Virology

DNA Viruses

DNA viruses generally carry double-stranded DNA genomes, enter the host cell nucleus, and use host DNA-dependent RNA polymerase to transcribe viral mRNA. The major exception is poxvirus, which replicates entirely in the cytoplasm because it encodes its own DNA-dependent RNA polymerase. Two other high-yield exceptions are parvovirus B19, a single-stranded DNA virus, and hepatitis B virus, a partially double-stranded circular DNA virus that replicates through an RNA intermediate using reverse transcriptase.

Core Classification

Family	Genome / Envelope	Key Diseases	High-Yield Features
Parvoviridae	Linear ssDNA, nonenveloped	Erythema infectiosum, aplastic crisis, hydrops fetalis	Replicates in rapidly dividing erythroid precursors; uses P antigen on RBC precursors
Polyomaviridae	Circular dsDNA, nonenveloped	JC virus: progressive multifocal leukoencephalopathy; BK virus: nephropathy, hemorrhagic cystitis	Reactivation in immunosuppression; JC infects oligodendrocytes
Papillomaviridae	Circular dsDNA, nonenveloped	Warts, cervical dysplasia/cancer, anogenital and oropharyngeal cancers	HPV E6 inhibits p53; E7 inhibits Rb; koilocytosis
Adenoviridae	Linear dsDNA, nonenveloped	Pharyngoconjunctival fever, pneumonia, gastroenteritis, hemorrhagic cystitis	Icosahedral capsid with fiber proteins; outbreaks in crowded settings
Herpesviridae	Linear dsDNA, enveloped	HSV-1/2, VZV, EBV, CMV, HHV-6/7, HHV-8	Latent infection with reactivation; multinucleated giant cells for HSV/VZV
Poxviridae	Linear dsDNA, enveloped	Smallpox, molluscum contagiosum	Replicates in cytoplasm; large brick-shaped virion
Hepadnaviridae	Partially ds circular DNA, enveloped	Hepatitis B, cirrhosis, hepatocellular carcinoma	Reverse transcriptase; Dane particle; serum markers define infection stage

Replication Principles

Most DNA viruses follow a nuclear replication strategy: attachment to host receptors, entry, uncoating, transport of the genome to the nucleus, early gene transcription, DNA replication, late structural protein synthesis, assembly, and release. Because host polymerases are most active during S phase, smaller DNA viruses often push cells into the cell cycle. This explains oncogenic mechanisms such as HPV E6-mediated degradation of p53 and E7-mediated inhibition of Rb, both of which remove normal G1-to-S checkpoint control.

Envelope status matters clinically. Nonenveloped viruses such as parvovirus, papillomavirus, polyomavirus, and adenovirus are relatively resistant to drying, detergents, acid, and bile, making fecal-oral and fomite transmission efficient. Enveloped viruses such as herpesviruses, poxviruses, and HBV are generally more sensitive to desiccation and detergents, but HBV is unusually stable in dried blood and is transmitted by blood, sexual contact, and perinatal exposure.

High-Yield DNA Virus Associations

• Parvovirus B19: causes “slapped-cheek” rash in children; transient aplastic crisis in sickle cell disease due to erythroid precursor arrest; fetal infection may cause severe anemia and hydrops fetalis.
• Adenovirus: produces fever, pharyngitis, conjunctivitis, and sometimes pneumonia; can cause hemorrhagic cystitis, especially in children and immunocompromised patients.
• HSV-1 and HSV-2: painful vesicles; HSV-1 classically oral lesions and encephalitis involving temporal lobes; HSV-2 classically genital lesions and neonatal herpes.
• VZV: chickenpox with diffuse vesicles in different stages; reactivation causes shingles in a dermatomal distribution.
• EBV: infectious mononucleosis with atypical lymphocytes; associated with Burkitt lymphoma, nasopharyngeal carcinoma, some Hodgkin lymphomas, and post-transplant lymphoproliferative disease.
• CMV: congenital infection with periventricular calcifications, sensorineural hearing loss, and “blueberry muffin” rash; in immunosuppression, causes retinitis, colitis, and pneumonitis.
• HHV-6: roseola infantum, characterized by high fever followed by rash after defervescence.
• HHV-8: Kaposi sarcoma, especially with impaired T-cell immunity.

