Premed · Premed · Microbiology
Lecture 25: Viral Pathogens of Clinical Importance
Microbiology
Learning Objectives
By the end of this lecture, students will be able to:
- Classify the major human viral pathogens by genome type, structure, and family
- Describe the pathogenesis, clinical features, diagnosis, and treatment of major DNA virus infections
- Describe the pathogenesis, clinical features, diagnosis, and treatment of major RNA virus infections
- Explain the mechanisms of viral persistence, latency, and oncogenesis
- Identify viruses associated with specific clinical syndromes
- Discuss strategies for prevention of viral infections including vaccines and antivirals
Lecture Content
I. DNA Viruses
A. Herpesviridae
The herpesviruses are large, enveloped, double-stranded DNA viruses that share the remarkable ability to establish lifelong latency with periodic reactivation. This property fundamentally shapes their clinical significance and makes them impossible to eradicate from an infected host.
HSV-1 (HHV-1) typically causes gingivostomatitis in children as its primary infection, though it may also present as pharyngitis. Recurrent disease manifests as orolabial herpes (cold sores), with the virus residing latently in the trigeminal ganglion between episodes. HSV-1 is also the cause of herpes encephalitis, which characteristically involves the temporal lobe and represents the most common sporadic viral encephalitis, carrying high mortality without treatment. Herpes keratitis caused by HSV-1 is the leading infectious cause of corneal blindness in developed countries. Treatment relies on acyclovir or valacyclovir.
HSV-2 (HHV-2) predominantly causes genital herpes, presenting as painful vesicles and ulcers, with latency established in the sacral ganglia. Neonatal herpes, acquired during delivery, can present as disseminated disease, CNS involvement, or skin-eye-mouth disease and carries high mortality. Treatment is the same as for HSV-1.
Varicella-zoster virus (VZV, HHV-3) causes varicella (chickenpox) as its primary infection, presenting with a generalized vesicular rash in which lesions appear in different stages of development, classically described as "dew drops on a rose petal." The virus establishes latency in dorsal root ganglia and reactivates as herpes zoster (shingles), a painful dermatomal vesicular rash that can be followed by postherpetic neuralgia. Prevention includes the varicella vaccine for children and the recombinant zoster vaccine (Shingrix) for adults aged 50 and older.
Epstein-Barr virus (EBV, HHV-4) causes infectious mononucleosis, characterized by fever, pharyngitis, lymphadenopathy, splenomegaly, and atypical lymphocytes (which are reactive CD8+ T cells). Heterophile antibodies are detected using the Monospot test. EBV establishes latency in B lymphocytes and is associated with several malignancies: Burkitt lymphoma (in conjunction with c-myc translocation), nasopharyngeal carcinoma, Hodgkin lymphoma, and post-transplant lymphoproliferative disorder (PTLD).
Cytomegalovirus (CMV, HHV-5) causes asymptomatic infection or a mononucleosis-like illness (heterophile-negative) in immunocompetent individuals. In immunocompromised patients, particularly transplant recipients and those with HIV, CMV causes retinitis (described as "pizza pie" fundus with cotton-wool spots), colitis, esophagitis, and pneumonitis. Congenital CMV is the most common congenital viral infection and the number one non-genetic cause of sensorineural hearing loss; it can also cause microcephaly, periventricular calcifications, and hepatosplenomegaly. Treatment uses ganciclovir or valganciclovir, with foscarnet reserved for resistant cases.
HHV-6 causes roseola infantum (exanthem subitum), which presents with high fever lasting 3 to 5 days followed by a diffuse macular rash that appears as the fever breaks. HHV-8 (Kaposi sarcoma-associated herpesvirus, KSHV) causes Kaposi sarcoma (a vascular tumor seen especially in AIDS patients), primary effusion lymphoma, and multicentric Castleman disease.
