Microcards - Viruses

Clinical case: A mother brings her 4-year-old child to the doctor because of a swollen, red right eye. She is frustrated, complaining that the symptoms appeared after she had taken her child to a local ophthalmologist. The doctor diagnoses conjunctivitis. Later that evening, the doctor learns that many other children have presented with similar symptoms after appointments with the same ophthalmologist.

*Adenovirus* DNA virus -> icosahedral nucleocapsid -> nonenveloped -> DS linear -> Adenoviridae -> Mastadenovirus *Clinical presentation*: Respiratory tract infection, conjunctivitis, hemorrhagic cystitis, gastroenteritis *Pathobiology*: Spread by aerosol, fecal-oral route, or direct contact => binds via hemagglutinin => enters and lyses mucosal cells of: a. upper respiratory tract => rhinitis, sore throat => may progress to lower respiratory tract => atypical pneumonia b. conjunctiva => conjunctivitis c. bladder => hemorrhagic cystitis => hematuria, dysuria d. gastrointestinal tract in young children => gastroenteritis with non-bloody diarrhea *Diagnosis*: Serology; isolation of virus in cell culture *Treatment*: Vaccine - live viruses of specific serotypes (only used in the military) *Quick facts*: Adenovirus is so named because latent viruses often remain in the tonsillar adenoids following infection There are over 40 serotypes of adenoviruses, each associated with specific sites of infection and diseases Live virus vaccines confer immunity without illness by being administered away from their primary site of infection (e.g. oral route for vaccine to respiratory serotypes). Adenovirus, as well as retrovirus and herpesvirus are potential vectors for gene therapy

Clinical case: A father brings his daughter to the ED a day after she develops severe headache, fever, and "seizures in her arms." During physical exam, the daughter seems to be confused; she manifests a (+) Babinski sign and partial paresis on the left side. CSF assay shows normal glucose and protein but the presence of PMNs and mononuclear cells. The doctor orders an ELISA to make a definitive diagnosis. The father is astonished to learn that his daughter may continue to exhibit seizures for several weeks and may suffer permanent cognitive changes. The doctor suggests that the illness was acquired from mosquitos near their forest home in Michigan.

*CALIFORNIA ENCEPHALITIS VIRUS* RNA virus -> helical nucleocapsid -> enveloped -> SS- segmented -> Bunyaviridae -> Bunyavirus *Clinical presentation*: encephalitis *Pathobiology*: Reservoir in forest rodents => spread to humans via mosquito bite => viremic spread to CNS => direct damage to neurons, inflammation => encephalitis, especially in children => low mortality but possible residual cognitive disorders *Diagnosis*: antiviral antibodies in serum or CSF *Treatment*: supportive; ribavirin (experimental) *Quick facts*: High risk of infection in Midwest forests Another Bunyaviridae, Bunyaviridae phlebovirus, causes fever: a. Rift Valley Fever (in sub-Saharan Africa)-spread by mosquito, can be fatal b. Sandfly Fever (in Asia, South America)-spread by sandfly; 3-day fever with quick resolution

Clinical case: A hiker in the Rocky Mountains stops at a ranger station complaining of fever and muscle aches. The symptoms have worsened since the day before, and he is also beginning to feel head and neck pain upon movement. When asked if he had been bitten by any ticks, the hiker seems alarmed, affirming that he thinks he was bitten several times. The ranger, now more certain of a diagnosis, informs the hiker that several hundred people suffer the same infection every year. He instructs the hiker to report to the base hospital and to avoid any aspirin or sharp bruising hits for fear of hemorrhage.

*COLORADO TICK VIRUS (COLTIVIRUS)* RNA virus -> icosahedral nucleocapsid -> nonenveloped -> DS segmented -> Reoviridae -> Coltivirus *Clinical presentation*: Fever, myalgia, ocular pain, and headache *Pathobiology*: Carried in rodents => transferred to humans via wood tick bite => virus may spread systemically (viremia) => virus may infect and cause lesions in any body organ If the virus infects bone marrow cells => infected erythrocytes, leukopenia, thrombocytopenia *Diagnosis*: Serology, isolation of virus from blood, detection of viral antigens on erythrocytes *Treatment*: none available *Quick facts*: Endemic to Rocky Mountains where hikers or campers are often infected following tick bites The differential diagnosis includes Rocky Mountain spotted fever and tularemia "Reo"virus = "respiratory enteric orphan" because we used to think it didn't cause any diseases NOTE that reoviruses (rotavirus and colorado tick virus) are the only double-stranded RNA viruses!

Clinical case: A mother calls her pediatrician, concerned about her son's "cold." Her son has developed a runny nose and a headache. By the time she brings her son to the doctor - a week after the onset of the symptoms - the son has recovered completely.

*CORONAVIRUS* RNA virus -> helical nucleocapsid -> enveloped -> SS+ nonsegmented -> Coronaviridae -> Coronavirus *Clinical presentation*: common cold *Pathobiology*: Transmission by respiratory secretions => virus infects upper respiratory tract cells => 3 day incubation => 6-7 day common cold *Diagnosis*: serology (no laboratory diagnosis usually made) *Treatment*: none; no vaccines *Quick facts*: Coronavirus infections account for 10-20% of common colds (#1 is Rhinovirus infections); clinically indistinguishable. The SARS coronavirus (SARS-CoV) is responsible for Severe Acute Respiratory Syndrome (= rapidly progressive respiratory illness that commonly presents with fever, dyspnea, and cough that can progress to respiratory failure and death). The virus caused a deadly outbreak of viral pneumonia from 2002-2003, spreading from China to over 35 countries in a few weeks.

Clinical case: A young man presents with chest pain, dyspnea, and early signs of heart failure. His history shows he had an upper respiratory infection 3 weeks ago. Examination reveals tachycardia and a gallop rhythm (S3), while ECG shows evidence of a conduction defect with nonspecific ST-T changes. Echocardiogram is ordered and shows cardiomegaly with contractile dysfunction. The doctor makes a viral diagnosis by serology and admits the patient for monitoring, assuring the patient that he will likely recover completely.

*COXSACKIEVIRUSES A & B* RNA virus -> icosahedral nucleocapsid -> nonenveloped -> SS+ nonsegmented -> Picornaviridae -> Enterovirus -> coxsackievirus A & B *Clinical presentation*: A: herpangina, hand-foot-mouth disease B: pleurodynia, myocarditis, pericarditis A or B: aseptic meningitis, paralysis, upper respiratory infection [Medscape says A also includes acute hemorrhagic conjunctivitis & B can also infect the pancreas and liver => hepatitis] [Medscape also says that myopericarditis from B group may present as pericardial friction rub, gallop rhythm, cardiomegaly, pericardial effusion, ECG abnormalities ranging from ST elevations to heart block, & LV wall abnormalities and reduced EF on echo] *Pathobiology*: Typical in summer and fall Fecal-oral or aerosol transmission => travels in GI tract (acid stable) => infects mucosal epithelial cells => replicates and spreads => viremia Infects and can lyse: -skin and mucosal epithelium (A) => forms vesicles => herpangina (red oropharynx vesicles, fever, sore throat), HFM disease -heart & pleural surfaces (B) => pleurodynia, myocarditis, pericarditis -meninges and ventral horn alpha motor neurons (A or B) => aseptic meningitis, paralysis *Diagnosis*: isolate virus; serology *Treatment*: anti-inflammatory agents for symptomatic treatment; no antivirals or vaccine *Quick facts*: HFM disease = vesicles on the hands, feet, and mouth; typically occurs in young children Coxsackievirus B is associated with 50% of cases of viral myocarditis ECHO (enteric cytopathic human orphan) viruses = enteroviruses that cause disease similar to coxsackieviruses A and B Other strains of enteroviruses are the main cause of acute hemorrhagic conjunctivitis

Clinical case: A 34-year-old kidney transplant patient currently on immunosuppressants complains of shortness of breath and coughing. Physical exam reveals fever and abnormal lung sounds while chest X-ray indicates interstitial infiltrates in the lungs. No cysts are detected on silver stain of bronchoalveolar lavage fluid, ruling out Pneumocystis jirocecii infection. The doctor makes a diagnosis after viewing a sample of the patient's lung tissue, which shows abnormal giant cells with "owl's eye" intranuclear inclusions.