Diagnosis and Prevention

For many DNA viruses, PCR nucleic acid amplification is the most sensitive and specific diagnostic method, particularly for HSV encephalitis, CMV disease, BK virus nephropathy, and adenovirus in severe disease. Cytopathic clues remain Step 1 favorites: HSV/VZV produce multinucleated giant cells with Cowdry type A inclusions; CMV produces enlarged cells with “owl’s eye” intranuclear inclusions; HPV produces koilocytes with perinuclear clearing.

Vaccine	Type	Key Schedule / Number	Exam Relevance
Hepatitis B	Recombinant HBsAg	Routine 3-dose series at 0, 1, and 6 months; birth dose recommended within 24 hours	Prevents chronic HBV and hepatocellular carcinoma
HPV	Recombinant virus-like particle vaccine	Routine at ages 11–12; 2 doses if started before age 15, 3 doses if started at age 15 or later or immunocompromised	Targets high-risk HPV types including 16 and 18
Varicella	Live attenuated	2 doses routinely in childhood	Contraindicated in pregnancy and severe immunodeficiency

Antiviral Pharmacology

Drug	Major Targets	Mechanism	Representative Adult Dose
Acyclovir / Valacyclovir	HSV, VZV	Guanosine analog phosphorylated by viral thymidine kinase; inhibits viral DNA polymerase and causes chain termination	Acyclovir 400 mg orally 3 times daily for mucocutaneous HSV; half-life about 2.5–3.3 hours
Ganciclovir / Valganciclovir	CMV	Guanosine analog phosphorylated by CMV UL97 kinase; inhibits viral DNA polymerase	Valganciclovir 900 mg orally twice daily for induction in CMV disease; major toxicity is myelosuppression
Foscarnet	Acyclovir-resistant HSV, ganciclovir-resistant CMV	Pyrophosphate analog directly inhibits viral DNA polymerase; does not require phosphorylation	Common toxicities: nephrotoxicity, hypocalcemia, hypomagnesemia, seizures
Cidofovir	CMV, adenovirus, poxvirus	Cytidine nucleotide analog inhibiting viral DNA polymerase	Nephrotoxic; given with probenecid and hydration in selected settings

The unifying Step 1 principle is that DNA virus disease reflects the interaction between viral genome strategy, tissue tropism, immune control, and latency or persistence. Antiviral selectivity usually comes from targeting virally encoded polymerases or virus-specific activating enzymes.

RNA Viruses

RNA viruses have RNA, rather than DNA, as their genetic material. Because human cells do not encode an RNA-dependent RNA polymerase, most RNA viruses must either carry this enzyme in the virion or encode it immediately after entry. RNA polymerases lack proofreading, producing high mutation rates, approximately 10⁻³ to 10⁻⁵ errors per nucleotide copied; this explains rapid antigenic variation, vaccine escape, and antiviral resistance. With the major exception of influenza virus, which replicates partly in the nucleus, most non-retroviral RNA viruses replicate in the cytoplasm.

Classification by Genome Polarity and Structure

Genome type	Key replication principle	Major families and examples	High-yield features
Positive-sense ssRNA	Genome functions directly as mRNA and is translated immediately by host ribosomes.	Picornaviridae: poliovirus, coxsackievirus, echovirus, rhinovirus, hepatitis A; Caliciviridae: norovirus; Flaviviridae: hepatitis C, dengue, yellow fever, Zika, West Nile; Togaviridae: rubella; Coronaviridae: SARS-CoV-2.	Often translated as a large polyprotein cleaved by viral proteases. Many naked positive-sense RNA viruses are acid-stable and transmitted fecal-orally.
Negative-sense ssRNA	Genome is complementary to mRNA; virion must carry RNA-dependent RNA polymerase.	Orthomyxoviridae: influenza; Paramyxoviridae: measles, mumps, RSV, parainfluenza; Rhabdoviridae: rabies; Filoviridae: Ebola, Marburg; Bunyaviridae; Arenaviridae.	All clinically important negative-sense RNA viruses are enveloped. Many have helical nucleocapsids.
Double-stranded RNA	Virion carries RNA-dependent RNA polymerase to transcribe mRNA from the negative strand.	Reoviridae: rotavirus.	Segmented genome; rotavirus has 11 segments and causes severe infantile gastroenteritis.