B. Papillomaviridae (HPV)
Human papillomaviruses are non-enveloped, double-stranded DNA viruses with over 200 identified types. The low-risk types, particularly 6 and 11, cause genital warts (condylomata acuminata) and laryngeal papillomas. The high-risk types (16, 18, 31, 33, and 45) are responsible for virtually all cervical cancer, as well as anal cancer, oropharyngeal cancer, and penile and vulvar cancers. Oncogenesis is driven by two viral oncoproteins: E6 targets p53 for degradation, while E7 inactivates Rb, together leading to uncontrolled cell proliferation. Screening methods include Pap smears and HPV DNA testing. The 9-valent HPV vaccine (Gardasil 9), covering types 6, 11, 16, 18, 31, 33, 45, 52, and 58, is recommended at ages 11 to 12.
C. Hepadnaviridae (Hepatitis B Virus)
Hepatitis B virus has a partially double-stranded, gapped circular DNA genome, is enveloped, and uniquely employs reverse transcriptase during replication. Transmission occurs through blood, sexual contact, and vertically from mother to child. Acute hepatitis B presents with jaundice and elevated transaminases, and 95% of immunocompetent adults clear the infection. However, approximately 90% of neonatal infections become chronic, progressing to cirrhosis and hepatocellular carcinoma (HCC).
The serologic markers of HBV are essential for clinical interpretation: HBsAg indicates current infection, anti-HBs indicates immunity, HBeAg indicates high viral replication and infectivity, anti-HBc IgM indicates acute infection, and anti-HBc IgG indicates past or chronic exposure. Prevention relies on the recombinant HBsAg vaccine given at birth. Chronic hepatitis B is treated with tenofovir, entecavir, or pegylated interferon-alpha.
D. Adenoviridae
Adenoviruses are non-enveloped, double-stranded DNA viruses with over 50 types. They cause a wide array of diseases including pharyngitis, conjunctivitis ("pink eye" and epidemic keratoconjunctivitis), pneumonia (particularly in military recruits), gastroenteritis (types 40 and 41 in children), and hemorrhagic cystitis. Their non-enveloped nature makes them extremely stable in the environment.
E. Poxviridae
The poxviruses are the largest DNA viruses, possessing a double-stranded DNA genome within an enveloped virion. Uniquely among DNA viruses, they replicate entirely in the cytoplasm because they encode their own DNA-dependent RNA polymerase. Variola virus caused smallpox, which was eradicated in 1980. Molluscum contagiosum produces characteristic umbilicated papules that are self-limited in immunocompetent individuals but common in children and HIV patients. Mpox (monkeypox) is a zoonotic infection causing vesiculopustular rash, with recent global outbreaks expanding awareness of this pathogen.
<image>A clinical presentation chart of the human herpesviruses. Eight rows for HHV-1 through HHV-8, each with columns for: virus name, primary disease, latency site, reactivation disease, associated malignancies (if any), and key diagnostic test. HHV-1: gingivostomatitis, trigeminal ganglion, cold sores, herpes encephalitis; Tzanck smear (multinucleated giant cells), PCR. HHV-2: genital herpes, sacral ganglia, recurrent genital ulcers, neonatal herpes; PCR, viral culture. HHV-3/VZV: varicella, dorsal root ganglia, herpes zoster; DFA, PCR. HHV-4/EBV: infectious mononucleosis, B lymphocytes, reactivation in immunocompromised; Burkitt lymphoma, nasopharyngeal carcinoma, Hodgkin lymphoma, PTLD; Monospot, EBV-specific antibodies. HHV-5/CMV: asymptomatic or mono-like, monocytes/myeloid progenitors, retinitis/colitis/pneumonitis in immunocompromised; congenital CMV; CMV PCR (viral load). HHV-6: roseola, T lymphocytes; clinical diagnosis. HHV-8/KSHV: often asymptomatic, B cells; Kaposi sarcoma, primary effusion lymphoma; biopsy with HHV-8 staining. Color-coding distinguishes alpha-herpesviruses (HSV-1, HSV-2, VZV), beta-herpesviruses (CMV, HHV-6, HHV-7), and gamma-herpesviruses (EBV, HHV-8).</image>
II. RNA Viruses
A. Orthomyxoviridae (Influenza)
Influenza viruses are enveloped viruses with a segmented negative-sense single-stranded RNA genome (eight segments for influenza A). Two surface glycoproteins dominate their biology: hemagglutinin (HA), which mediates viral attachment and entry (18 subtypes identified), and neuraminidase (NA), which cleaves sialic acid to enable viral release from infected cells (11 subtypes identified).