*Cytomegalovirus (CMV) or Herpesvirus 5* DNA virus -> icosahedral nucleocapsid -> enveloped -> DS linear -> Herpesviridae -> Cytomegalovirus *Clinical presentation*: Cytomegalic inclusion disease (newborns) Heterophil-negative mononucleosis Immunocompromised patients: retinitis, pneumonia, esophagitis *Pathobiology*: Transmitted by close contact (blood, breast milk, saliva, semen), organ transplantation, or transplacentally => can infect a diverse array of cells => replicates within cells and eventually kills them, causing: a) Cytomegalic inclusion disease: deafness, HSM, and microencephaly in newborns b) Mononucleosis: flu-like symptoms, abnormal lymphocytes Infection is contained by host immune response => virus remains latent in leukocytes => reactivates when host becomes immunocompromised, causing: a) Retinitis (especially in AIDS patients) b) Pneumonia (especially in transplant patients) c) Esophagitis *Diagnosis*: Giant cells with "owl's eye" intranuclear inclusion bodies found in tissues/urine Serology (NEGATIVE monospot test as compared to EBV mononucleosis) Detection in buffy coat culture (CMV infects WBCs) *Treatment*: Ganciclovir (NOT acyclovir, because no viral thymidine kinase is made) Foscarnet *Quick facts*: The giant cells, or "cytomegalo" cells, that form during the infection give CMV its name Most adults have been infected by CMV but show few symptoms because their normal immune response limits the infection Other viruses that infect lymphocytes are human herpesvirus 6 and 7 (HHV6, HHV7). They infect B and T cells, causing roseola (fever and rash on trunk) in infants

Clinical case: Late July, a father brings his daughter to the emergency department for fever, vomiting, and strange behavior that developed the day before. The ED physician notes that the daughter has head and neck pain and is photophobic. A quick neurological exam reveals hemiparesis and some cranial nerve deficits. The physician asks the father about any recent mosquito bites she may have had, and the father affirms that they are swarmed with mosquitoes in their Florida home. The physician fears a grave diagnosis with a high mortality rate or at least a slow recovery lasting weeks. This diagnosis is confirmed by detection of virus, PMN pleocytosis, normal glucose, and slightly elevated proteins in the CSF.

*EASTERN EQUINE ENCEPHALITIS (EEE)* *WESTERN EQUINE ENCEPHALITIS (WEE)* *VENEZUALAN EQUINE ENCEPHALITIS (VEE)* RNA virus -> icosahedral nucleocapsid -> enveloped -> SS+ nonsegmented -> Togaviridae -> Alphavirus *Clinical presentation*: encephalitis *Pathobiology*: Carried in birds or horses => transferred to humans via mosquito bite => enters circulation and infects endothelial cells & reticuloendothelial (RE) cells => lyses cells to produce primary viremia If the viremia persists, it infects CNS endothelial cells and neurons => hemorrhage, inflammation, necrosis => CNS symptoms including headache, meningitis, & photophobia => high mortality rate (EEE>WEE>VEE) *Diagnosis*: Serology; isolation of virus in brain tissue at autopsy *Treatment*: symptomatic Vaccine: formalin-inactivated or live attenuated virus *Quick facts*: Incidence of arboviral encephalitis is seasonal and regional: EEE localizes to swampy areas of the US east coast WEE localizes to western and central US and Canada VEE localizes to Venezuela, Colombia, Central America, and Texas

Clinical case: An anthropologist is brought to the emergency department one evening for high fever, vomiting, headache, confusion, and bloody diarrhea. He explains that he had cut an expedition in Zaire short and returned to the US when he developed the high fever. Physical exam is remarkable for a 40C fever, slight hypotension, a nonpruritic rash on the neck and arms, and a nosebleed. Upon reviewing the history, the ED physicians order an immediate hospital quarantine of the anthropologist and his family. They then investigate his exact itinerary in Zaire and all his close contacts in the past 3 weeks. The next day, the patient dies with disseminated intravascular coagulation.

*EBOLA VIRUS & MARBURG VIRUS* RNA virus -> helical nucleocapsid -> enveloped -> SS- nonsegmented -> Filoviridae -> filovirus (Ebola and Marburg virus) *Clinical presentation*: hemorrhagic fever *Pathobiology*: Reservoir in monkeys (Marburg) or unknown (Ebola) => transferred to humans by direct contact (e.g. bites, infected body fluids) => incubation period of 3-9 days => viremia with fever, flu-like symptoms => viral infection of almost all organs including brain, liver, and heart => focal necrosis and hemorrhagic manifestations (especially of GI, renal systems) => shock, multiorgan failure => high mortality 1-2 weeks after onset of symptoms Transmission to other humans via body fluids *Diagnosis*: Detection of virus, serology *Treatment*: None developed; in the future, could treat with serum from survivors *Quick facts*: Most outbreaks of Ebola have originated in sub-Saharan Africa Marburg virus is named after a 1967 outbreak in Marburg, Germany. The virus was spread to scientists from sub-Saharan monkeys. The Ebola virus and Marburg virus are BL4 pathogens and require maximum precautions when handled

Clinical case: A 20-year-old female college student reports to the medical center complaining of "the flu." She reports fever, night sweats, a very painful sore throat, and headaches. She thought she could endure the illness, but she became frustrated after feeling "so sleepy all the time." Physical exam reveals enlarged lymph nodes and a slight splenomegaly. Results from a blood smear later that day reveal lymphocytosis with about 20% lymphocytes having an abnormally large nucleus and vacuolated cytoplasm. The student is assured that the illness will spontaneously resolve within 2-3 weeks, but she should avoid contact sports during that time. She is also told not to share drinks to prevent spread of the illness.

*Epstein-Barr Virus (EBV) or Herpesvirus 4* DNA virus -> icosahedral nucleocapsid -> enveloped -> DS linear -> Herpesviridae -> Lymphocryptovirus *Clinical presentation*: Infectious mononucleosis Lymphoid organ-related cancers: Burkitt lymphoma, nasopharyngeal carcinoma (in East Asians) *Pathobiology*: Transmitted by saliva, respiratory secretions (e.g. kissing) => infects oropharynx epithelium => viremia => virus binds to and infects B cells via C3d complement receptor => virus remains latent in B cells as episomal DNA => infected B cells are transformed and multiply => immune response to infected cells => lymph nodes & spleen enlarge with flu-like symptoms & painful pharyngitis (mononucleosis) Immune response controls infected B-cell proliferation => mononucleosis resolves If immune system is compromised => uncontrolled B-cell proliferation => unrepaired mutations accumulate => may increase chances for neoplasms (e.g. Burkitt lymphoma) *Diagnosis*: Monospot test: detects heterophil antibody (nonspecific antibody that agglutinates sheep RBCs) Blood smear: atypical lymphocytes (cytotoxic T lymphocytes that react against infected B cells) Serology: anti-EBV IgM (acute infection), IgG (past infection) *Treatment*: Acyclovir (severe cases) *Quick facts*: Patients with infectious mononucleosis are at risk for splenic rupture secondary to splenomegaly and should avoid contact sports A rash occurs in few cases of mononucleosis; however, if ampicillin is given to treat tonsillitis (before viral etiology is known), rash occurs in most cases Similar to chickenpox and polio illnesses, EBV infections are more severe in high socioeconomic classes that have better sanitation and thus are infected later in life.