Enveloped versus Naked RNA Viruses

Envelope status is highly testable because it predicts transmission and environmental stability. Naked RNA viruses are more resistant to drying, acid, detergents, and bile; they commonly spread by the fecal-oral route. Classic naked RNA viruses include picornaviruses, caliciviruses, reoviruses, and hepatitis E virus. Enveloped RNA viruses are more fragile, require close contact, respiratory droplets, blood, sexual transmission, or arthropod vectors, and often enter by fusion of the viral envelope with host membranes.

Major RNA Virus Families and Classic Associations

• Picornaviruses are small, naked, positive-sense RNA viruses. Poliovirus infects via the fecal-oral route, replicates in the oropharynx and intestine, and may invade the CNS to destroy anterior horn motor neurons, causing asymmetric flaccid paralysis. Rhinovirus binds ICAM-1 and replicates best at approximately 33°C, favoring the nasal mucosa.
• Calicivirus, especially norovirus, causes acute vomiting and watery diarrhea in outbreaks on cruise ships, schools, and nursing homes. Incubation is typically 12–48 hours, with illness lasting 1–3 days.
• Flaviviruses are enveloped positive-sense RNA viruses. Hepatitis C establishes chronic infection through high mutation rates; dengue can cause hemorrhagic fever and shock, especially with secondary infection by a different serotype due to antibody-dependent enhancement.
• Coronaviruses are enveloped positive-sense RNA viruses with a large genome and spike proteins. SARS-CoV-2 binds ACE2, with spike protein priming by host proteases such as TMPRSS2.
• Orthomyxovirus influenza is enveloped, negative-sense, and segmented. Influenza A has 8 RNA segments; hemagglutinin binds sialic acid, and neuraminidase promotes viral release. Antigenic drift results from point mutations; antigenic shift results from reassortment of segmented genomes, enabling pandemics.
• Paramyxoviruses are enveloped, nonsegmented, negative-sense viruses. Their fusion proteins produce multinucleated giant cells, or syncytia. Measles causes cough, coryza, conjunctivitis, Koplik spots, and a descending maculopapular rash; RSV causes bronchiolitis in infants.
• Rhabdovirus rabies is bullet-shaped and travels retrograde along peripheral nerves to the CNS after animal bites, producing encephalitis, hydrophobia, and Negri bodies in neurons.
• Reovirus rotavirus causes nonbloody diarrhea in infants by damaging mature enterocytes and producing NSP4, a viral enterotoxin. Severe disease peaks around 6–24 months of age.

Antiviral and Vaccine Correlations

Step 1 emphasizes mechanisms. Oseltamivir and zanamivir inhibit influenza neuraminidase and are most effective when started within 48 hours of symptom onset; a common adult oseltamivir regimen is 75 mg orally twice daily for 5 days. Amantadine and rimantadine block the influenza A M2 proton channel but are rarely used because of resistance. Direct-acting hepatitis C antivirals include sofosbuvir 400 mg daily, an NS5B polymerase inhibitor; modern combinations achieve sustained virologic response at 12 weeks in >95% of many treated populations. Ribavirin inhibits IMP dehydrogenase and viral RNA synthesis but causes hemolytic anemia and is teratogenic. Live attenuated rotavirus vaccine is given orally in infancy, beginning at about 2 months, and is contraindicated in severe immunodeficiency.

Retroviruses

Retroviruses are enveloped, positive-sense, single-stranded RNA viruses that replicate through a DNA intermediate. Their defining enzyme is RNA-dependent DNA polymerase, better known as reverse transcriptase. Unlike ordinary positive-sense RNA viruses, retroviral RNA is not used directly as mRNA immediately after entry; instead, it is copied into double-stranded DNA, which integrates into the host genome as a provirus.

Core structure and classification

Retroviruses contain two identical copies of linear positive-sense ssRNA, making them functionally diploid. They are enveloped and therefore sensitive to drying, detergents, and solvents. The major human retroviruses are HIV-1, HIV-2, HTLV-1, and HTLV-2.