Two forms of antigenic change drive influenza evolution. Antigenic drift involves point mutations in HA and NA genes, producing the gradual variation responsible for seasonal epidemics and necessitating annual vaccine reformulation. Antigenic shift involves reassortment of entire genome segments between different influenza A strains, often occurring in a pig "mixing vessel" co-infected with human and avian strains. This can produce an entirely novel subtype against which the population has no immunity, creating pandemic potential.
Clinically, influenza presents with abrupt onset of fever, myalgia, headache, and cough. Complications include secondary bacterial pneumonia (particularly with S. pneumoniae and S. aureus), primary viral pneumonia, and myocarditis. Diagnosis uses rapid antigen testing or RT-PCR (the gold standard). Treatment options include neuraminidase inhibitors (oseltamivir, zanamivir) and the cap-dependent endonuclease inhibitor baloxavir. Prevention relies on annual influenza vaccination with either inactivated or live attenuated formulations.
B. Paramyxoviridae and Pneumoviridae
Measles (rubeola) is caused by an enveloped, negative-sense single-stranded RNA virus that is one of the most contagious pathogens known, with an R0 of approximately 12 to 18. The illness begins with a prodrome of cough, coryza, and conjunctivitis, accompanied by Koplik spots on the buccal mucosa, which are pathognomonic. A maculopapular rash then develops, starting on the face and spreading cephalocaudally. Serious complications include pneumonia (the most common cause of measles-related death), encephalitis, and subacute sclerosing panencephalitis (SSPE), a rare but fatal complication occurring years later. Measles also causes "immune amnesia," effectively resetting previously established immune memory. Prevention relies on the MMR vaccine.
Mumps characteristically causes bilateral parotid swelling (parotitis) and can be complicated by orchitis in post-pubertal males, meningitis, and pancreatitis. Respiratory syncytial virus (RSV) is the number one cause of bronchiolitis and pneumonia in infants, producing characteristic wheezing and syncytial giant cells in cell culture. Treatment is supportive, with palivizumab (a monoclonal antibody) used for prophylaxis in high-risk infants and nirsevimab (a long-acting monoclonal) available for all infants. RSV vaccines have been developed for pregnant women and older adults. Parainfluenza viruses, particularly types 1 and 2, cause croup (laryngotracheobronchitis), presenting with a barking or seal-like cough and the steeple sign on X-ray.
C. Picornaviridae
The picornaviruses are non-enveloped, positive-sense single-stranded RNA viruses. Rhinovirus is the most common cause of the common cold, with over 100 serotypes; it is acid-labile and destroyed by stomach acid. The enteroviruses include poliovirus, which destroys anterior horn motor neurons to cause flaccid paralysis and has been nearly eradicated through vaccination (IPV and OPV). Coxsackievirus A causes hand-foot-and-mouth disease and herpangina. Coxsackievirus B causes myocarditis, pericarditis, and pleurodynia (Bornholm disease). Echovirus is a common cause of aseptic meningitis. Hepatitis A virus is also a picornavirus, transmitted by the fecal-oral route and causing acute, self-limited hepatitis without chronicity; it is preventable with the HAV vaccine.
