaved during translation by signal peptidase + furin protease and palmitoylated in golgi.
Capsid protein: Cleaves itself, binds to the RNA packaging signal (nsP1 or nsP2).
E1: Transmembrane, used in low pH membrane fusion.
E2: Glycoprotein, binds to cell receptors.
E3: Translocates protein into ER to golgi and cleaved by furin to be lost by most alphaviruses. Semliki virus keeps it to form trimer glycoproteins.
6K: Interacts with E1 + E2 to move them to cell membrane where virions are assembled and bud out.

Disease

Symptoms: Encephalitis (inflammation in brain / CNS infection), fever, rash, arthiritis, joint pain, muscle ache. Rubella can cause fetal abnormalities. Immune system prevents CNS infection
Neuroinvasive disease: Virus enters the CNS through the blood stream by bypassing the blood-brain barrier (loosening the barrier, infecting lymphocytes, or infecting nasal epithelium) and replicates in CNS. Causes lethargy, altered mental state, incoordination, abnormal reflexes, paralysis, convulsions, stiff neck.
Encephalomyelitis: Brain and spinal cord infection from immune response, induces neuronal death.

Alphaviruses

Old World: Sindbis, Semliki Forest, Ross River, Chikungunya. Suppresses host transcription by nsP2.

New World: Western, Eastern, and Venezuelan Equine Encephalitis Viruses. Suppresses host transcription by capsid.

WEEV: Western US, transmitted by birds, 3-7% fatality, Mild-severe deficits in survivors. Humans and horses are dead end hosts.
EEEV: North / East US, transmitted by birds, long term immunity, doesn't protect from other EEVs, systemic (lasts 1-2 weeks) or encephalitic (20-80% mortality, mild to severe permanent neurologic damage). Humans and horses are dead end hosts.
VEEV: South / Central America, mosquitoes transmit, aerosol, 1% fatality, 20-30% fatality n kids, no therapeutics, unapproved live vaccine for people at risk only. Horses can infect mosquitoes. Subtypes arise from change in E2 protein which affects host range. Subtypes IAB and IC (major human epidemics, equine epizootics) and ID and IE (enzootic transmission, less virulent for horses).

Chikungunya: "That which bends up". Debilitating illness, can cause arthralgia. Spread by Aedes aegypti and Aedes albopictus. Found in Tanzania, spread to other parts of Africa and parts of Asia. Can last a week to months. Hemorragic fever in South Asia, transmitted to Europe / Italy by travelers, caused recent outbreak by mosquitoes in Americas. No vaccine or treatment, can only treat symptoms.

Coronaviruses

Groups: Based on genome sequence.

Alpha: Humans (HCoV-229E, HCoV-NL63), pigs, dogs, cats.
Beta: HVoV-SARS, MERS, SARS, MGV, rats, pigs, cows.
Gamma: Chicken and turkeys.
Delta: Birds.

Virion

Shape: Enveloped, helical nucleocapsids, spike proteins. Nucleocapsids formed from N protein helically bound to RNA. Some have a spherical core shell.
Genome: Linear +ssRNA, 5' cap, polyA tail. Gene1 is 2/3 of genome, includes replicase genes and nonstructural genes, polypeptide is cleaved by proteinases, pseudoknot.
Replication: Replication complexes associate with host cytoplasmic membrane, encapsidation of RNA, -RNA intermediate.
Transcription: Makes nested subgenomic mRNA, discontinuous, each -mRNA is used to make a +mRNA.
Assembly: At ER golgi intermediate compartment.

Envelope proteins

S Spike: Entry, spread, host range. Chain cleaved into S1 (attach) and S2 (fusion), binds to ACE2 receptor. Can cause syncytia.
HE Hemagglutinin: Binding, entry, release, can bind to sialic acid.
E Small envelope: Budding into ER or golgi.

Disease

Respiratory illness, 30% of common colds, rarely gastroenteritis and encephalitis. Feline peritonitis, bronchitis in animals, mouse hepatitis.

