Viruses, Antivirals, for I&I Block 8

DNA and RNA Viruses

Parvoviridae

Small naked/non-enveloped ssDNA virus. Parton-19 is the most common type in humans.

Causes several diseases:
- Erythema infectiosum (fifth disease) in children
- Pregnancy: spontaneous abortion/hydrops fetalis
- Transient arthritis
- Aplastic crisis in patients with blood disorders

Fifth Disease/Erythema infectious - Parvovirdae

• “Slapped cheek disease”, mild fever and rash in school-aged children, rash is post viral, due to immune complexes. Bilateral “slapped cheeks” progresses to reticular rash of trunk and limbs.

• Aplastic Crisis - virus replicates in S-phase (causing S-phase arrest), resulting in anemia is clinically significant in developing fetuses, sickle cell anemia & thalassemia

  • Pregnancy - pregnant woman with flu-like symptoms - followed by stillbirth or spontaneous abortion. Hydrops fetalis

Adenovirus

• naked dsDNA virus

• #1 cause for conjunctivitis, exudative pharyngitis, gastroenteritis, acute hemorrhagic cystitis - hematuria

  • Transmission = aerosol, fecal-oral, direct contact (fingers in mouth)

Acute Hemorrhagic Cystitis - Adenovirus

• Caused by Ad11 and 21 of subgroup B

• Targets DPS - outbreaks in daycares and schools (especially boys)

  • Presentation = hematuria, usually no fever or other symptoms, benign and self-limited

Human Papilloma Viruses - Papillomaviridae

• family of naked circular dsDNA viruses > 150 stereotypes

• Transmitted by skin-skin contact —> infected squamous epithelial cells may become koilocytes

• Some serotypes express two genes —> EP6 and EP7, proteins inactivate tumor suppressor genes p53 and RB

HPV types 1-4, 7, 10

Cause plantar and skin warts

HPV types 6 and 11

Cause genital warts

HPV 16 and 18, 31, 33, 45, 52, and 58

Cause high-risk anogenital cancer - cancers include uterine cervix, penis, and anus

HPV - Anogenital Warts

• caused by HPV types 6 and 11

• Soft, tan, cauliflower-like lesions (verrucous = wart)

• Located on penis, vulva, and perianal area

  • DOES NOT LEAD TO CANCER

Gardisal Vaccine - HPV

• why target HPV 6 and 11 = cosmetic genital wart

  • Why target HPV 16 and 18 = cancers

Polyomaviridae

• Naked dsDNA

• Causes disease in immunocompromised patients

• JC virus: PML

  • Progressive multifocal leukoencephlopathy

  • CNS disease in HIV patients

• BK Virus

  • Classic disease in post-kidney transplant patients

  • Slowly progressive rise in BUN and creatinine

Hepadnaviridae

Hep B - dsDNA, enveloped, circular

• Partially double-stranded DNA virus

• Uses reverse transcriptase (like HIV)

• Enveloped taken from ER

Disease caused by HBV:

• Acute hepatitis

• Fulminant hepatitis

• Chronic hepatitis

• Hepatitis D - only occurs with HBV

HBV Antigens and Antibodies

• Vaccinated (HBsAg)

• Infected and seroconverted (sick & cured). HBsAg is cleared by HBsAB; HBcAb & HBeAb

• HBV carriers - HBsAg POS, HBeAg POS

• Low infectivity carriers - HBsAg POS, HBeAg

HSV general information

• HSV-1 —> mostly oral herpes —> “cold-sores” - herpes labialis

• HSV-2 —> mostly genital herpes, tzanck smear has multinucleated giant cells with Cowdry type A eosinophilic intranuclear inclusions

• Transmission: direct lesion contact, saliva, sexual contact, vertical during child birth

• Presentation - clustered painful fluid-filled infectious vesicles, primary infections typically show lifelong reactivating of latent virus

• Diagnosis - screen with Tzanck smear (of DFA), confirm with culture of DNA testing; indirect ELISA for IgM/IgG