Clinical case: A recent college graduate has been camping in Arizona in a wooded area heavily populated with deer mice. He cuts his vacation short, however, when he develops a fever and begins vomiting. By the time he reports to the hospital 3 days later, he is hypotensive, cyanotic, and tachypneic. Fearing shock, emergency physicians begin to administer fluids but stop this treatment when chest X-rays reveal interstitial pulmonary edema. The patient develops respiratory failure within 24 hours and dies by the second day of hospitalization. A diagnosis is confirmed by IgM serum assay and a lung biopsy.

*HANTAVIRUS (SIN NOMBRE VIRUS)* RNA viruses -> helical nucleocapsid -> enveloped -> SS- segmented -> Bunyaviridae -> Hantavirus *Clinical presentation*: Hantavirus Respiratory Syndrome *Pathobiology*: Rodent hosts chronically shed virus in feces/urine => airborne transmission to humans => viremia => prodrome of flu-like symptoms followed by pulmonary capillary leakage => interstitial pulmonary edema => respiratory failure (Hantavirus Respiratory Syndrome) => high mortality within ~10 days *Diagnosis*: PCR from lung biopsy IgM antibody in serum *Treatment*: supportive *Quick facts*: Unlike other Bunyaviridae, hantavirus is an example of a robovirus (rodent-borne virus), as opposed to an arbovirus (arthropod-borne virus) Hantavirus respiratory syndrome was first discovered in 1993, following a fatal outbreak in the southwest U.S. Hantaan virus, a serotype of Hantavirus, causes Korean Hemorrhagic Fever (acute renal failure+fever)

Clinical case: A Boy Scouts troop master calls the doctor asking about symptoms that have developed in 7 of his 20 Scouts shortly after a camping trip. The ill boys complain of fever, nausea, loss of appetite, and vomiting. The Scout master also notes a yellow hue in some of the boys, especially visible in their eyes. Two of the affected boys are brought to the hospital where their urine is noted to be dark and their feces pale. Liver enzyme assays reveal an elevated ALT and AST level. The physician confirms the diagnosis with an assay of serum IgM and then assures the master and his Scouts that the illness will completely go away in several weeks.

*HEPATITIS A VIRUS* RNA virus -> icosahedral nucleocapsid -> nonenveloped -> SS+ nonsegmented -> Picornaviridae -> Enterovirus -> hepatitis A virus *Clinical presentation*: acute hepatitis *Pathobiology*: Fecal-oral transmission (acid-stable) => travels in GI tract => infects mucosal epithelial cells => replicates and spreads (viremia) => reaches liver by portal circulation => infects hepatocytes CTL response stimulated => kill infected hepatocytes => often asymptomatic but may cause jaundice *Diagnosis*: IgM detection in serum (note that IgG indicates past infections) *Treatment*: Supportive care (self-limiting) Pooled immune globulins Vaccine = formalin-inactivated HAV *Quick facts*: Epidemics among children are the most frequent cases (e.g. in summer camps, schools) because it is spread fecal-oral Most adults have been asymptomatically infected (as evidenced by anti-HAV IgG)

Clinical case: Feeling fatigued, a man visits his doctor. On physical examination, the patient has a reduced liver size. After a thorough history, the doctor learns that the patient had jaundice 5 years ago following a car accident for which he was hospitalized and received a blood transfusion. The doctor is not surprised to see an elevated serum level of ALT in his blood workup and awaits an ELISA to differentiate the causes of this illness.

*HEPATITIS C VIRUS* RNA virus -> icosahedral nucleocapsid -> enveloped -> SS+ nonsegmented -> Flaviviridae -> hepatitis C virus *Clinical presentation*: Acute hepatitis: jaundice, fever Chronic hepatitis: carrier state (asymptomatic), cirrhosis; predisposes to hepatocellular carcinoma *Pathobiology*: Human reservoir => transmission by blood (especially transfusion, IV drug use), semen, & in utero => virus infects hepatocytes => immune response by CTLs kills infected hepatocytes => acute hepatitis In 50-70% of cases, virus not eliminated => asymptomatic carrier state or may become chronic active hepatitis => cirrhosis & predisposition to HCC *Diagnosis*: Serology for anti-HCV antibody *Treatment*: Pegylated alpha-interferon Ribavirin No vaccine available [THERE ARE MORE RECENT MEDS - LOOK THEM UP] *Quick facts*: HCV poses a major problem to IV drug users and in blood transfusion banks HCV is clinically indistinguishable from HAV and HBV infections and is responsible for most cases of non-A and non-B hepatitis. HCV infections are more often chronic. Two important "negatives" for HCV: 1. The virus alone is NOT cytotoxic (requires host response) 2. The virus does NOT cause HCC via integration into host genome

Clinical case: A chronic drug user previously diagnosed with hepatitis B presents with a recurrence of symptoms, most notably yellow sclerae. Typical signs of chronic hepatitis - serum AST and ALT elevation, jaundice, hepatomegaly, splenomegaly - seem more severe in this patient. The physician suspects that hepatitis B is only part of his clinical picture and recommends treatment with alpha-interferon to reduce the symptoms. The patient is informed that he is at risk for liver failure.

*HEPATITIS D VIRUS* RNA virus -> icosahedral nucleocapsid -> enveloped -> SS- circular -> Deltavirus *Clinical presentation*: hepatitis *Pathobiology*: Transmitted through blood, sexual contact, or transplacentally => travels in blood to hepatocytes => infects cells => replicates and released only from those cells also infected with HBV, because it requires hepatitis B surface antigen to form the infectious particle (HDV is defective and can't replicate alone) *Diagnosis*: delta antigen detection, anti-delta antigen IgM antibodies *Treatment*: alpha-IFN (controls HBV infection, which limits HDV infection) Vaccine - recombinant Hepatitis B surface antigen to prevent HBV infection *Quick facts*: HBV carriers who become superinfected with HDV have a much poorer prognosis, with a greater chance of fulminant hepatitis and liver failure HDV may also have a cytopathic effect independent of a host immune response The HDV genome is a ribozyme, which is an RNA particle able to cleave and ligate itself. No other human viruses behave this way, but many plant viruses in the viroid group do.

Clinical case: A man goes to India on a hiking trip in the Himalayas. Upon returning, he develops nausea, vomiting, malaise, and headache. His doctor notices jaundice and hepatosplenomegaly on physical exam, and labs detect increased AST, ALT, and direct serum bilirubin levels. Immunization records show that the man had received HAV and HBV vaccines before leaving. The symptoms are traced back to a shared water supply along the hiking route.