Epidemiology: Worldwide, seasonal, common in early childhood, through droplets and contact, high symptoms in the first few days.
Symptoms: Upper respiratory tract infections in children, pneumonia + lower respiratory tract infections in elderly and immunocompromised.
SARS-CoV: New pandemic in 2002 from Guangdong, first in the 21st century. Related to bat coronaviruses. Spread by droplets, super spreaders, and fomites, and is stable in feces. Transmission in 2nd week. Caused fever, pneumonia, hypoxemia, and death. 8000 cases and 770 deaths. 10-15% mortality rate, 44% in people 65+. Contaminated sewage spread it in Amoy Gardens because aerosol was created from using fans with closed doors.
MERS-CoV: In 2012 in Saudi Arabia. Camel reservoir. Direct human to human transmission. Fever, cough, shortness of breath. 2000 cases, 800 deaths, 35% mortality.
SARS-Cov-2: Newly emerged in 2019 in Wuhan likely from bat reservoirs. Malayan pangolins had a similar virus. Spreads through droplets, saliva, nasal discharge, and fomites, can transmit between pets and zoo animals. Causes fever, cough, muscle / head aches, loss of taste and smell, congestion, runny nose, nausea, diarrhea, chest pressure, confusion, blue lips, pneumonia, hypoxemia. 600 million cases, 6.5 million deaths, 1% mortality. 13 billion vaccine doses administered. Receptor binding domain binds well to ACE2, likely came from recombination and mutation in spike protein. Test for active infection through PCR / antigene or antibody / serology. Vaccines from Pfizer-BioNTech (mRNA), Moderna / Spikevax (mRNA, monovalent or bivalent), Janssen (adenovirus with spike protein, single dose, less effective), Novavax (ajuvanted, contains the spike protein from insects and matrix ajuvant from Chillean Soapbark tree). Treat by antivirals Remdesivir / Paxlovid / Dexamethasone steroid, antibody serum, lab created monoclonal antibodies only for high risk.

Variants

Alpha
Delta: First found in India, spreads faster and causes severe symptoms, vaccines effective, monoclonal antibody treatment.
Omicron: First found in South Africa, spreads more easily but less severe.
Deltacron: First found in France, Netherlands, and Denmark, rare.
SARS-CoV-2 Interagency Group: Monitors variants.
COVAX: Group of WHO, CEPI (accelerate vaccine development), and Gavi (lower vaccine losts) to try to end the pandemic by 2021.

Hemorrhagic Fever Viruses

Filoviruses, Arenaviruses, Bunyaviruses, Flaviviruses. In Africa, Asia and places without proper healthcare. Study in primates, guinea pigs, and mice. Make good bioweapons if turned into an aerosol because low infection dose, high morbidity and mortality (90%), no vaccine or treatments.

Disease

Initial: Fever, headache, myalgia, fatigue, abdominal pain.
Advanced: Bleeding, maculopapular rash, pharyngitis, meningoencephalitis, jaundice.

Filoviruses

Monomegalovirales. Nonsegmented -ssRNA, enveloped. Ebola, Marburg, Cueva (Lloviu infects bats).

Virion

Shape: Worm shaped.
Genome: 7 genes, polarity of transcription.

Proteins

NP: Nucleocapsid.
VP24: Blocks interferon, minor matrix.
VP30: Minor nuclearprotein, transcription and replication.
VP35: Interferon antagonist, RNA polymerase + cofactor.
VP40: Matrix protein, envelope assembly.
GP: Glycoprotein, use RNA editing to make 2 glycoproteins from the same gene, secreted shorter protein doesn't include transmembrane domain.
sGP: Could bind to antibodies to decrease immune response.

Disease

Symptoms: Abrupt fever, chills, malaise, myalgia. Death in 7-11 days. Painful recovery.
Treatment: Inmazeb (3 monoclonal antibodies, targets glycoprotein to block entry), Ebanga (1 human monoclonal antibody), Remdesivir (Investigational, effective against Coronavirus, Paramyxovirus, and Filovirus).
Vaccine: VSV / EBOV-GP (live virus, protects before and after exposure, very effective. Ring Vaccination Program offers vaccines to people who are likely to be exposed), VLP (virus like particle. Contains GP, NP, and VP40. Safe but less effective), VRP (VRRV replicon with Filovirus genes), Adenovirus (Defective Adenovirus with Filovirus GP).

Ebola

6 species (Zaire, Sudan, Reston, Tai Forest, Bundibugyo, Bombali).