Herpes Labialis - HSV disease

“Fever blisters,” “Cold sores”, recurrent HSV infection on lips or nares

Gingivostomatitis - HSV diseases

occurs primarily in children, primary HSV infection of the mouth - lesions in mouth, herpes labialis on lips, oral lesion, fever, irritability

Genital Herpes - HSV disease

painful vesicles below the waistline (genital region, rectum, lower part of the waistline), primary infections typically show includes fever and inguinal lymphadenopathy, recurrent flares usually not accompanied by fever and lymphadenopathy

Herpes Keratoconjuctivitis - HSV disease

HSV infection of conjunctiva and cornea, causes a dendritic corneal ulcer that can be sight-threatening

Herpes Whitlow Finger - HSV disease

Finger lesions from touching herpetic lesions

Herpes encephalitis - HSV disease

not a typical viral meningitis, causes necrosis of one temporal lobe, fever, HA, nausea/vomiting, altered mental status; often accompanies herpes outbreak elsewhere —> HIGH DEATH RATE, start treatment upon suspicion and then testing is done

Neonatal herpes - HSV disease

acquired via contact with active herpes lesions during vaginal birth, PREVENTED BY C-SECTION, ranges from asymptomatic, to skin, eye, mouth, and body-wide vesicles; to encephalitis with permanent neurological damage or death

Chickenpox - Varicella Zoster Virus (VZV)

infects upper respiratory mucosa, spreads by blood to skin, causes vesicular rash on trunk, then spreads, asynchronous lesions blister, crust, and itch, infections until all lesions are crusted over

Shingles - Varicella Zoster Virus

reactivation of latent VZV (Vesicles erupt along a dermatomes), diagnosis - screen with Tzanck smear and confirm with VZV titer, prevention - herpes zoster (shingles) vaccine - recommended for those age > 60.

Epstein-Barr Virus

• causes infectious mononucleosis

• Transmitted by saliva

• Produces heterophile antibodies and ATYPICAL/REACTIVE lymphocytes

• Heterophile antibodies/monospot - rapid test for EBV

• Classic presentation = teen/college - age student = pharyngitis, fever, fatigue, hepatosplenomegaly, posterior cervical lymphadenopathy, heterophile antibody positive, atypical lymphocytes

• No TX - symptoms normally resolve in weeks, feature may last months even years

• Amoxicillin “mono” rash when TX for strep throat - diffuse maculopapular rash

• VDRL cross reactivity - false positive —> NOT SYPHILIS

• Associated with many cancers: lymphomas, oral hairy leukoplakia, tumors in HIV patients

CMV

Enveloped dsDNA

• transmitted via saliva, sexual, blood, transplant, and in-utero

• does not produce heterophile antibodies —> infected cells contain Owl’s Eye Nuclei

• Infections impact immunocompromised and fetuses

  • HIV/AIDS (CD4<50)

  • TORCH Infection —> rashes (blueberry muffin syndrome), seizures, hepatosplenomegaly

  • Exception = CMV mononucleosis - similar to EBV mononucleosis, monospot negative, less lymphadenopathy/splenomegaly

Roseola infantum - Human Herpes Virus

• transmission = sporadic

• Presentation = abrupt high fever for up to 5 days in child < 2 years old (irritable baby, lymphadenopathy)

  • Rash - fever breaks, maculopapular rash, starts on neck/trunk and spreads to face and limbs

Kaposi’s sarcoma - Human Herpes Virus

• occurs in AIDS patients, HIV sets stage for HHV-8

• Transmission unclear

• Infects/transforms endothelial cells

• Inactivates tumor-suppressor genes

  • Purplish plaques/nodules on skin - sometime in mouth, GI tract, lungs

Poxviridae

large, dsDNA, enveloped virus - REPLICATES IN CYTOPLASM

• Variola/smallpox - inhaled > disseminates>flu-like illness>rash

  • DNA dependent RNA-polymerase

Cowpox and Vaccinia - Poxviridae

• DNA-dependent RNA polymerase

• Cowpox - causes pustules on cow teeth/utters

  • Vaccinia - close relative to cowpox, used to vaccinate against smallpox

Molluscum Contagiosum Virus - Poxviridae

• DNA-dependent RNA polymerase

• Resembles chronic, localized miniature smallpox

• Infection common in children and young adults - wrestlers, gymnast from contaminated mats