Virus	Retrovirus group	Major disease association	High-yield mechanism
HIV-1	Lentivirus	AIDS worldwide	Infects CD4+ T cells, macrophages, dendritic cells via CD4 plus CCR5 or CXCR4
HIV-2	Lentivirus	AIDS, mainly West Africa	Generally lower transmissibility and slower progression than HIV-1
HTLV-1	Deltaretrovirus	Adult T-cell leukemia/lymphoma, tropical spastic paraparesis	Tax protein promotes T-cell proliferation and genomic instability
HTLV-2	Deltaretrovirus	Less clearly pathogenic	Associated with some neurologic syndromes but weaker disease link

Genome organization and replication cycle

The essential retroviral genes are gag, pol, and env. gag encodes structural capsid proteins; pol encodes reverse transcriptase, integrase, and protease; env encodes envelope glycoproteins required for attachment and fusion. HIV also contains regulatory/accessory genes, including tat, rev, nef, vif, vpr, and vpu.

1. Attachment: HIV gp120 binds CD4 on helper T cells, macrophages, and dendritic cells, then binds a chemokine coreceptor. CCR5 is commonly used early in infection; CXCR4 is more associated with T-cell tropism and later disease.
2. Fusion: gp41 mediates fusion of the viral envelope with the host cell membrane.
3. Reverse transcription: reverse transcriptase converts viral RNA into double-stranded DNA. This enzyme lacks proofreading, producing a high mutation rate and rapid drug resistance if therapy is inadequate.
4. Integration: viral integrase inserts proviral DNA into the host chromosome. Integrated provirus may remain transcriptionally silent or produce new virions.
5. Transcription and translation: host RNA polymerase II transcribes proviral DNA. Viral proteins are synthesized as polyproteins.
6. Assembly, budding, and maturation: immature virions bud from the plasma membrane. HIV protease cleaves gag-pol polyproteins, producing mature infectious virions.

HIV pathogenesis and laboratory staging

HIV causes progressive loss and dysfunction of CD4+ T lymphocytes. Mechanisms include direct viral cytopathic effect, syncytium formation, pyroptosis of abortively infected cells, and immune-mediated killing. Normal adult CD4 count is approximately 500–1500 cells/mm³. AIDS is defined by a CD4 count <200 cells/mm³ or by an AIDS-defining illness regardless of CD4 count. Acute HIV often presents 2–4 weeks after exposure with fever, lymphadenopathy, pharyngitis, rash, and high plasma HIV RNA, often >100,000 copies/mL.

CD4 count	Classic opportunistic infections
<500 cells/mm3	Candida esophagitis, recurrent bacterial pneumonia
<200 cells/mm3	Pneumocystis jirovecii pneumonia; AIDS threshold
<100 cells/mm3	Toxoplasmosis, cryptococcosis
<50 cells/mm3	Mycobacterium avium complex, CMV retinitis

Diagnosis and antiretroviral pharmacology

Current diagnostic algorithms use a fourth-generation HIV-1/2 antigen-antibody immunoassay, which detects HIV antibodies and p24 antigen. It typically becomes positive about 2–3 weeks after infection. Positive screening is followed by an HIV-1/HIV-2 differentiation assay; if discordant or indeterminate, HIV RNA nucleic acid testing is used.

Antiretroviral therapy targets distinct steps in the replication cycle. Modern first-line therapy generally uses two nucleoside/nucleotide reverse transcriptase inhibitors plus an integrase strand transfer inhibitor. Step 1 emphasizes mechanisms and toxicities rather than regimen selection.

Drug class	Mechanism	High-yield toxicities/examples
NRTIs	Nucleoside analogs; competitively inhibit reverse transcriptase and cause DNA chain termination	Zidovudine: bone marrow suppression; abacavir: HLA-B*57:01 hypersensitivity; tenofovir: renal dysfunction, ↓ bone mineral density
NNRTIs	Bind reverse transcriptase at an allosteric site	Efavirenz: neuropsychiatric effects; nevirapine: hepatotoxicity, rash
Protease inhibitors	Prevent cleavage of gag-pol polyproteins, producing immature noninfectious virions	Metabolic syndrome, lipodystrophy, insulin resistance; ritonavir inhibits CYP3A4 and is used as a booster
Integrase inhibitors	Block insertion of viral DNA into host genome	Raltegravir, dolutegravir, bictegravir; generally well tolerated
Entry/fusion inhibitors	Block CCR5 or gp41-mediated fusion	Maraviroc blocks CCR5; enfuvirtide binds gp41

For prevention, post-exposure prophylaxis is most effective when started within 72 hours and is given for 28 days. Common adult dosing includes tenofovir disoproxil fumarate/emtricitabine 300/200 mg once daily plus dolutegravir 50 mg once daily or raltegravir 400 mg twice daily. Pre-exposure prophylaxis commonly uses tenofovir disoproxil fumarate/emtricitabine 300/200 mg once daily. These details are clinically relevant but, for Step 1, the essential concept is that combination therapy suppresses replication at multiple enzymatic targets to prevent resistance.