Zaire: In West Africa, China, US. From African fruit bat in 2013. 11 people infected in US in 2014-2016 outbreak. 52-75% mortality rate in outbreak that was thought to be over. Kivu outbreak in 2018-2020. Congo outbreak in 2020, has vaccine.
Reston: 82% primate mortality rate. Not pathogenic to humans but they develop antibodies. From Philippines.
Bundibugyo: Sporadic outbreaks, genetically distinct so less effective diagnostics and treatment, from Uganda.

Marburg

1 species, 7 strains. First case in Germany.

Disease: Transmit through bodily fluids, contact with infected monkeys. A lot of bleeding. Outbreaks in areas of poverty. 21-100% mortality rate.

Arenaviruses

In Africa and South America. Transmit through rodents' urine, feces, excrements, natal between rodents and humans.

Virion

Shape: Not perfect shape, grainy image because of ribosomes. Helical with nucleocapsid, enveloped.
Envelope: Matrix Protein Z. Receptor binding, RNA replication, no cell lysis.
Genome: Antisense. More S RNA than L RNA. Noncoding IGR region between genes forming hairpin in L and S strands.

Proteins

NP: Nucleocapsid, most abundant structural protein, interacts with C-terminus glycoproteins.
L Polymerase
GPC: Envelope glycoprotein, cleaved to GP1 and GP2. Has stable signal peptide.
Z protein: Matrix protein, budding. Has late domains.

Disease

Symptoms: Chronic mild infection with lifelong shedding of virus except Tacaribe virus. Fever and malaise in 2-4 days.
LCMV: Model for chronic virus infection. Asymptomatic infection in humans.
Lassa Virus: Can cause deafness 1/3, asymptomatic in 80%, occasional epidemics, severe in pregnant women.
Junin / Argentine: 15-30% mortality, in field workers with skin abrasions.
Luna virus: Newly discovered, nonpathogenic.
Lujo virus: Pathogenic.
Treatment: Immune serum, gamma globulins, Ribavirin, Junin vaccine candidate (live attenuated, protects against Machupo strain).
Prevention: Proper food storage, cleaning homes, trapping rodents, hospital training programs, sharing diagnostic technology.

Flaviviruses

Flaviviridae. +ssRNA. Includes Hepacivirus (infects humans) and Pegivirus (+ bats and monkeys).

Virion

Shape: Spherical, enveloped, golf ball appearance (monkey's fist knot like appearance because of T=3 surface dimers). Lipid bilayer with glycoproteins. Nucleocapsid and envelope have icosahedral symmetry.
Envelope: Glycoproteins.
Genome: +ssRNA, linear, 5' cap with no poly A tail. 9-12.3 kb.
Unique features: Internal ribosome entry site (IRES) in Hepacivirus, Pegivirus, and Pestivirus. Does not enter cell cucleus.

Disease

Yellow Fever: Transmitted by mosquitoes and infected patient serum. Isolated in 1648 in Yucatan, originated in W Africa, spread through slave trade. Widespread outbreaks in Americas. 3 stages: Initial (chills, fever, muscle pain, nausea), quiescent (silent), final (symptoms reoccur but more severe, organ failure, leads to hepatitis, 20-50% mortality rate). Vaccines availlable, but no specific treatments, so no cure.
West Nile Virus: Transmitted by mosquitoes and birds. First isolated in Uganda, prevalent in S Africa, S Europe, and W Asia. Can cause neurological effects (encephalitis and meningitis)in 1/150 people and be fatal to 1/10 of these. No vaccine or treatments. Most recover, but weakness can last for months. Prevent by mosquito control and insect repellant.
Hepatitis C Virus: Hepacivirus.
Dengue Hemorrhagic Fever
Japanese Encephalitis Virus
Tick-Borne Encephalitis

Hepacivirus

7 genotypes, 75% are Type 1 (1a, 1b). First isolated in 1989 by cDNA cloning. >4 million cases in the US, 170 million cases worldwide, 1/2 are unaware. Routine testing for baby boomers.

Virion

Shape: Particles are smaller than other flavivirus particles.
Translation and replication: IRES-mediated translation. mir122 microRNA binds to 5' UTR and stabilizes viral RNA. ER membrane altering (into membranous web) is needed to form replicase. NS3 and NS4B are involved.
Assembly: p7 stabilizes particle, E1 / E2 become glycosylated, association of host lipoproteins.

Disease

Infects only human livers, attaches by receptor induced endocytosis. Causes chronic hepatitis and Hepatocellular carcinoma. Transmits through blood, needles, sexual contact.