  • Appearance - pearly, umbilicated “flesh-colored dome” papillae “Central Dimple”

Monkeypox - Poxviridae

enveloped, dsDNA virus

• DNA-dependent RNA polymerase

Lassa Fever Virus (West Africa) - Arenaviridae

enveloped, helical, circular, segmented (2), ssRNA (-), rodent-borne

• Hemorrhagic, multisystem, including encephalitis

• 50% fatality rate (much higher in pregnant women)

  • BSL-4 isolation due to human-human transmission

Lymphocytic Choriomeningitis Virus - Arenaviridae

enveloped, helical, circular, segmented (2), ssRNA(-)

• flue symptoms to aseptic meningitis/encephalitis

  • No person-person other than a vertical

California Equine and LaCrosse Encephalitis Virus - Bunyaviridae

enveloped, helical, segmented (3), ssRNA(-)

• Mosquito-borne in North Central US

• Usually, mild viral encephalitis with HA

  • Rarely causes death

Hanta Virus - Bunyaviridae

enveloped, helical, segmented (3), ssRNA(-)

• rodent-borne; virus in deer, mice urine/feces/saliva

• Mostly western US/four-corners region

  • Flu-like symptoms>acute respiratory failure

Crimean-Congo hemorrhagic Fever - Bunyaviridae

enveloped, helical, segmented (3), ssRNA (-)

• most widely distributed hemorrhagic fever in the world

• Endemic in Africa, Europe, Asia, and Mediterranean

• Tick-borne

Rift Valley Fever Virus - Bunyaviridae

enveloped, helical, segmented (3), ssRNA (-)

• virus in cattle, sheep, humans found in Africa

• Transmitted via mosquitos and handling of meat

• Flu-like symptoms and may mimic meningitis

Mumps - Paramyxoviruses

spikes bind to UR tract glycoprotein receptors

• parotitis: inflamed/tender chipmunk parotid glands

• Orchitis: exquisitely painful & inflamed testes

• Aseptic meningitis —> causes HA, fever, meningitis

Measures - Paramyxoviruses

spikes bind to UR track glycoprotein receptors

• Rubeola —> protected against with the MMR vaccine

• Incubation - 2 weeks prior to characteristic rash

• Prodrome - flu-like illness, conjuctivitis, swelling of eyelids, Koplik’s spots appear ~2 days prior to skin rash

  • Skin rash - red maculopapular (flat to bumpy), head-down-to-toes disappears over 3 days

• Complications - pneumonia, eye damage, myocarditis, and encephalitis. Measles in pregnancy causes spontaneous abortion, premature delivery, and fetal death in 20% of cases —> does not cause birth defects

Orthomyxoviruses - Influeza virus

enveloped, (-) ssRNA, linear, helical, and segmented

• Flu A: occurs in many animals, multiple subtypes

• Flu B: less widespread (humans)

• Flu C: rare (humans)

Two types of spikes

• Hemagglutinin (HA) —> attachment

• Neuraminidase (NA) —→ release/budding

Ebola Virus - Filoviridae

enveloped, (-) ssRNA, linear, helical

• Ebola Virus > fever > HA > diarrhea > vomiting > thrombocytopenia > hemorrhage/shock > DIC

• Nearly 100% mortality rate

• Transmission - via body fluids

• Hosts - bats, chimpanzees, monkeys, humans

• Reservoirs - unknown

  • BSL4 pathogen

Rabies - Rhabdoviridae

enveloped, (-) ssRNA, linear, helical

• variable incubation —> usually 1-3 months

• Human “dumb” rabies: fever, confusion, anxiety, encephalitis, death

• Two vaccines

  • Human diploid cell vaccine - requires 7-10 days to induce active immunity

  • Passive immunization - human rabies immune globulin and provides immediate protection

Hepatitis B - Deltaviridae

Diseases —> fulminant hepatitis, chronic hepatitis
Hep D —> cannot occur without HBV