*HEPATITIS E VIRUS* RNA virus -> icosahedral nucleocapsid -> nonenveloped -> SS+ nonsegmented -> Caliciviridae -> Calicivirus -> hepatitis E virus *Clinical presentation*: acute hepatitis *Pathobiology*: Fecal-oral transmission => travels in GI tract (acid stable) => infects mucosal epithelial cells => replicates and spreads (viremia) => reaches liver by portal circulation => infects hepatocyte CTL response stimulated => kills infected hepatocytes => often asymptomatic but may cause jaundice [this is all identical to HAV] *Diagnosis*: symptoms; rule out HAV *Treatment*: none developed *Quick facts*: HEV resembles HAV but is also associated with a high mortality in pregnant women. HEV may be responsible for 2/3 of epidemic "non-A, non-B" hepatitis cases in India, Russia, and other Asian countries.

Clinical case: A 45-year-old homeless man complains to an ED doctor of fever, cough, and a burning pain in his chest. These symptoms have 'lingered on and off' for several weeks, and weight loss forces him to resolve the vague illness once and for all. The physician notes no chest sounds, and chest X-ray reveals only a faint interstitial infiltrate. Suspecting some sort of pneumonia, the physician requests a sputum analysis. Lab results reveal the presence of Pneumocystis jirovecii confirmed by PCR. Concerned about this fungal infection, the physician administers TMP/SMX and requests a blood count. The results - a WBC value of 2000 cells/uL and a CD4+ T cell count of 500 cells/uL - confirm a grave suspicion. The physician tells the patient the likely diagnosis and asks if he would like a social worker's help.

*HUMAN IMMUNODEFICIENCY VIRUS (HIV-1, HIV-2)* RNA virus -> icosahedral nucleocapsid -> enveloped -> SS+ diploid -> Retroviridae -> Lentivirus *Clinical presentation*: AIDS and opportunistic infections *Pathobiology*: A. Primary infection stage (first months): transmission by bodily fluids, i.e. sexual contact, blood transfer, maternal transfer (transplacental, during birth, in breastmilk) => infects CD4+ cells, including Th lymphocytes in blood and macrophages in epidermis => replicates in spleen and lymphoid organs => viremia => (contained by host immune response) => mononucleosis-like symptoms => equilibrium established between viral production and host containment B. Clinical latency stage (7-10 years): mutations in antigens help virus evade host immune response => virus replicates, especially in lymphoid organs => host responds with increased Th cell production & CTL response against infected cells => no or low-level symptoms Continued viral evasion by mutations => viral load gradually increases & CD4+ count gradually drops [This depletion of CD4+ cells occurs via several mechanisms: immune attack on infected cells by CTLs, cell lysis from extensive viral budding, & syncytia formation between infected & uninfected cells, mediated by gp120-CD4 interactions] C. Advanced disease (AIDS): CD4+ T cell count < 200 cells/uL => opportunistic infections/ neoplasms causing death, e.g. Pneumocystic jirovecii pneumonia, Candida albicans thrush, disseminated HSV, CMV infection, histoplasmosis, toxoplasmosis, cryptococcal meningitis, Mycobacterium tuberculosis, Mycobacterium avium-intracellulare (MAC), Kaposi's sarcoma Infection of brain microglia, oligodendrocytes, and astrocytes => neuropathy, encephalopathy, and dementia *Diagnosis*: detection of virus by ELISA, Western blot, PCR *Treatment*: NRTI = nucleoside reverse transcriptase inhibitors (nucleoside analogs) - e.g. AZT (zidovudine), ddl, lamivudine, abacavir, tenofovir, emtricitabine NNRTI = nonnucleoside reverse transcriptase inhibitors (bind outside active site) - e.g. efavirenz, nevirapine, delavirdine PI = protease inhibitors (e.g. indinavir, nelfinavir) FI = fusion inhibitors (e.g. enfurvitide) HAART = Highly Active AntiRetroviral Therapy = drug cocktail (e.g. NNRTI+2NRTI, PI+2NRTI) initiated for symptomatic HIV or low CD4 count Prevention: protected sex, screening of blood, AZT (zidovudine) to infected pregnant mothers *Quick facts*: HIV-1 and HIV-2 have similar clinical presentations and share common antigens. HIV-1 is found throughout the world, whereas HIV-2 is found mainly in West Africa. Monocytes and macrophages advance HIV infection in two ways: 1) they transport HIV to the CNS and 2) they are a reservoir for HIV, especially when T-cell counts are low Kaposi's sarcoma has been associated with human herpesvirus 8 (HHV8) infection (can be transmitted sexually)

Clinical case: A 57-year-old Caribbean woman seeks the attention of her physician when her legs "do not seem to function appropriately." She tells the physician that she began to feel a stiffness in her left leg and then both legs over the past few weeks, as well as occasional back pain. A neurological exam reveals slight sensory losses, hyperreflexia, and extensor plantar responses in both legs; no cognitive or cranial nerve dysfunction is noted. The physician requests an MRI, which reveals lesions in the white matter of the brain and spinal cord as well as in the paraventricular gray matter of the brain. Although the woman does not have leukemia or lymphoma, the physician suspects a diagnosis that is confirmed by detection of specific antibodies in her (serum?). She begins the patient on a regimen of glucocorticoids and explains that her symptoms may progress to paraplegia.

*HUMAN T-CELL LYMPHOTROPIC VIRUS (HTLV-1, HTLV-2)* RNA virus -> icosahedral nucleocapsid -> enveloped -> SS+ diploid -> Retroviridae -> HTLV-1, HTLV-2 *Clinical presentation*: T-cell leukemia, lymphoma Tropical spastic paraparesis *Pathobiology*: Transmission by sexual contact or blood transfer => infection of CD4+ T cells & B cells => proviral DNA integrates into genome => viral genes expressed => viral proteins increase production of cytokines and cytokine receptors => IL-2 promotes hyperproliferation of infected cells => rapidly dividing cells accumulate mutations => malignant transformation => T-cell leukemia, lymphoma If infection of CNS => antibodies produced and CTLs activated => attack neural cells => weakness/stiffness in legs (tropical spastic paraparesis) *Diagnosis*: antibody titers in serum, CSF *Treatment*: supportive *Quick facts*: HTLV-1 and HTLV-2 have 60% homology - can't be distinguished by serology, but can be distinguished by PCR HTLV-1 was first isolated from a patient with cutaneous T-cell lymphoma, and HTLV-2 was first isolated from a patient with hairy cell leukemia T-cell leukemia associated with HTLV-1 is endemic to Japan and the Caribbean. HTLV-2 is endemic to Native American populations. Multiple sclerosis has been associated with HTLV-1 infection and its autoimmune consequences in the CNS.

Clinical case: A middle-aged immigrant from China presents with right upper quadrant pain and a 'full stomach' despite a recent history of weight loss. He remembers having bouts of 'turning yellow' since childhood and recalls many in his family - including his mother - having similar experiences. Immunization records are unavailable, and lab values show elevated ALT levels and alpha-fetoprotein levels. Further imaging reveals the presence of hepatocellular carcinoma.