D. Flaviviridae
The flaviviruses are enveloped, positive-sense single-stranded RNA viruses. Hepatitis C virus (HCV) is blood-borne, with approximately 80% of infections becoming chronic and progressing to cirrhosis and hepatocellular carcinoma. Remarkably, HCV is now curable with direct-acting antivirals (DAAs), particularly sofosbuvir-based regimens that achieve sustained virologic response rates exceeding 95%; no vaccine is available. Dengue virus is transmitted by Aedes mosquitoes and exists as four serotypes; secondary infection with a different serotype increases severity through antibody-dependent enhancement (ADE), potentially causing dengue hemorrhagic fever or dengue shock syndrome. Zika virus is transmitted by Aedes mosquitoes and sexually, causing congenital Zika syndrome (microcephaly, ocular defects) and Guillain-Barre syndrome. West Nile virus, transmitted by Culex mosquitoes, is usually asymptomatic but can cause meningoencephalitis with flaccid paralysis.
E. Retroviridae (HIV)
Human immunodeficiency virus is an enveloped, diploid positive-sense single-stranded RNA virus that uses reverse transcriptase to generate proviral double-stranded DNA, which integrates into the host genome. HIV-1 is the pandemic strain, while HIV-2 is less virulent and confined largely to West Africa. The virus primarily targets CD4+ T cells, with the gp120 envelope protein binding CD4 and co-receptors CCR5 or CXCR4; macrophages and dendritic cells are also infected.
The natural history progresses from acute retroviral syndrome (a mononucleosis-like illness) through years of clinical latency to AIDS (defined by a CD4 count below 200 per microliter or the development of an AIDS-defining illness). AIDS-defining conditions include Pneumocystis jirovecii pneumonia, Kaposi sarcoma (HHV-8), CMV retinitis, cerebral toxoplasmosis, Mycobacterium avium complex (MAC), cryptococcal meningitis, and progressive multifocal leukoencephalopathy (JC virus).
Diagnosis employs a fourth-generation antigen/antibody combination test (detecting both p24 antigen and HIV-1/2 antibodies), followed by a confirmatory Western blot or HIV-1/2 differentiation immunoassay, with viral load measured by RT-PCR. Treatment consists of combination antiretroviral therapy (cART), typically two NRTIs plus one INSTI (such as bictegravir/emtricitabine/tenofovir alafenamide), with long-acting injectables (cabotegravir-rilpivirine) available as an alternative. Prevention strategies include condoms, pre-exposure prophylaxis (PrEP with TDF/FTC or long-acting cabotegravir), post-exposure prophylaxis (PEP), and prevention of mother-to-child transmission (PMTCT).
F. Coronaviridae
Coronaviruses are enveloped viruses with the largest RNA genome known (approximately 30 kilobases) consisting of positive-sense single-stranded RNA. SARS-CoV-2 causes COVID-19, using its spike protein to bind the ACE2 receptor on host cells. It is transmitted via respiratory droplets and aerosols, with a clinical spectrum ranging from asymptomatic infection to acute respiratory distress syndrome, multi-organ failure, and long COVID. SARS-CoV (2003) caused severe acute respiratory syndrome with civet cats serving as intermediate hosts. MERS-CoV (2012) causes Middle East respiratory syndrome with dromedary camels as intermediate hosts and a high case fatality rate of approximately 35%. The common cold coronaviruses (HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1) cause mild upper respiratory illness.
G. Rhabdoviridae (Rabies)
Rabies virus is an enveloped, bullet-shaped, negative-sense single-stranded RNA virus transmitted through animal bites (from dogs, bats, raccoons, skunks, and foxes). After inoculation, the virus travels via retrograde axonal transport to the central nervous system. Clinical disease begins with a prodrome including paresthesia at the bite site, progresses to the acute neurologic phase (either encephalitic/furious with hydrophobia, aerophobia, and agitation, or paralytic/dumb with ascending paralysis), then coma, and ultimately death. Rabies is nearly 100% fatal once symptoms appear.
Post-exposure prophylaxis (PEP) consists of wound washing, rabies immune globulin (RIG) infiltrated at the wound site, and a rabies vaccine series (four doses); it is highly effective if administered before symptom onset. Pre-exposure prophylaxis is recommended for veterinarians, travelers to endemic areas, and laboratory workers.