Positive Sense RNA Viruses

Viral mRNA that can be directly translated into proteins. Families are Flaviviridae, Matonaviridae, Togaviridae, Retroviridae, Coronaviridae, Picornaviridae, Caliciviridae, Reoviridae, Hepeviridae

Flaviviridae

Icosahedral Enveloped (+) ssRNA virus family, all are arboviruses (mosquito-Bourne, Vector: Aedes), except Hepatitis C. Key Members: Dengue, Saint Louis Encephalitis, West Nile Encephalitis, Yellow fever, Zika

Dengue Fever: Flaviviridae

Four major strains (1-4), occurs in Asia and South America, First infection =“Breakbone Fever”, Aedes mosquito transmits dengue virus, high fever, severe muscle and bone pain. Second infection = if infected with a 2nd Dengue strain, high fever and rash from skin hemorrhages, severe vomiting and shock —> often fatal

St. Louis & West Nile Virus: Flaviviridae

outbreaks occur in UR, bird virus transmitted by mosquitoes, also infects horses and humans, fever and “flu-like” muscle aches and pains

Yellow Fever Virus: Flaviviridae

aedes mosquito transmits, occurs in South America and Africa, also called “yellow jackets” fever = high fever and jaundice, infects liver = liver enzyme AST»» ALT, bleeding gums, bloody stools, hematomas is - 50% mortality due to internal bleeding

Zika Virus: Flaviviridae

Found in tropical/subtropical regions, asymptomatic or mild - fever, rash, conjuctivitis, muscle and join pain, malaise, and headache, fetal infection causes microcephaly. Transmitted via: mosquito, mother to unborn child, sexual intercourse, blood transfusion

Hepatitis C Vius: Flaviviridae

#1 cause of chronic hepatitis, cirrhosis, and liver cancer, 90% of HCV+ are asymptomatic and chronic carriers. Transmission: percutaneous blood and needles risk = high, mucosal sex and mother to infant risk = very low

Rubella: Matonaviridae

enveloped (+) ssRNA Virus

• “3-day measles”

• One of several childhood rashes

• Acquired via inhalation of respiratory droplets

• Congenital Rubella Syndrome

  • TORCH infection - mother acquires infection via resp droplets —> classic triad in newborn: deafness, cataracts, cardiac disease

Equine Encephalitis: Togaviridae

enveloped (+) ssRNA virus

• Eastern and Western Equine Encephalities

• Found in North America —> mosquito - borne

• Viruses reside in birds and can infect humans and horse

  • Most patients asymptomatic; may cause encephalitis —> fever, mental status changes

HIV and HTLV-1: Retroviridae

enveloped, ssRNA, reverse transcriptase (RNA-dependent DNA polymerase)

• HIV = two copies of ssRNA genome

• HTLV-1 = linked to adult T-cell leukemia/lymphoma

Corona Virus: Coronaviridae

enveloped, (+) ssRNA, helical

• URI - Common cold

  • Clinical Presentation - up to 1-week prodrome = fever, HA< malaise myalgia, cough, dyspnea, loss of smell/taste, nuisance to respiratory failure and earth

Picornaviridae

All fecal-oral transmission, except rhinoviruses, naked (+) ssRNA virus

Poliovirus: Picornaviridae

Polio = febrile illness followed by weakness/paralysis
1. Inactivated poliovirus vaccine (IPV/Salk) Killed = cannot cause vaccine-associated polio, only used in US, systemic antibody response IgG

2. Live attenuated oral polio vaccine (OPV/Sabin) = cheap and easy to administer (oral), fecal-oral transmission to some unimmunized contacts, live polio virus…carries a risk of causing polio, triggers local immunity in GI mucosa IgA

Echovirus: Picornaviridae

Aspetic (viral) meningitis, 90% of viral meningitis cases caused by Coxsackieviruses and Echoviruses

Enteroviruses: Picornaviridae

Common cause of mild, febrile illness, occasional aseptic meningitis, enterovirus 70 can cause hemorrhagic conjunctivitis

Rhinovirus: Picornaviridae

Viral upper respiratory illness, most common virus associated with common cold

Coxsackievirus: Picornaviridae

• Aspetic meningitis (group A and B)