*Hepatitis B Virus* DNA virus -> icosahedral nucleocapsid -> enveloped -> DS circular -> Hepadnaviridae -> Orthohepadnavirus *Clinical presentation*: Acute hepatitis - jaundice, fever Chronic hepatitis - carrier state (asymptomatic); cirrhosis; predisposes to HCC *Pathobiology*: Transmitted through blood, sexual contact, or transplacentally => travels in blood to hepatocytes => infects cells and replicates by completing the partially dsDNA viral genome via viral DNA polymerase => now complete dsDNA generates mRNA transcripts => mRNA produces viral proteins => mRNA is also used to make partially dsDNA by RNA-dependent DNA polymerase => partially dsDNA is packaged and particle buds through cell membrane *Diagnosis*: Detection of HbsAg Abnormal liver function tests *Treatment*: Alpha-interferon or pegylated alpha-interferon (but carrier state will persist) Lamivudine Vaccine: recombinant HbsAg Hepatitis B Immune Globulin (HBIG): contains anti-HBsAg antibodies *Quick facts*: HBV is a common cause of fulminant hepatitis; a severe acute hepatitis that damages the liver If a medical student is stuck with a needle exposed to hepatitis-positive blood, the student should receive both "active" (vaccine) and "passive" (immune globulin) treatment Infants of HBsAg+ mothers are given HBIG immediately after birth, followed by Hepatitis B vaccination Unlike non-enveloped viruses (e.g. HAV) that can survive outside a host, HBV and other enveloped viruses are vulnerable and spread only by close contacts between hosts Strength of immune response determines clinical course of infection: a strong response produces a severe course that resolves quickly, whereas a weak response produces a mild but chronic course

Clinical case: A 55-year-old man is hospitalized for a recent onset of high fever, headaches, and sporadic sensations of smelling sausages. Physical exam reveals neck stiffness, prompting the physician to perform a lumbar puncture. CSF values indicate elevated lymphocytes, elevated protein, and normal glucose. A CT image confirms encephalitis localized to the temporal lobes. A diagnosis is confirmed by PCR of the CSF. The physician begins treatment with acyclovir and informs the patient that he may suffer permanent neurological abnormalities from the infection.

*Herpes Simplex Virus 1 (HSV-1) or Herpesvirus 1* DNA virus -> icosahedral nucleocapsid -> enveloped -> DS linear -> Herpesviridae -> Simplexvirus -> HSV-1 *Clinical presentation*: Gingivostomatitis, keratoconjunctivitis, herpes labialis (cold sores), temporal lobe encephalitis *Pathobiology*: Only human reservoir => transmitted via saliva => virus invades mucous membranes => local primary infection => typically asymptomatic but can cause vesicular lesions that ulcerate in: a) mouth => gingivostomatitis b) eye => keratoconjunctivitis (on cornea, typically presents as branching 'dendritic ulcer') Primary infection resolves after 2-3 weeks => virus enters local sensory nerve endings => axonal transport proximally to sensory ganglion cell bodies => latent infection of trigeminal ganglion or other sensory ganglia Stress (fever, menstruation, sunlight) => viral reactivation => axonal transport of virus from ganglia to nerve endings => recurrent local infection => may result in herpetic labialis (cold sores around mouth), gingivostomatitis, or keratoconjunctivitis Rarely, virus may spread via cranial nerves to brain => focal necrotic lesions in temporal lobe => inflammation => encephalitis => permanent neurological abnormalities or death *Diagnosis*: Detection of virus (PCR, especially for early detection in encephalitis) Multinucleate giant cells on Tzanck smear of skin lesions Eosinophilic Cowdry intranuclear inclusion bodies on skin biopsy *Treatment*: Acyclovir; trifluridine (topical, for eye infections) *Quick facts*: Herpesviruses are the most common cause of sporadic encephalitis in the US: HSV-1 in adults, HSV-2 in neonates Most adults have been infected by HSV-1 or -2, but very few infections are symptomatic and only 25% of latent infections exhibit recurrent infections Herpetic whitlow is a painful hand vesicle that can occur in healthcare workers who come into contact with herpetic lesions Recurrent keratoconjunctivitis is a common cause of blindness in the US

Clinical case: At a preterm evaluation, a 31-year-old pregnant mother reports pain on urination and a burning, itching sensation in the genital area. A careful examination of her vagina reveals a vesicular rash. The physician confirms a diagnosis with a Tzanck smear of the lesions showing multinucleate giant cells with intranuclear inclusion bodies. The mother is administered acyclovir with assurances that the infection will likely resolve, but she is informed that should the infection persist, her child will have to be delivered by cesarean section.

*Herpes Simplex Virus 2 (HSV-2) or Herpesvirus 2* DNA virus -> icosahedral nucleocapsid -> enveloped -> DS linear -> Herpesviridae -> Simplexvirus -> HSV-1 *Clinical presentation*: Genital herpes; neonatal herpes *Pathobiology*: Only human reservoir => transmission by sexual contact => virus invades mucous membranes => local primary infection => typically asymptomatic but can cause vesicular lesions in genital/perianal area Primary infection resolves after 2-3 weeks => virus enters local sensory nerve endings => axonal transport proximally to sensory ganglion cell bodies => latent infection of lumbosacral ganglia Stress (fever, menstruation, sunlight) => viral reactivation => axonal transport of virus from ganglia to nerve endings => milder, recurrent vesicular infection at primary site If pregnant mother is infected: virus may transfer to fetus through placenta or during delivery => child infected => congenital defects, abortion, or neonatal encephalitis *Diagnosis*: Detection of virus Multinucleate giant cells on Tzanck smear of skin lesions Eosinophilic Cowdry intranuclear inclusion bodies on skin biopsy *Treatment*: Acyclovir; prevention via cesarean section in infected mothers *Quick facts*: Herpesviruses are the most common cause of sporadic encephalitis in the US: HSV-1 in adults, HSV-2 in neonates Most adults have been infected by HSV-1 or -2 and reactivation is common, but not all infections are symptomatic Herpetic whitlow is a painful hand vesicle that can occur in healthcare workers who come in contact with herpetic lesions

Clinical case: A 22-year-old sexually active man complains of warts on his penis. He does not report pain, but he is concerned that he might be spreading them to his female sexual partner. The doctor, diagnosing the warts as condyloma acuminata, treats the patient by (ablation of?) the warts. He also decides to test the sexual partner, fearing that if she contracted the patient's illness, she would be at increased risk for cervical cancer.

*Human Papilloma Viruses (HPV)* DNA virus -> icosahedral nucleocapsid -> nonenveloped -> DS circular -> Papovaviridae -> Papillomavirus (HPV) *Clinical presentation*: Acute - warts (on penis, vulva, cervix, fingers, hands, soles, knees, elbows, oropharynx, larynx) Chronic - asymptomatic; carcinomas (cervical, squamous cell, laryngeal carcinoma) *Pathobiology*: Transmitted by close contact => virus infects squamous epithelial cells in epidermis or mucous membranes a. Lysogenic cycle: infects basal cells => attempts to replicate => basal cell environment disfavors viral replication => virus can transform basal cells via E6 (blocks p53) and E7 (blocks Rb) viral proteins => benign cell growth and vacuolization (warts) b. Lytic cycle: infects upper keratinized epithelium or progresses with basal cell as it rises/differentiates => keratinized cell environment favors viral replication => replicates DNA, assembles => vacuolizes cytoplasm => lyses cell, viral particles released for further infection Infection controlled by cell-mediated immunity *Diagnosis*: 1% acetic acid turns lesions white Colposcopy + biopsy of white lesions PCR using viral specific primers *Treatment*: 50% of warts spontaneously regress in 1-2 years Ablation HPV vaccine available to prevent cervical cancer. Gardasil (quadrivalent) protects against HPV 6, 11, 16, 18 Cervarix (bivalent) protects against HPV 16 and 18 *Quick facts*: HPV virus 16 and 18 cause genital warts that can progress to cervical carcinoma Warts in the larynx (which can be acquired by infants vaginally borne to mothers with genital warts) cause airway swelling, hoarseness, and secondary bacterial pneumonia Epidermodysplasia verruciformis presents as many flat warts on the skin, which may progress to squamous cell carcinomas HPV is a very parsimonious virus, using host machinery for most of its replicative functions. It also codes for proteins in all three reading frames of a single DNA strand. Papanicolaou testing ("Pap smears") has been effective in detecting dysplastic HPV-infected cells before they transform into neoplastic cells Fun fact - "Papovaviridae" is derived from PApillomaviruses, POlyomaviruses, and VAcuolating viruses.

