Positive-strand RNA viruses

🧬 Positive-Sense RNA: Core Principles

Defining logic

Genome has the same polarity as mRNA
Ribosomes translate it immediately after uncoating
Product is one long polyprotein
- Viral protease cuts it into functional units
Includes the viral RNA-dependent RNA polymerase
- Made de novo after entry
- Not packaged in the virion
Genome RNA alone is infectious when introduced into a cell

Cycle in order

Entry→Uncoating→Translation to polyprotein→Protease cleavage→Polymerase copies (+) to (−)→(−) templates make new (+)→Assembly→Release

Naked members exit by lysing the cell
All replication occurs in the cytoplasm, except retroviruses

Family comparison

Family	Envelope	Shape	Examples
Calici	Naked	Icosahedral	Norovirus
Hepe	Naked	Icosahedral	Hepatitis E
Picorna	Naked	Icosahedral	Polio, coxsackie, echo, rhino, hepatitis A
Flavi	Enveloped	Icosahedral	Yellow fever, dengue, Zika, West Nile, St. Louis encephalitis, hepatitis C
Toga	Enveloped	Icosahedral	Rubella, equine encephalitis viruses, chikungunya
Corona	Enveloped	Helical	Seasonal coronaviruses, SARS, MERS, SARS-CoV-2
Retro	Enveloped	Icosahedral or conical core	HIV, HTLV

Exception

Retroviruses carry two copies of the genome plus packaged reverse transcriptase and replicate through the nucleus.
Their RNA alone cannot start an infection.

🦠 Naked Positive-Sense Viruses: Noro, Picorna

Norovirus (Caliciviridae)

Reservoir: human gut
Spread: fecal-oral, food, water, surfaces
Outbreaks in cruise ships, schools, care homes
Syndrome
- Vomiting, watery diarrhea, nausea
- Noninflammatory: no blood or pus
Leading viral cause of nonbacterial gastroenteritis in adults
Diagnosis: antigen or molecular assays
Treatment: fluids, self-limited
Prevention: handwashing, surface disinfection

Picornavirus family traits

Very small, naked, icosahedral
Resist alcohol and detergents
Peak in summer and fall
Genera
- Enteroviruses: acid-stable, fecal-oral, mostly children
- Rhinoviruses: acid-labile, grow best near 33 °C (nose)
- Hepatovirus: hepatitis A
Enteroviruses rarely cause diarrhea despite the gut route

Picornavirus disease map

Virus	Features
Poliovirus	Fecal-oral; infects anterior horn motor neurons Most cases silent or mild febrile Aseptic meningitis in some Paralytic: flaccid, asymmetric, no sensory loss Post-polio syndrome: new weakness and atrophy decades later Diagnosis: serology and stool culture; virus rarely in CSF Prevention: inactivated (injected) or live oral vaccine
Coxsackie A	Hand-foot-mouth disease (A16) Herpangina Aseptic meningitis, colds
Coxsackie B	Pleurodynia (Bornholm disease) Myocarditis and pericarditis Severe neonatal systemic illness Aseptic meningitis
Enterovirus D68	Respiratory illness Acute flaccid myelitis in children
Echovirus	Fever with rash Aseptic meningitis
Rhinovirus	Most frequent cause of the common cold More than 100 serotypes: no durable immunity, no vaccine Diagnosis clinical
Hepatitis A	Fecal-oral; hepatocyte injury Anti-HAV IgM marks acute infection Inactivated vaccine; immune globulin for exposure

Enterovirus therapy is supportive
Pleconaril blocks uncoating, limited availability, needs early use

Exam trap

Paralytic polio spares sensation because only motor neurons are destroyed.
Acid stability separates enteroviruses from rhinoviruses.

🦟 Enveloped (+) RNA: Flavi, Toga, Corona

Flaviviruses (mostly arthropod-borne)

Virus	Vector	Reservoir	Disease	Prevention
St. Louis encephalitis	Culex mosquito	Birds	Encephalitis	Vector control
West Nile	Culex mosquito	Birds (die-offs)	Encephalitis, flaccid paralysis	Vector control
Dengue	Aedes mosquito	Humans, primates	Breakbone fever: fever, rash, severe muscle and joint pain Second infection with a different serotype can cause hemorrhage and shock	Vector control
Yellow fever	Aedes mosquito	Humans, primates	Fever, jaundice, hemorrhage Liver, kidney, heart injury Black vomit in severe cases	Live attenuated vaccine
Zika	Aedes; also sexual and vertical	Vertebrates	Mild fever, rash, arthralgia, conjunctivitis Congenital: microcephaly, fetal loss	Vector control, safe sex