HTLV overview

HTLV-1 is transmitted by breastfeeding, sexual contact, blood exposure, and injection drug use. Unlike HIV, which primarily causes immunodeficiency through CD4 depletion, HTLV-1 drives clonal proliferation of infected T cells. It is classically associated with adult T-cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis, a chronic upper motor neuron syndrome.

Latent Infections

Latency is a reversible state in which a virus persists in host cells with minimal or absent production of infectious virions, while retaining the capacity to reactivate. This is distinct from chronic productive infection, in which virions are continuously produced, and from slow infection, in which disease progresses over years after prolonged replication or immune-mediated injury. Latency is a central mechanism by which viruses evade immune clearance and is especially high-yield for herpesviruses, retroviruses, and some DNA viruses that persist as episomes or integrated genomes.

Core Mechanisms of Viral Latency

• Genome persistence: latent viral genomes may remain as circular episomes in the nucleus, such as Epstein-Barr virus, or integrate into host DNA, such as HIV provirus.
• Restricted gene expression: only a small subset of viral genes is expressed, minimizing antigen presentation on MHC class I and reducing CD8⁺ T-cell recognition.
• Cell-type specificity: latency occurs in long-lived or immune-privileged cell populations, such as sensory neurons, memory B cells, monocytes/macrophages, or resting CD4⁺ T cells.
• Reactivation triggers: fever, ultraviolet light, trauma, stress, menstruation, immunosuppression, chemotherapy, transplantation, and HIV/AIDS can shift the virus from latency to lytic replication.
• Antiviral limitation: most antivirals inhibit active viral replication and have little effect on nonreplicating latent genomes; therefore, they suppress disease but usually do not eradicate latent infection.

Major Latent Viruses and Reservoirs

Virus	Latent Reservoir	Genome State	Classic Reactivation Syndrome	High-Yield Mechanism
HSV-1	Trigeminal ganglia	Episomal dsDNA	Herpes labialis, keratitis, encephalitis	Latency-associated transcripts reduce lytic gene expression
HSV-2	Sacral dorsal root ganglia	Episomal dsDNA	Genital herpes, neonatal herpes	Reactivation travels anterograde down sensory axons
VZV	Dorsal root or cranial nerve ganglia	Episomal dsDNA	Herpes zoster in dermatomal distribution	Primary infection is varicella; reactivation is shingles
EBV	Memory B cells	Episomal dsDNA	Mononucleosis-like symptoms, lymphoproliferation	Latent membrane protein 1 mimics CD40 signaling and promotes B-cell survival
CMV	Monocytes, macrophages, myeloid progenitors	Episomal dsDNA	Retinitis, colitis, pneumonitis in immunocompromised hosts	Reactivation risk rises markedly with impaired T-cell immunity
HHV-6	T cells and other tissues	May integrate into telomeric DNA	Roseola reactivation, encephalitis in transplant patients	Primary infection causes high fever followed by rash
HIV	Resting memory CD4+ T cells, macrophages	Integrated proviral DNA	Viremia after stopping therapy	Reverse transcriptase and integrase establish a lifelong reservoir

Herpesvirus Latency: Step 1 Framework

All herpesviruses are enveloped, linear double-stranded DNA viruses that replicate in the nucleus and can establish latency. During primary infection, viral replication produces local disease and viremia or neuronal spread. The viral genome then persists in a nonproductive state. For HSV and VZV, latency occurs in sensory neurons; reactivation produces lesions in the same anatomic distribution because virions travel along axons to the skin or mucosa.