Clinical case: A child presents with altered mental status and seizures. During the exam, the doctor notes epistaxis, gum bleeding, and right lower quadrant pain. Further questioning reveals that 3 weeks ago, the child had general weakness, myalgias, fever, and a cough. His mother had similar flu-like symptoms a week before and treated both herself and her child with aspirin. The doctor suspects that the child's serious symptoms would have been prevented had the mother given Tylenol instead of aspirin to her child. Liver function and blood tests are ordered immediately.

*INFLUENZA VIRUS ('THE FLU')* RNA virus -> helical nucleocapsid -> enveloped -> SS- segmented -> Orthomyxoviridae -> Influenza virus A, B, C *Clinical presentation*: Flu (and croup in children) Secondary bacterial pneumonia *Pathobiology*: Inhaled through aerosols => infects upper and lower respiratory tract ciliated epithelium via two surface proteins: a) hemagglutinin (HA) envelope protein binds sialic acid on cells => virus endocytosed; b) neuraminidase (NA) envelope protein cleaves HA-sialic acid interaction to permit viral spread Replicates in and lysis cells => necrosis of epithelium => epithelial intracellular contents exposed and stimulate inflammation => macrophages produce fever via IL1 => lymphocytes produce myalgia via IFN-gamma => vasodilation and edema in: 1. nose (=> rhinorrhea), 2. pharynx and larynx (=>swelling obstructs flow through sinuses and eustachian tubes => croup in children with secondary sinusitis and otitis), and 3. trachea/bronchi (=>inflammatory mucus cleared by ciliated cells => cough) Viral shedding resolves after 2-5 days => IgA secretory immunity against viral HA and NA If infection persists => ciliary columnar epithelial cells damaged => cannot perform normal task of clearing bacteria => secondary bacterial pneumonia *Diagnosis*: Symptoms Rapid antigen test on nasopharyngeal swab Can culture nasopharyngeal sample and detect HA via RBC agglutination test [...think of the name: heme+agglutinin = agglutinates red blood cells] *Treatment*: Supportive-acetaminophen, hydration, rest Influenza A: amantadine or rimantadine for treatment and prophylaxis Influenza A & B: zanamivir and oseltamivir (neuraminidase inhibitors) Vaccines: inactivated (with HA and NA antigens from influenza A and B) live, attenuated *Quick facts*: HA and NA undergo antigenic variation, allowing new outbreaks resistant to previous vaccinations. a. Antigenic shifts (~every 20 years): exchange of RNA segments between human & animal viruses => radically new HA or NA acquired => pandemics b. Antigenic drifts (every year): spontaneous mutations => slightly altered HA or NA => endemic infections The 2009 "swine flu" pandemic was caused by the H1N1 subtype of influenza A and contained genes from human, pig, and avian influenza viruses. Most commonly reported symptoms include fever, cough, headache, sore throat, vomiting, and diarrhea. A vaccine is available, and zanamivir or oseltamivir can be given for treatment and prophylaxis. Influenza B and C differ from influenza A in the following: a. Less virulent, with influenza C infections often asymptomatic b. No animal reservoir => no antigenic shifts c. Unresponsive to amantadine or rimantadine Reye's syndrome (liver damage, encephalomyelitis): associated with aspirin treatment for aspirin treatment for influenza in children

Clinical case: A middle-aged man, diagnosed with AIDS, presents to the ED complaining of "seeing double." Physicians perform a complete neurological examination and further discover problems in talking, coordinating movements, and remembering things. Imaging of the brain reveals deep densities localized to the white matter that span the frontal, parietal, and temporal lobes. The doctors make an infectious disease diagnosis and discuss how to best tell the patient about his very grave prognosis.

*JC Virus* DNA virus -> icosahedral nucleocapsid -> nonenveloped -> DS circular -> Papovaviridae -> Polyomavirus (JC virus) *Clinical presentation*: Progressive Multifocal Leukoencephalopathy (PML) *Pathobiology*: Virus infects children => produces a mild illness, which is contained by host immune response => virus becomes latent in CNS Immunocompromise (AIDS, chemotherapy) allows latent virus to activate => infects myelinating oligodendrocytes in white matter throughout CNS => demyelination => impairs coordination, speech, memory (=PML) *Diagnosis*: symptoms, imaging, detection in CNS biopsy *Treatment*: no treatment available *Quick facts*: Papovaviridae is derived from PApillomaviruses, POlyomaviruses, and VAcuolating viruses Another polyomavirus, BK virus, causes mild infections in children and was first isolated from the urine of an immunosuppressed kidney transplant patient Worldwide, most people carry anti-JC virus antibodies by age 14 and anti-BK antibodies by age 5

Clinical case: A 34-year-old woman, during a visit to Nigeria, develops a fever over the course of the fifth week of her visit. The fever progresses to headache, nausea, and diarrhea. By the time she arrives at a hospital, her physician notes signs of pericardial effusion. Furthermore, a diarrhea sample contains blood, indicating GI hemorrhage. The physician is quite familiar with the symptoms in that region of Nigeria. He explains that she likely contracted her illness from rodents or from someone who had come into close contact with rodents. The woman is required to remain hospitalized because she is considered contagious.

*LASSA VIRUS* RNA viruses -> helical nucleocapsid -> enveloped -> SS- segmented -> Arenaviridae -> Arenavirus *Clinical presentation*: hemorrhagic fever *Pathobiology*: Reservoir in rodents => spread to humans by contamination of food or water with animal excretions => can further spread person-to-person => viremia => gradual onset of hemorrhagic fever => internal bleeding at GI tract and other organs => hemorrhagic shock, high mortality *Diagnosis*: detection of virus; serology *Treatment*: ribavirin, serum from convalescent individuals (severe cases) [NOTE that the CDC website seems to say that this is not recommended anymore due to risk of transmission of blood-borne pathogens] Prevention - rodent control *Quick facts*: The Lassa virus is a BL4 pathogen and requires maximum precautions when handled First identified in 1969 in Lassa, Nigeria, and endemic to central West Africa Another arenavirus transmitted from rodents is Lymphocytic Choriomeningitis Virus (LCMV) => rare cause of aseptic meningitis

Clinical case: An 11-month-old who attends daycare presents with rashes that blanch upon pressing as well as fever, conjunctivitis, and runny nose. The rashes have spread from the hairline to the trunk and then to extremities over time and have become bright red and raised. Now, the rash is already starting to disappear in the same sequence it appeared. While the symptoms resolve over a week, the doctor wonders whether the child will ever have neurological problems from a latent recurring infection, and whether other children in the daycare will have the same illness. To contain the illness, the doctor urges the mother to keep the child away from others for at least a few weeks. He also writes a note to the daycare center reminding them that all children 12-15 months should receive a vaccination for this illness.