Diagnosis: serology, PCR; treatment: supportive
Hepatitis C is also a flavivirus (see hepatitis notes)

Togaviruses

Virus	Key points
Eastern, Western, Venezuelan equine encephalitis	Mosquito-borne; birds and horses Encephalitis Inactivated vaccines exist for horses and some at-risk people
Chikungunya	Aedes mosquito Fever, severe polyarthralgia, arthritis
Rubella	Respiratory spread; humans only Mild rash from face to trunk, lymphadenopathy Live attenuated vaccine (MMR) Vaccine contraindicated in pregnancy

Congenital rubella

Worst when maternal infection falls in the first trimester
Cardiac: patent ductus arteriosus, pulmonary artery stenosis
Eye: cataracts
Ear: sensorineural deafness
CNS: microcephaly, developmental delay

Coronaviruses

Enveloped, helical, large (+) RNA genome
Spike glycoprotein gives the crown appearance
Host receptor: ACE2 (for SARS-CoV and SARS-CoV-2)
Seasonal strains: second most common cause of colds, winter-spring

SARS-CoV

Animal reservoir (civets, bats); droplet spread
Atypical pneumonia: fever, dry cough, dyspnea, hypoxia
Patchy interstitial infiltrates
Linked to travel to affected regions
Diagnosis: RT-PCR, antibody, culture
Treatment: supportive

SARS-CoV-2 (COVID-19)

Droplet and aerosol spread; asymptomatic carriers contribute
- Higher severity in elderly and immunocompromised
Incubation about 4–14 days
Systemic: fever, chills, myalgia, fatigue, headache
Respiratory: cough, sore throat, congestion, dyspnea, loss of smell or taste
GI symptoms possible
Severe: bilateral infiltrates, ARDS, ventilation
Diagnosis
- Nucleic acid amplification (RT-PCR) is most sensitive
- Antigen tests: faster, less sensitive
- Serology shows past exposure
Treatment by severity
- Mild: supportive
- Hospitalized: remdesivir (adenosine analog), dexamethasone if oxygen needed
Prevention
- Masks, distancing, isolation of exposed persons
- Vaccines: mRNA, adenoviral vector, protein nanoparticle; all target spike

MERS-CoV

Reservoir: bats, camels
Severe respiratory illness similar to SARS

Exam trap

Culex transmits West Nile and St. Louis encephalitis; Aedes transmits dengue, yellow fever and Zika.

🩸 Retroviruses and HIV

Retrovirus features

Enveloped, diploid (+) RNA
Virion carries reverse transcriptase
Integrates as a DNA provirus
Groups
- Oncoviruses: HTLV
- Lentiviruses: HIV

HTLV

T-cell tropic; Tax protein drives transformation
Adult T-cell leukemia with flower-shaped nuclei
HTLV-1 associated myelopathy (spastic paraparesis)
Endemic: Japan, Caribbean, South America

HIV virion parts

Host-derived envelope with gp120 (surface) and gp41 (transmembrane)
Matrix p17 under envelope
Conical capsid p24
Nucleocapsid p7/p9 around two RNA copies
Enzymes: reverse transcriptase, integrase, protease

Cell entry

gp120 binds CD4→Conformation change exposes coreceptor site→CCR5 (macrophage-tropic) or CXCR4 (T-cell-tropic)→gp41 mediates fusion

Targets: helper T cells, macrophages, microglia, dendritic cells

Gene functions

Gene	Product	Role
gag	p24, p17, p7/p9	Capsid, matrix, nucleocapsid
pol	Reverse transcriptase	Makes dsDNA provirus; error-prone, drives variation
pol	Integrase	Inserts viral DNA into host genome
pol	Protease	Cleaves polyproteins for maturation
env	gp120	Receptor binding, tropism, antigenic variation
env	gp41	Membrane fusion
LTR	Long terminal repeats	Promoter and integration sites
tat	Transactivator	Boosts transcription
rev	RNA transport protein	Exports unspliced RNA to cytoplasm
nef	Regulatory protein	Lowers CD4 and MHC I on host cells; needed for progression

Host and viral variants

Change	Effect
Defective nef	Slow or absent progression
Defective tat or rev	No replication
Defective vif	Slow progression
CCR5 loss, homozygous	Strong resistance to infection
CCR5 loss, heterozygous	Slower progression