Acute stage: Jaundice, hepatitis.
Persistent infection: Chronic infection, vasculitis. 70-98% only have asymptomatic persistent infection.
End stage liver disease: Encephalopathy. 2-30%.
Vaccine and treatment: Vaccine under development. Treat with pegylated interferon alpha and ribavirin. EPCLUSA can be used, but can reactivate Hepatitis B infection and is harmful to fetuses and can pass through breastmilk, cannot take if patient has liver or kidney problems or HIV.

Papillomaviruses

Small dsDNA tumor virus. Infect specific vertebrate hosts, name based on species they infect and # of identification.

Virion

Shape: Icosahedral, no envelope.
Genome: Circular supercoiled dsDNA, minichromosome with histones. 8-10 open reading frames, two promoters and two polyadenylation signals, spliced to at least 10 mRNAs. Can integrate into chromosome regions associated with tumor phenotypes.
Replication: Can initiate replication multiple times in S phase. Needs (insert proteins here). Plasmid replication in undifferentiated cells, tight control of 50-100 copies, L1 binds to host receptor for endocytosis, uncoated in nucleus. Replication is uncontrolled.
Unique characteristics: Not easily grown in culture. Can cultivate in raft culture systems.

Proteins

Early nonstructural, late structural.

L1 / L2: Major / minor capsid.
E6: Degrades p53 to suppress apoptosis after E7 releases E2F, creating E6AP complex.
E7: Oncoprotein, binds to Rb and releases E2F transcription factor to activate cell cycle, convinces keratinocytes to keep replicating.

Disease

Most common STI, 1% of infections persist.

Spread: Spreads by direct contact. Infects squamous epithelial cells, infected daughter cells move up to surface, causes warts.
Cancer: Linked to cervical cancer (16, 18, 31), anogenital cancers, oral nasal cancers, head and neck cancers. Inactivates tumor suppressors.
Cervical HPV: Cofactors include women who never had a pap smear, early age of first intercourse, multiple partners, oral contraceptives, smoking. Almost every active person will get it if they don't get the vaccine.
Vaccine: GARDACIL 9 valent VLP, L1 in Baculovirus vector, not oncogenic. Live attenuated vaccines are unsuitable because they can't be cultured easily and they are oncogenic. Not therapeutic.

Herpesviruses

Spread lesions (creep), 9 human herpesviruses including herpes simplex, varicella zoster, epstein barr, cytomegalovirus. Over 100 known species. Known since Greek philosophers' times.

Types

Alpha: Grow quickly, latent in sensory ganglia. Herpes simplex 1 and 2 (gingivitis, stomatitis), varicella zoster (Small, causes chickenpox, shingles), keratitis, encephalitis.
Beta: Grows slower, less common, lower host range. Cytomegalovirus is huge, opportunistic, and causes birth defects, pneumonia in transplant patients, retinitis and colitis in AIDS patients, athero sclerosis, coronary restenosis, gliomas. Human herpes virus 6A associated with MS, 6B associated with roseola infantum (6B and 7).
Gamma: Epstein barr, human herpes 8, monocucleosis, Hodgkin's disease. Lymphoproliferative.

Virion

Shape: Icosahedral capsid, enveloped, 6 capsid proteins, tegument between capsid and envelope has 14 proteins including VP16 and VHS.
Envelope: Contains 14 proteins (IE and VHS viral host shutoff), gB-gM glycoproteins.
Genome: Linear dsDNA, unique (UL and US) and inverted repeated sequences, lack of splicing. A sequences with no open reading frame at the end to circularize and package DNA upon infection, B sequence has 4 ORFs, codes for immediate early regulatory protein (a0) latency associated transcript, UL encodes 56 proteins, replication enzymes, capsid proteins, has ori, another ori in Rs, C sequence encodes transcriptional activator with a0 and a27 (in UL), US has 12 ORFs for glycoproteins.
Binding and fusion: Binds to heparin sulfate proteoglycans by gB and gC, fusion releases tegument proteins in cytoplasm. Penetration by gD binding to coreceptors nectin1 and HVEM. DNA enters the nucleus.
Transcription: By RNA polymerase II, most is unspliced, units encode one protein.
Replication: Bidirectional from ori (UL9 protein), unwind DNA (ICP8 protein), change to rolling circle with only one strand extended, leads to activation of Y1 and Y2 for structural proteins.
Assembly: DNA is cleaved and stuffed into capsids using pac1 and pac2 by VP5 and ends with a sequence, scaffolding proteins are dismantled. Three routes of envelopment resulting in vesicles carrying virus out of nucleus.
Egress model 1: Nucleocapsids bud through nuclear membrane, acquiring an envelope.
Egress model 2: Nucleocapsids bud through the inner nuclear membrane, lose their membrane, and are reenveloped at the golgi.
Egress model 3: Nuclear pores become enlarged, allowing nucleocapsids to go to the cytoplasm and get enveloped by the golgi.
Unique characteristics: Large, temporal regulation of gene expression, HSV can shut down cellular gene expression, large number of enzymes, latency in neurons with LAT RNAs complementary to ICP0 and ICP4 RNA.