<image>A clinical syndrome-based chart matching viral pathogens to disease presentations. Organized by organ system. Respiratory: influenza (sudden onset fever, myalgia), RSV (infant bronchiolitis), parainfluenza (croup), SARS-CoV-2 (COVID-19 pneumonia, ARDS), measles (cough/coryza/conjunctivitis, Koplik spots, rash), adenovirus (pharyngitis). Neurologic: rabies (hydrophobia, fatal encephalitis), HSV-1 (temporal lobe encephalitis), West Nile (meningoencephalitis), poliovirus (flaccid paralysis), JC virus (PML in AIDS). Hepatic: HAV (acute, fecal-oral), HBV (acute/chronic, vertical/blood/sexual), HCV (chronic, blood-borne, curable with DAAs). Skin/mucosal: HSV-1/2 (vesicles), VZV (varicella, zoster), HPV (warts, cervical cancer), molluscum contagiosum (umbilicated papules), measles (maculopapular rash), Coxsackie A (HFMD). Congenital/neonatal: CMV (hearing loss, microcephaly), rubella (cataracts, cardiac defects, deafness), Zika (microcephaly), parvovirus B19 (hydrops fetalis), HSV-2 (neonatal herpes). Each entry is color-coded by DNA vs RNA virus.</image>
III. Oncogenic Viruses
Approximately 15 to 20% of human cancers are associated with viral infections. Among the DNA viruses, HPV causes cervical, anal, and oropharyngeal cancers; EBV is associated with Burkitt lymphoma, nasopharyngeal carcinoma, Hodgkin lymphoma, and PTLD; HHV-8 causes Kaposi sarcoma; HBV contributes to hepatocellular carcinoma; and Merkel cell polyomavirus causes Merkel cell carcinoma. Among the RNA viruses, HCV causes hepatocellular carcinoma, HTLV-1 causes adult T cell leukemia/lymphoma, and HIV indirectly enables malignancy through immunosuppression that permits HHV-8 and EBV-associated tumors to develop. The mechanisms of viral oncogenesis include inactivation of tumor suppressors by viral oncoproteins (E6 targeting p53, E7 targeting Rb), activation of proto-oncogenes, induction of chronic inflammation, and generation of genomic instability.
IV. Viral Diagnostics Summary
Direct detection methods include electron microscopy (rarely used today), viral culture (historically the gold standard but slow), and antigen detection through rapid tests for influenza, RSV, SARS-CoV-2, and rotavirus. Nucleic acid amplification tests (NAATs), particularly PCR and RT-PCR, have become the gold standard for many viral infections because of their high sensitivity and specificity; quantitative viral load assays are essential for managing HIV, HBV, HCV, CMV, and EBV infections. Serology detects virus-specific IgM (indicating acute infection) and IgG (indicating past infection or immunity) and remains important for EBV, hepatitis viruses, HIV, rubella, and measles. Sequencing provides genotyping for resistance mutations (in HIV and HCV) and variant surveillance (for SARS-CoV-2).
<image>A diagnostic decision tree for viral infections. Starting with clinical presentation, branching into: (1) Respiratory syndrome -- rapid antigen test for influenza/RSV/SARS-CoV-2; if negative, RT-PCR respiratory panel. (2) Vesicular rash -- Tzanck smear (multinucleated giant cells, non-specific), DFA or PCR for HSV/VZV. (3) Mononucleosis-like illness -- Monospot (heterophile antibodies) for EBV; if negative, check CMV IgM, HIV Ag/Ab. (4) Hepatitis (elevated LFTs) -- hepatitis panel: HAV IgM, HBsAg, anti-HBc IgM, HCV Ab followed by HCV RNA. (5) CNS infection (encephalitis/meningitis) -- CSF PCR panel (HSV, enterovirus, VZV, CMV, EBV, WNV). (6) Congenital infection -- TORCH workup (Toxoplasma, rubella, CMV, HSV) with appropriate serology and PCR. Each branch lists the preferred diagnostic test and expected results.</image>