Replication of HIV

Attachment and fusion→Uncoating→Reverse transcription to dsDNA→Nuclear import with integrase→Provirus integrated→Transcription (tat boosts)→Spliced RNA to mRNA; unspliced to genomes→Translation to polyproteins→Assembly and budding→Protease maturation

Coinfections that activate immune cells increase viral output

Transmission and natural history

Spread: sexual contact, blood exposure (needles, transfusion), vertical (birth, breastfeeding)
Reservoir: helper T cells and macrophages

Acute retroviral syndrome→Asymptomatic phase→Persistent lymphadenopathy→Symptomatic disease→AIDS

Course tracks falling CD4 count; viral load tracks prognosis

Staging by CD4 count (age 6 and older)

Stage	CD4 count	CD4 %
1	≥ 500/µL	≥ 26%
2	200–499/µL	14–25%
3 (AIDS)	< 200/µL	< 14%

Younger children use higher thresholds because normal counts are higher
Any stage-3-defining opportunistic illness places the patient in stage 3 regardless of count
Count takes priority over percentage

Early symptomatic conditions

Oral thrush, recurrent vaginal candidiasis
Oral hairy leukoplakia
Bacillary angiomatosis
Cervical dysplasia
Prolonged fever or diarrhea
Immune thrombocytopenia
Listeriosis
Pelvic inflammatory disease
Peripheral neuropathy

AIDS-defining conditions

Recurrent pneumonia; leading cause of death
HIV encephalopathy; wasting
Fungal
- Pneumocystis pneumonia
- Esophageal, bronchial or pulmonary candidiasis
- Disseminated coccidioidomycosis, histoplasmosis
- Extrapulmonary cryptococcosis
Viral
- CMV retinitis or disseminated disease
- Chronic or invasive herpes simplex
- Progressive multifocal leukoencephalopathy
Parasitic
- Cerebral toxoplasmosis
- Chronic cryptosporidiosis, isosporiasis
Bacterial
- Tuberculosis at any site
- Disseminated Mycobacterium avium complex
- Recurrent nontyphoidal Salmonella bacteremia
Cancers
- Kaposi sarcoma, invasive cervical carcinoma
- Primary CNS lymphoma, Burkitt and immunoblastic lymphoma

Prophylaxis thresholds

Pathogen	Start below CD4 of
Pneumocystis jirovecii	200
Toxoplasma gondii	100
Histoplasma (endemic area)	100
M. avium complex	50
CMV	50
Cryptococcus	50

Laboratory testing

Goal	Test
Screening	Fourth-generation antigen/antibody immunoassay
Confirmation	HIV-1/HIV-2 differentiation assay; viral RNA test if unclear
Viral load, treatment monitoring	RT-PCR of plasma RNA
Infant of infected mother	PCR for proviral DNA or RNA
Earliest marker	p24 antigen
Disease progression	CD4 count, CD4:CD8 ratio

Maternal antibody crosses the placenta, so infant antibody tests mislead

Antiretroviral classes

Class	Examples	Notes
Nucleoside/nucleotide RT inhibitors	Zidovudine, tenofovir, lamivudine	Zidovudine: marrow suppression, anemia
Non-nucleoside RT inhibitors	Efavirenz, nevirapine	Cross-resistance common
Protease inhibitors	Names end in -navir (ritonavir)	Fat redistribution, glucose and lipid changes, drug interactions
Integrase inhibitors	Raltegravir	High barrier to resistance
Fusion inhibitor	Enfuvirtide	Blocks gp41
CCR5 antagonist	Maraviroc	Only for CCR5-tropic virus

Standard therapy combines several classes to prevent resistance
No vaccine exists
Prevention: safe sex, screening blood and organs, sterile needles, perinatal antiretrovirals

Exam trap

RT-PCR measures circulating virus; proviral PCR detects integrated DNA.
Oral hairy leukoplakia is an early marker, not an AIDS-defining illness.

