13.2 Medical Virology: DNA, RNA, Retroviruses, and Viral Pathogenesis

Structural Classification and Viral Architecture

Viruses are obligate intracellular parasites composed of genetic material (DNA or RNA) enclosed within a protein shell termed a capsid. Capsid architecture exhibits either icosahedral or helical symmetry. Some viruses acquire an outer envelope\u2014a lipid bilayer derived from host cell membranes embedded with viral glycoproteins during budding.

Understanding envelope status dictates transmission dynamics and environmental resilience. Non-enveloped (naked) viruses are resistant to heat, acid, drying, and bile, allowing them to survive in the gastrointestinal tract and ambient environment. Conversely, enveloped viruses are fragile, sensitive to ether, detergents, and heat, typically requiring direct mucosal or parenteral contact for transmission.

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DNA Viruses & The HHAPPPPy Rules

Human DNA viruses belong to seven primary families remembered by the mnemonic HHAPPPPy: Herpesviridae, Hepadnaviridae, Adenoviridae, Poxviridae, Parvoviridae, Papillomaviridae, and Polyomaviridae.

General DNA Rules & Exceptions

1. Strandness: All DNA viruses are double-stranded (dsDNA) EXCEPT Parvoviridae, which is single-stranded (ssDNA).
2. Genome Shape: All DNA viruses have linear genomes EXCEPT Papillomaviridae, Polyomaviridae, and Hepadnaviridae, which have circular DNA genomes.
3. Replication Site: All DNA viruses replicate in the host cell nucleus EXCEPT Poxviridae, which carries its own DNA-dependent RNA polymerase and replicates independently in the host cytoplasm.

Herpesviridae

Enveloped, linear dsDNA viruses capable of establishing lifelong latent infections within specific host cell reservoirs:

• HSV-1 (Herpes Simplex Virus 1): Causes oral herpes (cold sores), gingivostomatitis, and keratoconjunctivitis. Establishes latency in the trigeminal ganglion. Leading cause of sporadic temporal lobe encephalitis.
• HSV-2 (Herpes Simplex Virus 2): Causes painful genital herpes lesions and neonatal herpes. Establishes latency in the sacral ganglia.
• VZV (Varicella-Zoster Virus / HHV-3): Primary infection causes varicella (chickenpox, "dew drops on a rose petal"); reactivation causes herpes zoster (shingles) in a dermatomal distribution. Establishes latency in dorsal root ganglia or cranial nerve ganglia.
• EBV (Epstein-Barr Virus / HHV-4): Infects B cells via CD21. Causes infectious mononucleosis presenting with fever, pharyngitis, lymphadenopathy, and splenomegaly. Associated with heterophile positive antibodies (Monospot test) and atypical reactive CD8+ T lymphocytes (Downey cells). Etiologically linked to Burkitt lymphoma (t(8;14) translocation of c-myc), nasopharyngeal carcinoma, and primary CNS lymphoma in AIDS.
• CMV (Cytomegalovirus / HHV-5): Causes heterophile-negative mononucleosis. Histology demonstrates classic "owl-eye" intranuclear inclusion bodies. Leading cause of congenital viral infection (sensorineural hearing loss, chorioretinitis, periventricular calcifications).
• HHV-6: Causes roseola infantum (exanthem subitum), characterized by high fever for 3-4 days followed by a maculopapular rash upon defervescence.
• HHV-8: Causes Kaposi sarcoma in HIV/AIDS patients\u2014a vascular tumor presenting as dark purple violaceous skin and visceral lesions.

Papillomaviridae

Naked, circular dsDNA virus. Human Papillomavirus (HPV) infects basal epithelial cells:

• HPV Types 6 and 11: Cause benign condyloma acuminata (genital warts) and laryngeal papillomatosis.
• HPV Types 16 and 18: High-risk oncogenic strains causing cervical, anal, and penile dysplasia and squamous cell carcinoma. Carcinogenesis is driven by viral oncogenes: E6 (promotes ubiquitin-mediated degradation of p53 tumor suppressor) and E7 (inactivates Rb tumor suppressor protein).