*MEASLES VIRUS (RUBEOLA)* RNA virus -> helical nucleocapsid -> enveloped -> SS- nonsegmented -> Paramyxoviridae -> Morbillivirus (measles virus) *Clinical presentation*: flu-like symptoms Koplik's spots, followed by rash encephalitis Complications => SSPE (Subacute Sclerosing Panencephalitis) *Pathobiology*: Spread between humans via respiratory aerosol droplets => infects, replicates within, & lyses respiratory epithelial cells => primary viremia => infects and replicates in reticuloendothelial cells => secondary viremia => spread to: a) mucosa => promotes inflammation around capillaries => Koplik's spots in the mouth (red lesions with a blue-white center) b) dermis => promotes inflammation around capillaries => rash starts at head and progresses to feet, disappearing in the order it appears (head->feet) c) respiratory tract, lungs => giant cells form with inclusion bodies (Warthn-Finkeldey cells) => cell damage leads to cough, rhinorrhea d) brain => meningitis, encephalitis If infected with a variant of measles virus => over years, chronic low-level infection of CNS => inflammatory lesions of brain => gradually presents as personality and cognitive changes (subacute sclerosing panencephalitis or SSPE) => death *Diagnosis*: Isolate virus from nasopharyngeal secretions, blood, and urine Warthin-Finkeldey cells (multinucleated giant cells with inclusion bodies in nucleus and cytoplasm [pathognomonic for measles] in respiratory secretions) Serology *Treatment*: Vaccine - live-attenuated measles virus (in MMR) Severe cases in infants treated with high doses of vitamin A *Quick facts*: Measles is one of the most transmissible viral infections. Killed virus vaccine is no longer used because it promotes a hypersensitivity reaction on subsequent exposure to the virus (atypical measles syndrome). Pneumonia, secondary to respiratory tract cell infection, is the most common reason for measles hospitalization. MMR is the only live viral vaccine that can be given to HIV-positive individuals.

Clinical case: A 16-year-old male requests the private attention of a doctor for testicular pain. He explains that his left testis became tender and enlarged yesterday. A few days before, he recalls suffering from a mild fever and muscle aches. The doctor confirms a diagnosis after seeing the teenager's vaccination records and receiving lab reports that show elevated serum amylase.

*MUMPS VIRUS* RNA virus -> helical nucleocapsid -> enveloped -> SS- nonsegmented -> Paramyxoviridae -> Rubulavirus (Mumps virus) *Clinical presentation*: Parotitis, orchitis, pancreatitis, aseptic meningitis *Pathobiology*: Transmitted by respiratory droplets => attaches and invades upper respiratory tract epithelium via viral hemagglutinin envelope proteins => viremia => 2-3 week incubation period => infection of glandular tissues (parotid gland, testes) => inflammatory infiltration and edema => painful enlargement of glands Virus may spread to meninges => aseptic meningitis Lifelong immunity after one infection *Diagnosis*: Symptoms Detection of virus in saliva, urine, CSF, serum Serology *Treatment*: Supportive - analgesics, compression of parotid Vaccine - live-attenuated mumps virus (in MMR vaccine) *Quick facts*: Rarely, orchitis affects both testes, leading to sterility A mumps skin-antigen test is used to demonstrate functional cell-mediated immunity Viral fusion (F) surface proteins, common to all Paramyxoviridae, cause infected cells to form multinucleate giant cells MMR is the only live viral vaccine that can be given to HIV-positive individuals

Clinical case: A 5-year-old boy is brought to the pediatrician's office for 'bumps on his arm.' His mother reports that a classmate had similar skin lesions 2 months earlier. The pediatrician notes flesh-colored, pearly nodes with central craters. She reassures the family that the child does not have chickenpox and recommends they cover the lesions to prevent scratching and spread to others.

*Molluscum contagiosum* DNA virus -> icosahedral nucleocapsid -> enveloped -> DS linear -> Poxviridae -> Molluscipoxvirus *Clinical presentation*: Pearly skin papules/nodules *Pathobiology*: Virus transmitted by casual contact => infects epidermal cells => large eosinophilic inclusion bodies form containing virus particles (molluscum bodies) => molluscum bodies enlarge infected cells, forming dome-like structure => eventual rupture of cells, forming central crater *Diagnosis*: Clinical presentation (non-painful domes with dimpled center) Skin biopsy (molluscum bodies in epidermal layer, limited inflammation) *Treatment*: Self-resolves in 6-12 months Surgically remove lesions (cryotherapy, laser treatment) *Quick facts*: Autoinoculation, in which virus from one lesion spreads to other parts of the body via scratching, is common in children Immunosuppressed individuals may have multiple, large lesions that do not resolve spontaneously Unlike varicella or HSV infections, MCV infection is limited to the epidermis and does not establish a dormant state

Clinical case: Thirteen people attending an oyster dinner abruptly develop nausea and abdominal pains 2 days later. Soon after the onset of pain, they begin to vomit and some also have diarrhea.

*NORWALK VIRUS (NOROVIRUS)* RNA virus -> icosahedral nucleocapsid -> nonenveloped -> SS+ nonsegmented -> Caliciviridae -> Calicivirus -> Norwalk virus *Clinical presentation*: gastroenteritis *Pathobiology*: Transmitted by contact or contaminated food/water => local infection and inflammation in proximal small intestine => gastroenteritis *Diagnosis*: typically not done but can visualize virus in stool specimens *Treatment*: self-limited so usually not required; rehydration for severe fluid loss *Quick facts*: Norwalk virus is a major cause of group-related or institutional diarrhea

Clinical case: A father brings his baby girl to the ED in the middle of the night. Before leaving the house, the girl had a high fever, nasal discharge, and barking cough. Now, however, the barking cough seems to have disappeared. The doctor on call realizes that the cool night air probably relieved the child's symptoms before she arrived at the hospital. Because no inspiratory stridor is noted on physical exam, the doctor sees no need to give the girl corticosteroids and assures the father that the illness will go away in a few days.

*PARAINFLUENZA VIRUSES* RNA virus -> helical nucleocapsid -> enveloped -> SS- nonsegmented -> Paramyxoviridae -> Paramyxovirus (parainfluenza virus) *Clinical presentation*: Children - croup (laryngotracheobronchitis); pneumonia Adults - common cold *Pathobiology*: Inhaled through aerosols => infects larynx mucosa via two surface proteins: a) hemagglutinin (HA) envelope protein binds sialic acid on cells => virus endocytosed; b) neuraminidase (NA) envelope protein cleaves HA-sialic acid interaction to permit viral spread [same proteins as influenza virus] Infection progresses downward to tracheal and bronchial epithelium => inflammation and swelling of mucous membranes => narrowing of lumen => obstruction of inspiration (inspiratory stridor) and expiration (barking cough) => croup May invade lower respiratory tract => pneumonia *Diagnosis*: symptoms, detection of virus (hemagglutination activity in respiratory secretions), serology (anti-HA antibodies inhibit hemagglutination) *Treatment*: Supportive (cool mist; oxygen in severe cases) Corticosteroids *Quick facts*: In contrast to croup in children, upper respiratory tract infections (of parainfluenza virus) in adults present as bad colds Viral fusion (f) surface proteins, common to all Paramyxoviridae (parainfluenza virus, RSV, mumps virus, measles virus), cause infected cells to form multinucleate giant cells Parainfluenza viruses 1 and 3 belong to genus Paramyxovirus; parainfluenza viruses 2 and 4 belong to genus Rubulavirus

Clinical case: A woman in India complains of fever, muscle pains, and weakness of her trunk, abdomen, and legs. This morning, she notes difficulty in swallowing and neck pain, which prompts her to come to the hospital. Physical exam reveals fasciculations and flaccid paralysis of the lower limbs and trunk. Breathing seems to be troubled. A CSF analysis reveals lymphocytosis, PMNs, and normal glucose and protein levels. The physician confirms the diagnosis by checking the woman's vaccination history and prepares respiratory support in case her breathing difficulties worsen.