🔄 Negative-Sense RNA: Principles and Paramyxoviruses

Shared rules

Genome is complementary to mRNA, so it cannot be translated directly
Virion packs its own RNA-dependent RNA polymerase
All are enveloped with helical nucleocapsids
Replicate in the cytoplasm, except influenza (nucleus)

Entry→Polymerase transcribes (−) into mRNAs→Proteins made→Full-length (+) copy→New (−) genomes→Budding

Family structure

Family	Genome layout	Examples
Paramyxo	Linear, one piece	Measles, mumps, RSV, parainfluenza, metapneumovirus
Rhabdo	Linear, one piece; bullet shape	Rabies, vesicular stomatitis
Filo	Linear, one piece; filamentous	Ebola, Marburg
Orthomyxo	Linear, 8 segments	Influenza A, B
Bunya	Circular-like, 3 segments	California and LaCrosse encephalitis, hantavirus
Arena	Circular, 2 segments	LCMV, Lassa

Bunya and arena genomes contain ambisense segments

Measles

Single serotype; hemagglutinin and fusion proteins; no neuraminidase
Respiratory spread; extremely contagious
Fusion causes multinucleated giant cells
Illness
- Cough, coryza, conjunctivitis, photophobia
- Koplik spots in mouth
- Rash from head downward
- Giant-cell pneumonia (Warthin-Finkeldey cells)
Subacute sclerosing panencephalitis
- Late complication, several years later
- Defective virus persists in brain
- Progressive neurodegeneration
Diagnosis: serology
Treatment: supportive; vitamin A in children
Prevention: live attenuated MMR

Mumps

Single serotype; HN and F glycoproteins
Droplet spread; infects upper airway then parotids
Parotitis, fever, malaise (some subclinical)
Complications
- Orchitis, with possible infertility
- Pancreatitis
- Meningoencephalitis
Diagnosis: clinical, serology, PCR
Prevention: live attenuated MMR

Other paramyxoviruses

Virus	Disease	Diagnosis	Management
Parainfluenza	Croup in children: subglottal swelling, barking cough, stridor; also colds, pneumonia	RT-PCR	Supportive; steroids and racemic epinephrine for croup
RSV	Infant bronchiolitis: bronchiolar necrosis, wheeze, tachypnea; adult colds; severe in premature infants	Antigen assay, RT-PCR	Supportive; palivizumab (anti-fusion protein antibody) prevents severe disease in high-risk infants; ribavirin in select cases
Human metapneumovirus	Colds, bronchiolitis, pneumonia	RT-PCR	Supportive

Concept

Paramyxovirus fusion proteins create syncytia, so infected cells merge into giant cells.

🐕 Rabies, Filoviruses, Influenza

Rabies virus

Bullet-shaped, enveloped, helical
Reservoirs: bats, raccoons, skunks, foxes; dogs worldwide
Spread: bite or contact with saliva of rabid animal
Pathogenesis
- Replicates in muscle at the bite
- Binds nicotinic acetylcholine receptors on nerves
- Retrograde axonal transport to spinal cord and brain
Clinical
- Flu-like prodrome, pain or tingling at bite
- Hydrophobia, agitation, seizures, hallucinations
- Coma and death
Almost uniformly fatal once symptomatic
Diagnosis
- Negri bodies (cytoplasmic inclusions) in brain neurons
- Direct fluorescent antibody on tissue or corneal smears
- PCR
Postexposure prophylaxis
- Wound washing
- Human rabies immune globulin
- Inactivated vaccine series on days 0, 3, 7, 14
Prevention: vaccinate pets; preexposure vaccine for high-risk workers

Filoviruses

Enveloped, filamentous, helical
Members: Ebola (Zaire species most lethal), Marburg
Reservoir: bats (possible for Ebola, confirmed for Marburg)
Spread: contact with blood or body fluids, handling infected animals or bushmeat
Pathogenesis
- Macrophages and dendritic cells infected first
- Spread via lymph nodes to blood
- Cytokine storm, vascular leak, multi-organ failure
Clinical
- Incubation about 6–12 days
- Fever, chills, malaise, headache
- Vomiting and diarrhea with major fluid loss
- Bleeding is possible but not dominant
- Rash, meningoencephalitis
Diagnosis: exposure history, RT-PCR confirms
Treatment: aggressive supportive care; monoclonal antibodies targeting glycoprotein
Prevention: isolation and infection control; live recombinant vesicular stomatitis vaccine

Influenza virus

Enveloped, 8 RNA segments, replicates in nucleus
Surface proteins
- Hemagglutinin (H): attachment and fusion
- Neuraminidase (N): releases new virions
Reservoirs
- Influenza A: birds, pigs, humans
- Influenza B: humans only
Spread: droplets and contact
Antigenic drift
- Point mutations in H and N
- Influenza A and B
- Causes seasonal epidemics
Antigenic shift
- Influenza A only
- Cell coinfected with two strains; segments reassort
- Novel subtype with no population immunity
- Causes pandemics
Example: 2009 H1N1 was a reassortant of swine, avian and human segments