HSV reactivation commonly causes grouped vesicles on an erythematous base. HSV-1 classically causes oral lesions and temporal lobe encephalitis, while HSV-2 classically causes genital lesions and neonatal disseminated disease. VZV primary infection has an incubation period of approximately 10–21 days; reactivation causes shingles, often with painful vesicles limited to one dermatome. Antiviral therapy such as acyclovir requires viral thymidine kinase for activation and inhibits viral DNA polymerase; typical oral dosing for recurrent genital HSV is 400 mg three times daily for 5 days, but the key exam concept is that acyclovir treats lytic replication and does not eliminate neuronal latency.

EBV, CMV, and Immune Control

EBV infects B cells via CD21, the complement receptor 2. Latency programs vary in gene expression: some express EBNA proteins and latent membrane proteins, while others express very few antigens. This graded latency explains why EBV can persist in memory B cells for life yet cause malignancy when immune surveillance fails. CMV latency is controlled mainly by T-cell immunity; reactivation is especially important in AIDS, transplant recipients, and congenital infection. CMV retinitis classically occurs in advanced HIV when CD4⁺ count is <50 cells/mm³.

Retroviral Latency

In HIV, latency is fundamentally different from herpesvirus latency because the viral RNA genome is reverse-transcribed into DNA and integrated into the host genome. Resting memory CD4⁺ T cells can harbor transcriptionally silent provirus. Combination antiretroviral therapy can reduce plasma HIV RNA to below common assay detection thresholds, typically <20–50 copies/mL, but it does not remove integrated proviral DNA. The latent reservoir is long-lived, with an estimated half-life of approximately 44 months, explaining why therapy interruption usually leads to viral rebound.

Clinical and Pharmacologic Implications

• Latency explains recurrence: repeated HSV outbreaks, shingles decades after chickenpox, CMV disease after transplantation, and HIV rebound after stopping therapy.
• Cell-mediated immunity is critical: CD8⁺ T cells and NK cells restrain latent viruses; severe T-cell dysfunction predisposes to reactivation.
• Serology indicates exposure, not eradication: IgG to HSV, VZV, EBV, or CMV usually reflects prior infection and lifelong persistence.
• Vaccination can prevent latent reservoirs: VZV vaccination prevents or attenuates primary infection; recombinant zoster vaccine reduces shingles risk in older adults by boosting VZV-specific cellular immunity.
• Exam principle: latent viral genomes are usually not susceptible to drugs targeting viral DNA polymerase, reverse transcriptase, or protease unless the virus re-enters active replication.

Viral Oncogenesis

Viral oncogenesis is malignant transformation driven by viral gene products, viral genome integration, chronic inflammation, or immune dysregulation. For USMLE Step 1, the central concept is that cancer arises when normal controls on cell-cycle progression, apoptosis, DNA repair, and genomic stability are disrupted. Viruses promote this by either encoding proteins that mimic growth signals or by inactivating tumor suppressors such as p53 and Rb.

Core Mechanisms of Viral Carcinogenesis

• Inactivation of tumor suppressors: viral proteins bind and degrade or inhibit p53 and Rb, allowing unchecked G1-to-S phase progression.
• Activation of cellular oncogenes: viral integration or transactivation increases expression of growth-promoting genes such as MYC.
• Chronic inflammation and regenerative proliferation: repeated hepatocyte injury in chronic hepatitis B or C increases DNA replication errors and oxidative DNA damage.
• Inhibition of apoptosis: infected premalignant cells survive despite DNA damage.
• Immune evasion or immunosuppression: impaired immune surveillance allows oncogenic viruses or transformed cells to persist.

Virus	Genome/Class	Major Associated Malignancies	High-Yield Mechanism
HPV 16, 18	Nonenveloped dsDNA	Cervical, anal, penile, vulvar, vaginal, oropharyngeal cancers	E6 degrades p53; E7 inhibits Rb
EBV	Enveloped dsDNA herpesvirus	Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma, post-transplant lymphoproliferative disease	B-cell immortalization; LMP1 mimics CD40 signaling; EBNA proteins maintain viral episome
HBV	Enveloped partially dsDNA hepadnavirus	Hepatocellular carcinoma	Chronic inflammation, cirrhosis, HBx effects on transcription and p53; possible integration
HCV	Enveloped +ssRNA flavivirus	Hepatocellular carcinoma, mixed cryoglobulinemia-associated lymphoma	Chronic hepatitis, oxidative stress, cirrhosis; no DNA intermediate
HTLV-1	Enveloped +ssRNA retrovirus	Adult T-cell leukemia/lymphoma	Tax protein activates NF-κB and IL-2 signaling; clonal T-cell proliferation
HHV-8	Enveloped dsDNA herpesvirus	Kaposi sarcoma, primary effusion lymphoma	LANA inhibits p53/Rb; viral IL-6 and angiogenic signaling
Merkel cell polyomavirus	Nonenveloped dsDNA	Merkel cell carcinoma	Large T antigen disrupts Rb-dependent cell-cycle control