• Group A = hand-foot-mouth - benign, self-limiting, small lesions on hands, feet, buttock and in mouth, childhood illness

• Group A = herpangina - high fever, painful mouth blisters, classically in children during the summer

  • Group B = myocarditis, pericarditis

Hepatitis A: Picornaviridae

Foodborne, acute viral hepatitis, no chronic disease, no carriers (100% clearance)

Calicivirus: Caliciviridae

naked, (+) ssRNA virus

• Norovirus/Norwalk-like virus: #1 cause of gastroenteritis

  • 2-3 days of watery diarrhea, nausea, vomiting

  • Not inflammatory

  • Watery diarrhea….negative fecal leukocytes

  • Fecal-oral, low infectious dose, shed for weeks after infection

  • Common cause of outbreaks: schools, cruise ships, hospitals, nursing homes

Coltivirus/Colorado Tick Fever: Reoviridae

Naked, (+) dsRNA virus, contains RNA-dependent RNA polymerase

• transmitted by Rocky Mountain wood tick

• Lives in Rocky Mountains rodents

• Fever, chills, myalgias, headache

Rotavirus: Reoviridae

make, (+) dsRNA virus

• most common cause of gastroenteritis in infants and young children

• Fecal-oral transmission

• Infects mucosal cells

• Vomiting, diarrhea and fever

• Excess loss of fluids and electrolytes

• Watery diarrhea - no blood or fecal leukocytes

Hepatitis E: Hepeviridae

Naked, (+) ssRNA virus

• causes transient watery diarrhea

• Fecal-oral transmission through contaminated water

• Common in SE Asia

Amantadine & Rimantadine MOA

prevents uncoating and disassembly, blocks matrix-2 (M2) proton ion channel of virus particles —> interferes with uncoating of viral RNA of influenza A —> prevents viral replication

Amantadine & Rimantadine Resistance

Amantadine resistance influenza A common via change in one amino acid in channel protein

Amantadine & Rimantadine Adverse Effects

Amantadine: Neuropsychiatric (hallucinations, insomnia, confusion, seizures, depression); Anticholinergic

Influenza A & B: Oseltamivir, Zanamvir, Peramivir MOA

Inhibition or neuraminidases in influenza A & B, neuraminidase enzyme cleaves silica acid from viral and host cell surface proteins thus helping in vision release and anticlumping

Influenza A & B: Oseltamivir, Zanamvir, Peramivir Resistance

Via mutation in neuraminidase

Influenza A & B: Oseltamivir, Zanamvir, Peramivir Spectrum

decrease duration (by 1-1.5 days) and severity if used in 48 hours, prophylactic use is effective (outbreak —> prevention)

Influenza A & B: Oseltamivir, Zanamvir, Peramivir AE

Oseltamivir: GI discomfort

Ribavirin - RSV: MOA

Antimetabolite, A triazine ribosome analog. Converted intracellularly to a 5’-triphosphate derivative that inhibits viral RNA polymerase

Ribavirin - RSV: Use

RSV in hospitalized infants, Hepatitis C infection, orally and only in combo with other HCV drugs

Ribavirin - RSV: AE

Hemolytic anemia, aerosolized ribavirin (sudden deterioration of respiratory function in infants, not indicated for use in adults —> testicular lesions and teratogenicity)

Acyclovir - HSV1, HSV2, and VZV: MOA

Antimetabolite, drug activated by viral (thus infected cells most susceptible) and then host enzyme, acts as competitive substrate to DNA polymerase & terminates chain post incorporation into viral DNA

Acyclovir - HSV1, HSV2, and VZV: AE

CNS: tremor, seizures, nephrotoxicity: obstructive crystalline nephropathy and AKI if dehydrated (increase hydration); Eliminated via kidneys, solubility is low

Ganciclovir - CMV: MOA

Antimetabolite, purine nucleoside analog. Activated via phosphorylation by viral and then host enzymes. CMV viral kinase —> UL97 and thymidine kinase for HSV and VZV. Inhibits polymerases of CMV and others and halt in chain elongation.