Clinical
- Abrupt fever, chills, headache, myalgia, cough, malaise
- Children: croup, otitis media, vomiting
- Complications: secondary bacterial pneumonia, myocarditis
- Associations: Reye syndrome (aspirin), Guillain-Barré syndrome
Diagnosis: rapid antigen or PCR testing plus season
Treatment
- Neuraminidase inhibitors: oseltamivir (oral), zanamivir (inhaled)
- M2 blockers (amantadine, rimantadine): most strains now resistant
Prevention
- Annual inactivated vaccine, updated each year
- Live intranasal vaccine exists but is not generally recommended

Exam trap

Drift happens in both A and B; shift and pandemics are influenza A only.
Rabies is diagnosed by Negri bodies but treated before symptoms begin.

🐀 Bunyaviruses, Arenaviruses, Reoviruses

Bunyaviridae

Enveloped, 3 segments (one ambisense)
Mostly arboviruses, hantavirus is the exception (rodent-borne)

Virus	Spread	Disease	Diagnosis
California and LaCrosse	Mosquito	Viral encephalitis, mainly in children	Serology
Hantavirus (Sin Nombre)	Inhaled rodent excreta; southwestern U.S.	Cough, myalgia, fever, dyspnea Noncardiogenic pulmonary edema, effusions Hypotension; mortality about 50%	RT-PCR

Arenaviridae

Pleomorphic, enveloped, 2 segments (one ambisense)
Sandy appearance from host ribosomes in virion

Virus	Spread	Disease	Treatment
Lymphocytic choriomeningitis	Mice and pet hamsters	Flu-like illness with aseptic meningitis	Supportive, ribavirin
Lassa fever	Rodents, then person to person (West Africa)	Hemorrhagic fever, high fatality, deafness	Supportive, ribavirin

Lassa needs high-containment handling

Reoviridae (double-stranded RNA)

Only RNA virus family with a double-stranded genome
Naked, icosahedral, double protein shell
10–12 genome segments; packaged RNA polymerase
Segmentation permits reassortment
Members: reovirus, rotavirus, Colorado tick fever virus

Virus	Spread	Disease	Diagnosis	Prevention
Reovirus	Fecal-oral, respiratory	Mild cold-like or gastrointestinal illness	Serology	None needed
Rotavirus	Fecal-oral	Infant watery diarrhea, dehydration, no blood or pus	Stool antigen assay	Live attenuated oral vaccine
Colorado tick fever virus	Tick bite	Biphasic fever, myalgia	Serology, PCR	Tick avoidance

Rotavirus is the leading cause of severe diarrhea in young children
Treatment centers on oral or IV rehydration

High-yield

Rotavirus vaccine is given by mouth, not injection.

🧠 Prions and Slow Infections

Prion biology

Infectious protein with no nucleic acid
Extremely resistant to heat, radiation, standard disinfectants and protease
Normal form: PrP^C
- Made by neurons, sits on cell surface
- Gene on chromosome 20
- Protease-sensitive, mostly alpha-helical
Abnormal form: PrP^Sc
- Misfolded, beta-sheet rich
- Protease-resistant, aggregates

Conversion chain

PrP^Sc contacts PrP^C→PrP^C refolds to PrP^Sc→More PrP^Sc templates more→Aggregates build in neurons→Vacuoles, neuron loss→Spongiform encephalopathy

No inflammatory response and no antibody response
Brain shows vacuolation, gliosis, no inflammation
No effective treatment; always fatal

Human and animal prion diseases

Disease	Host	Notes
Kuru	Human	Ritual cannibalism, Papua New Guinea highlands
Creutzfeldt-Jakob disease	Human	Rapid dementia, myoclonus Mostly sporadic; some inherited; some iatrogenic Variant form linked to contaminated beef
Gerstmann-Sträussler-Scheinker	Human	Inherited, ataxia then dementia
Fatal familial insomnia	Human	Inherited, thalamic degeneration, intractable insomnia
Scrapie	Sheep	Animals scratch against objects

Slow conventional virus infections

Condition	Agent	Setting
Subacute sclerosing panencephalitis	Defective measles virus	Years after early measles infection
HIV-associated dementia	HIV (microglia)	Advanced immunodeficiency
Progressive multifocal leukoencephalopathy	JC polyomavirus	AIDS, transplant, immunomodulator therapy; oligodendrocyte destruction

Exam trap

Prions are not destroyed by routine autoclaving, so specialized sterilization is required.
Viral slow infections are true viruses with nucleic acid; prions are not.