Human Papillomavirus: Prototype of Direct Viral Oncogenesis

HPV infects basal squamous epithelial cells through microabrasions. Low-risk types 6 and 11 cause condyloma acuminata and laryngeal papillomas, whereas high-risk types 16 and 18 cause most HPV-associated cancers. HPV 16 is classically linked to squamous cell carcinoma, and HPV 18 to adenocarcinoma of the cervix.

The viral proteins E6 and E7 are central. E6 promotes ubiquitin-mediated degradation of p53, impairing DNA damage-induced cell-cycle arrest and apoptosis. E7 binds Rb, releasing E2F transcription factors and driving entry into S phase. The result is accumulation of mutations in proliferating epithelial cells.

Cervical Intraepithelial Neoplasia

• CIN 1: dysplasia limited to the lower one-third of epithelium; often transient HPV infection.
• CIN 2: dysplasia involving up to two-thirds of epithelium.
• CIN 3: full-thickness dysplasia/carcinoma in situ; basement membrane remains intact.
• Invasive carcinoma: malignant cells breach the basement membrane.

HPV vaccination prevents infection with oncogenic types. The 9-valent vaccine covers 6, 11, 16, 18, 31, 33, 45, 52, and 58. Routine vaccination is recommended at age 11–12 years; if started before age 15, a 2-dose series is used at 0 and 6–12 months. If started at age 15 or later, or in immunocompromised patients, a 3-dose series is used at 0, 1–2, and 6 months.

Epstein-Barr Virus

EBV infects B cells via CD21, the complement receptor 2. It establishes latency and expresses proteins that promote B-cell survival. LMP1 mimics constitutively active CD40 signaling, activating NF-κB and JAK/STAT pathways. EBNA proteins help maintain the viral episome and alter transcription.

EBV is associated with Burkitt lymphoma, classically involving t(8;14), which places MYC under control of the immunoglobulin heavy-chain promoter. Histology shows a “starry-sky” pattern from macrophages clearing apoptotic tumor cells. EBV is also linked to nasopharyngeal carcinoma, some Hodgkin lymphomas, and post-transplant lymphoproliferative disease, especially when T-cell immune surveillance is impaired.

Hepatitis Viruses and Hepatocellular Carcinoma

HBV and HCV both increase hepatocellular carcinoma risk, but by different virologic logic. HBV is a DNA virus with reverse transcriptase activity and may integrate into host DNA; its HBx protein can alter transcription and interfere with p53 function. HCV is an RNA virus that does not integrate into host DNA; carcinogenesis is mainly due to chronic necroinflammation, fibrosis, cirrhosis, and oxidative stress.

HBV vaccination is a recombinant HBsAg vaccine typically given at 0, 1, and 6 months. Prevention of chronic HBV infection is therefore also cancer prevention. Chronic HBV infection acquired perinatally has a high risk of chronicity, approximately 90%, compared with about 5% after adult-acquired infection.

Retroviral and Herpesviral Oncogenesis

HTLV-1 causes adult T-cell leukemia/lymphoma after a long latency, often 20–30 years. It infects CD4+ T cells, and its Tax protein promotes IL-2-dependent proliferation and NF-κB activation. HHV-8 is strongly associated with Kaposi sarcoma, especially in AIDS or transplant immunosuppression. Its LANA protein inhibits p53 and Rb, while viral cytokine homologs promote angiogenesis and spindle-cell proliferation.

A key exam distinction is that oncogenic viruses do not all cause cancer by the same mechanism: HPV is a direct tumor suppressor-inactivating virus, EBV immortalizes lymphocytes, HBV/HCV act largely through chronic hepatic injury, HTLV-1 drives T-cell proliferation through a retroviral transactivator, and HHV-8 combines latency proteins with angiogenic signaling.