Proteins

gB - gM: Envelope proteins.
VP5: Capsid protein.
VP16: Activates transcription.
VHS: Degrades host mRNA. Found in tegument.
ICP4: Needed for beta and gamma gene expression, promotes replication and expression of late genes.
ICP27: Inhibits mRNA splicing.
ICP47: Blocks antigen presentation by MHC-1.
ICP34-5: Reverses the effect of protein kinase.

Temporal gene expression

Alpha / immediate early: Early gene activation.
Beta / early: Replication, late gene activation. Have 3 ori, replication in nucleus. Requires ICP4.
Gamma / late: Make regulatory proteins for new virion.

Disease

Spread: Spreads by personal contact, mucous, abraded skin.
Reactivation: Can reactivate in immunicompromised patients and AIDS patients. Can reactivate from physical or emotional stimulili like UV, fever, nerve damage, hormones, and prostaglandins.
KSHV / HHV-8: Described in Hungary as rise in Kaposi's Sarcoma came with rise in HIV and Herpesvirus-like DNA was found in KS tissue in AIDS patients. Infects B cells and endothelial cells, found in saliva and semen. Not ubiquitous. More frequent in AIDS patients, and in all variants of KS which requires environment and genetic cofactors. Found in primary effusion lymphoma and Multicentric Castleman's disease (lymphoproliverative condition). LANA-1 antigen required for replication binds to H2A-H2B dimer, p53, and Rb, alters host cell genes. vCyclin promotes cell cycle progression, blocks Rb-mediated growth arrest, is expressed from LANA promoter by alternative splicing.
Treatment: Treat single lesion by surgery. Treat multifocal with radiation, chemotherapy, and antiviral drugs. HAAART helps treatment.

Poxviruses

Blistering skin lesions, large enough to see under a light microscope.

Types

Chordopoxviridae: Infects vertebrates (variola, vaccinia, molluscum contagiosum infect humans), birds, mammals (monkeys, cattle).
Entomopoxviridae: Infects insents (beetles, butterflies, flies).

Virion

Shape: Ovoid or brick shaped, no symmetry.
Envelope: Mature virus has one lipid membrane, and extracellular virus has two lipid membranes.
Genome: Linear dsDNA. Covalently closed hairpin ends, no free 3' or 5' ends, variable ends. Inverted terminal repeats. Lack introns, has central conserved region for essential genes. Large amount of DNA taken from hosts during evolution, 100-200 genes and proteins including immunomodulatory proteins.
Entering: Mature virus attaches to cell receptor, enters by fusion or endocytosis, is stable, and is responsible for person to person transmission. Extracellular virus enters by phagocytosis or by releasing a mature virus when the outer membrane ruptures, is fragile and responsible for cell to cell and tissue to tissue spread.
Transcription: Expressed in a transcriptional cascade controlled by transcription factors. Virus early transcription factors are packaged into virion and act when entering cytoplasm. Viral intermediate transcription factors trigger immediate gene expression. Viral late transcription factors activate late genes.
Enzymes: In core, carry out early RNA synthesis and packaging. Transcribe, cap, methylate, and polyadenylate mRNA. Capping requires guanylytransferase and ribose-methyltransferase.
Replication: In cytoplasm.
Assembly: Within virus "factories" (crescent shaped membrane structures that will become mature virus), lipids are delivered to crescents, crescents become spheres and enclose virus. DNA enters spheres later. Mature virus is wrapped at the golgi, transported to membrane, and released as an extracellular virus.
Unique characteristics: Internal core with proteins for mRNA synthesis in folded tubular structure. Lateral bodies containing protein.