Hepadnaviridae

Enveloped, partially dsDNA circular virus. Hepatitis B Virus (HBV) replicates through an RNA intermediate using a viral reverse transcriptase.

• HBsAg (Hepatitis B surface antigen): Indicates active HBV infection (acute or chronic).
• Anti-HBs (Antibody to HBsAg): Indicates immunity due to vaccination or cleared natural infection.
• HBeAg: Indicates active viral replication and high infectivity.
• Anti-HBc IgM: Diagnostic of acute/recent infection; sole positive marker during the "window period."

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RNA Viruses & Clinical Presentations

RNA viruses possess single-stranded (ssRNA) or double-stranded (dsRNA) genomes with positive (+) or negative (-) polarity.

Picornaviridae

Naked, positive ssRNA viruses including Poliovirus, Coxsackievirus, Echovirus, Hepatitis A Virus (HAV), and Rhinovirus. Coxsackie A causes hand-foot-and-mouth disease and herpangina; Coxsackie B causes myocarditis and pericarditis.

Orthomyxoviridae

Enveloped, negative ssRNA virus with an 8-segmented genome. Influenza virus utilizes Hemagglutinin (HA) for surface cell attachment (binds sialic acid) and Neuraminidase (NA) for viral progeny release.

• Antigenci Drift: Minor point mutations in HA or NA genes causing minor annual epidemics.
• Antigenic Shift: Major genetic reassortment between human and animal strains when co-infecting a single host cell, creating novel surface antigens resulting in global pandemics.

Paramyxoviridae

Enveloped, negative ssRNA non-segmented viruses:

• Measles Virus (Rubeola): Presents with prodromal 3 Cs (cough, coryza, conjunctivitis), Koplik spots (bluish-white buccal mucosal lesions), and a maculopapular exanthem spreading cephalocaudally. Complication includes subacute sclerosing panencephalitis (SSPE).
• Mumps Virus: Causes bilateral parotitis, orchitis (can lead to infertility), and aseptic meningitis.
• Respiratory Syncytial Virus (RSV): Leading cause of bronchiolitis and pneumonia in infants. Surface F-protein induces cell-cell fusion (syncytia formation); targeted by the monoclonal antibody Palivizumab.

Rhabdoviridae

Bullet-shaped enveloped negative ssRNA Rabies virus. Binds acetylcholine receptors at the neuromuscular junction, traveling retrograde along peripheral nerves to the CNS. Pathognomonic histology reveals Negri bodies (eosinophilic cytoplasmic inclusions) in hippocampal neurons and cerebellar Purkinje cells.

Coronaviridae

Enveloped, positive ssRNA virus. SARS-CoV-2 utilizes its surface spike (S) protein to bind the host cell ACE2 receptor, mediating entry into respiratory epithelial cells.

Flaviviridae

Enveloped positive ssRNA viruses including Hepatitis C Virus (HCV) (causes chronic hepatitis, cirrhosis, and hepatocellular carcinoma), Dengue virus, Zika virus, and Yellow fever virus.

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Retroviridae & Human Immunodeficiency Virus (HIV)

HIV is an enveloped, diploid positive ssRNA retrovirus containing key structural components and enzymes:

• Envelope Glycoproteins: gp120 mediates viral attachment to host cell CD4 receptors and chemokine coreceptors (CCR5 on macrophages for early tropism, CXCR4 on T cells for late tropism). gp41 mediates viral fusion and host cell entry.
• Viral Enzymes: Reverse Transcriptase converts viral ssRNA into cDNA; Integrase integrates viral cDNA into the host cell chromosome; Protease cleaves polyprotein precursors into functional structural and enzymatic proteins.
• AIDS Diagnosis: Defined by a CD4+ T-cell count < 200 cells/\u00b5L or presence of AIDS-defining opportunistic conditions, including Pneumocystis jirovecii pneumonia, Toxoplasma gondii brain abscesses, primary CNS lymphoma, Cryptococcal meningitis, and Kaposi sarcoma.