Ganciclovir - CMV: Pharmacokinetics

Given PO (less bio available) and IV, Valganciclovir (prodrug) given orally, more bio available

Ganciclovir - CMV: AE

Bone marrow suppression (black box warning: leukopenia, neutropenia, thrombocytopenia, anemia)

Foscarnet: MOA

Synthetic, phosphate derivative does not require phosphorylation/kinase-activation for antiviral activity. Inhibits viral RNA & DNA Polymerase and inhibits HIV reverse transcriptase

Foscarnet: Clinical Use

Given only IV, Ganciclovir-resistant cytomegalic retinitis in HIV, Acyclovir - resistant HSV, VZV

Foscarnet: AE

Nephrotoxicity, Electrolyte abnormality (ion chelator), seizures

Interferons: MOA

decrease viral replication, produced by DNA recombinant technology - 3 types: alpha, beta, gamma. Induces host cell enzymes (ribonucleases —> degrade viral mRNA)/antiviral proteins (RNase, JAKS) and host immune responses (NK cells), inhibits foreign viral RNA translations, protein synthesis; blocks viral penetration

Antiviral Hep B agents

Lamivudine (polymerase inhibitor), Tenofovir (Nucleotide, polymerase inhibitor), Adefovir (Nucleotide, used in HBV, polymerase inhibitor), Entecavir (used in HBV, polymerase inhibitor), interferon alpha (used in both HBV and HCV)

HCV targets of drug action - NS3/4A protease inhibitor

Telaprevir, Simeprevir, Grazoprevir. NS3/4A cleaves HCV polyprotein into proteins needed for RNA replication

HCV targets of drug action - NS5A inhibitor

Ledipasvir, Velpatasvir. NS5A viral protein essential for replication

HCV targets of drug action - NS5B polymerase inhibitor

nucleoside (needs activation): sofosbuvir, non-nucleoside: dasabuvir. NS5B an RNA-dependent RNA polymerase needed for HCV replication

Maraviroc - Anti HIV Drug MOA

Binds to CCR5 receptor on T cell surface/macrophage —> prevents interaction of host cell CCR5 with viral gp120 —> blocks viral docking and subsequent entry

Maraviroc - Anti HIV Drug Indication

Treatement of resistance cases

Maraviroc - Anti HIV Drug Pharmacokinetics

CYP3A4 substrate

Maraviroc - Anti HIV Drug AE

Respiratory: cough, URTI, Hepatotoxicity

Enfuvirtide - Anti HIV Drug MOA

Drug blocks entry of virus by binding to gp41 subunit of the viral envelope glycoprotein, preceding fusion of virus with host cell membrane

Enfuvirtide - Anti HIV Drug Indications

Resistant HIV patients

Enfuvirtide - Anti HIV Drug Pharmacokinetics

Non-CYP metabolism

Enfuvirtide - Anti HIV Drug AE

injection site reaction

NRTIs: Zidovudine: MOA

Nucleoside analog/like thymidine. Competitively bind viral reverse transcriptase (RT) (no DNA synthesis from viral RNA) and are incorporated in the growing viral DNA —> chain termination. Requires cytoplasmic activation to the triphosphate form

NRTIs: Zidovudine: Common AE

Mitochondrial Toxicity (rare but fatal’ associated with inhibition of human mitochondrial DNA polymerase: lactic acidosis (LA), liver toxicity, lipodystrophy, neuropathy, pancreatitis, myelosuppresion (anemia, neutropenia with Zidovudine), Abacavir hypersensitivity reaction (AHR) - HLA allele associated with—> delayed hypersensitivity reaction type IV (fever, malaise, GI upset, delayed rash)

NNRTIs: Delaviridine: MOA

bind allosterically to a site (different than NRTI; non-competitive) on RT< alter its shape and prevent viral RNA from becoming DNA. Do not require activation via phosphorylation or compete with nucleotides (so incorporation in growing chain)

NNRTIs: Delaviridine: Side Effects

Skin rash (Steven’s-Johnson syndrome, toxic epidermal necrosis) - not HLA allele associated, liver toxicity, CNS toxicity