Gene expression

Early: Dissolve core, direct DNA replication and intermediate gene expression, combat host defenses.
Intermediate: Direct late gene expression, combat host defenses.
Late: Virion structural proteins and transcription enzymes.

Immunomodulary strategies

Immunomodulatory proteins: Affect apoptisis, production of interferons, chemokines, inflammatory cytokines.
Virostealth: Mask signals of infection.
Virotransducers: Inhibit antiviral pathways like apoptosis, host signal transduction pathways (influence host range).
Viromimicry: Promote a protected microenvironment. Virokines and viroreceptors.
Virokines: Block host receptors.
Viroreceptors: Mimic cell receptors.

Disease

Spread: Direct face to face contact, aerosols, air droplets, bodily fluids, fomites. Spread is reduced in variola major because patients are bedridden, but spread is wider for variola minor.
Pathogenesis: Severity not influenced by source. Longer exposure, concentration, strain, severity of rash, and host immunity are factors / indicators.
Ordinary: Prodome phase / preeruptive phase has initial symptoms (fever, malaise, head and body ache, prostration, nausea), febrile prodrome with rash is characteristic of smallpox. Sometimes contagious. Rash phase leaves depigmented, pitted scars.
Modified: Mild and may occur in vaccinated people. Less severe than ordinary. Skin lesions evolve more quickly and can be superficial.
Flat and hemorragic: Very severe, uncommon, most cases are fatal. Flat smallpox can be in cases of dermatitis / eczema. Fever remains through course of the illness. Lesions are soft to the touch. Hemorrhagic smallpox is with high viremia, restlessness, bleeding into the skin, mucous membranes, and GI tract.
Smallpox (Variola): Human only, but primates can be infected in lab. Contagious, fatal. Raised bumps on face and body. No treatment, prevent by vaccination. Variola major (severe, more common, rash and high fever, 30% death rate) and variola minor (less severe, less common , 1% death rate). No animal reserviors or human carriers. Ramses had it. Diagnose by centrifugal rash (on face and limbs more than trunk), lesions on palms and soles, same level of lesions on all areas, firm pustules. Contagious until the last scab falls off.
Outcomes of infection: Can cause blindness, immunity to reinfection, no evidene of chronic or recurrent infection. Death involves multiple organs.
Vaccine: Vaccine 4 days after exposure can prevent infection. No effective treatment. Variolation is inoculation of smallpox lesion material into the skin more than 1000 years ago in Asia. Fatality rate is 2%, and can transmit disease to others. Vaccination is innoculation of cowpox into the skin to cross-protect against smallpox, developed by Edward Jenner (had been variolated and given variolations). Cowpox lesions were taken from Sarah Nelmes and given to James Phipps who had no response to smallpox. Virus used for smallpox changed from cowpox to vaccinia. Dryvax has lyophilized vaccinia, comes with needle, has antibiotics, 95% effective.
Vaccine complications: May develop eczema, progressive vaccinia in people with immune deficiency, generalized vaccinia rash, or encephalitis in children (35% mortality rate). Safer vaccines were developed (Modified vaccinia Ankara in Germany, LC16m8 temperature sensitive mutant in Japan). WHO wanted to eliminate disease in 1959, last natural case was in 1977, eradicated in 1979, no more vaccinations since 1980.
Bioterrorism: Smallpox is a category A agent, requires BSL-4, risk to national security, high mortality. Only two stocks held in USA (CDC) and Russia (Vector). France gave infected blankets to Native Americans, used in US Civil War, by Japan in China. Ebola-smallpox chimera blackpox can be aerosolized, 100% lethal.
Monkeypox: In Africa, first isolated in 1958, can infect other animals (squirrels, rats, mice, rabbits), isolated in humans in 1970. More mild than smallpox, but enlarged lymph nodes. 1-10% mortality rate, vaccine is effective. Found in the US in 2003 from pet prairie dogs that were housed with rodents in Ghana. No treatment, but tecovirimat (TPOXX) for other viruses can work on monkeypox. Only for people with severe disease or at high risk. JYNNEOS can prevent smallpox and monkeypox, primary vaccine now, two doses between skin layers, has wait time. ACAM2000 is a JYNNEOS alternative, single dose. Monkeypox used as model for smallpox.