*POLIOVIRUS* RNA virus -> icosahedral nucleocapsid -> nonenveloped -> SS+ nonsegmented -> Picornaviridae -> Enterovirus -> poliovirus *Clinical presentation*: 1. Paralytic poliomyelitis 2. Nonparalytic poliomyelitis (aseptic meningitis) 3. Abortive poliomyelitis (sore throat, malaise) [More information from Medscape]: -"Minor associated illnesses": 1-3 days before the onset of paralysis - GI complaints, sore throat, fever, malaise, headache, muscle tenderness; lasts 2-3 weeks usually -"Major associated illnesses": CNS disease - aseptic meningitis ("nonparalytic polio"), polio encephalitis, bulbar polio, and paralytic polio, along or in combination => fever, nuchal rigidity, CSF pleocytosis, profound asymmetrical muscle weakness followed by some recovery of muscle strength, rarely a transverse myelitis -"Recovery stage": acute sx disappear & paralyzed muscles begin to recover; lasts up to 2 years after disease onset -"Residual-paralysis stage": no more recovery; muscle atrophy from disuse & deformities can occur *Pathobiology*: Fecal-oral transmission (acid stable) => infects small intestine & oral pharynx epithelium => replicates in tonsils and Peyer's patches => transient viremia Spreads to the CNS via blood and/or retrograde transport in peripheral nerves (incompletely understood) Binds receptors on ventral horn alpha motor neurons innervating distal muscles and/or proximal muscles => replicates & lyses cells Distal muscles affected => LMN type paresis Proximal muscles affected => respiratory insufficiency and potentially death IgG and secretory IgA generated by immune response protects against future infections *Diagnosis*: Aseptic meningitis - CSF lymphocytes increased, glucose normal, protein normal or increased Throat, stool, or spinal specimen - isolate cytopathic effect Serology *Treatment*: Supportive ("iron lungs"), passive immunization with IgG *Vaccines*: Inactivated polio vaccine (IPV) = Salk vaccine (killed virus) Oral polio vaccine (OPV) = Sabin vaccine (live attenuated) *Quick facts*: Polio has been eradicated in the Western Hemisphere for the most part, barring rare instances of OPV reactivation Infection in adults (versus infants) more often leads to paralysis Post-paralytic syndrome (post-polio syndrome) - gradual muscle wasting presenting years (most often upwards of 15 years) after the initial infection

Clinical case: An African American girl with sickle cell anemia visits the doctor after developing weakness, fatigue, and pallor. She tells her physician that several days before, she felt a fever, headache, and muscle aching. She also began to feel joint pain and developed a rash that had a "slapped-face" appearance on her face. A blood tests reveals severe anemia, as well as a decline in neutrophils and lymphocytes. The myeloid lineage seems normal. Serology confirms the diagnosis, and the doctor orders a transfusion of erythrocytes to prevent life-threatening anemia.

*Parvovirus B19* DNA virus -> icosahedral nucleocapsid -> nonenveloped -> SS linear -> Parvoviridae -> Erythrovirus *Clinical presentation*: Erythema infectiosum ("fifth disease") Transient aplastic anemia crisis *Pathobiology*: Inoculates nasal cavity => 6-day incubation => viremia and fever => virus infects and lyses erythroid precursor cells in the bone marrow => mildly reduced reticulocytes, lymphocytes, neutrophils, platelets (NOTE that hosts can normally tolerate a lack of erythropoiesis for 1 week) Immune complexes form and deposit => erythema infectiosum (rash with "slapped cheek" appearance, arthralgias for several days) In patients requiring increased erythropoiesis (e.g. sickle cell anemia, thalassemias): transient aplastic crisis (= severe reticulocytopenia w/ normal myeloid lineage) *Diagnosis*: Detect viral DNA, serology *Treatment*: Supportive - RBC transfusion In immunodeficient patients - Ig transfer *Quick facts*: In immunodeficient patients, parvovirus infection can lead to chronic severe anemia Fetuses, who require higher RBC production and are immunodeficient, are especially vulnerable to parvovirus infections: infected fetuses may develop severe anemia and hydrops fetalis Erythema infectiosum is called "fifth disease" because it is one of the five most common pediatric diseases with rash

Clinical case: A graduate student, while vacationing in India, is bitten by a wild dog. Because he is not near a hospital and because he is eager to continue his trip, he washes his wound thoroughly with water and continues on. When he returns to the US a few months later, the student is admitted to the university hospital complaining of pain on swallowing, increased muscle tone, and hallucinations. He appears agitated, confused, and sensitive to bright light. A neurological exam reveals cranial nerve dysfunction and upper motor neuron problems. Despite intensive supportive measures, the patient falls into a coma and soon dies.

*RABIES VIRUS* RNA virus -> helical nucleocapsid -> enveloped -> SS- nonsegmented -> Rhabdoviridae -> Lyssavirus (rabies virus) *Clinical presentation*: Dysphagia, encephalitis *Pathobiology*: Infects many mammalian species, including dogs => transfers to humans via animal bite => localizes to bite site for days to months => binds to ACh receptors and enters peripheral nerves => travels proximally to CNS (distance determines incubation time) => infects neurons of brainstem and brain => cytoplasmic inclusions (Negri bodies) form => cell necrosis => cranial nerve palsies and encephalitis => dysphagia, agitation, and seizures => coma => death *Diagnosis*: Identify Negri bodies in neurons and other infected cells PCR for viral RNA Serology *Treatment*: Wash wound immediately HRIG (Human Rabies Immune Globulin) antibodies for passive immunity Human Diploid Cell Vaccine: live-attenuated virus (often administered following bite) Prevention: immunize domesticated (dogs, cats) and wild (skunks, foxes, bats, wolves, coyotes, raccoons) animals *Quick facts*: The human rabies vaccine is the only vaccine administered after viral exposure; it works by boosting the immune system during the long viral incubation period "Foaming of the mouth" is a classic sign - reflects an inability to clear saliva because of painful spasms of pharyngeal muscles on swallowing; patients often avoid drinking for this reason (hydrophobia) Rabies virus multiplies in the CNS and travels via axons to many different organs (especially the well-innervated submaxillary gland) Rabies causes a few deaths at most in the US per year but causes many more in countries with unvaccinated animals (e.g. tens of thousands of deaths by dog bites in India each year)

Clinical case: An infant girl who was hospitalized and released for a previous illness returns to the hospital 2 days later with fever, cough, and wheezing. The parents, both asthmatic, think their child is now developing asthma. A CXR reveals hyperinflated lungs with infiltrates. The doctor is convinced that this is a nosocomial viral infection, as many other children admitted to the hospital develop the same symptoms. He transfers the baby to the neonatal intensive care unit, where she is treated with aerosolized ribavirin.

*RESPIRATORY SYNCYTIAL VIRUS (RSV)* RNA virus -> helical nucleocapsid -> enveloped -> SS- nonsegmented -> Paramyxoviridae -> Pneumovirus (RSV) *Clinical presentation*: Children - bronchiolitis, pneumonia Adults - common cold *Pathobiology*: Discharged in nasal secretions => transmitted easily by hand-to-hand contact or aerosol => attaches to bronchiolar and alveoli epithelium via protein G on viral envelope => lower respiratory tract infection => necrosis and inflammation of: a) bronchioles => mucous obstruction of airway => bronchiolitis, wheezing b) alveoli => pneumonia Recurrent infection builds IgA immunity against further infection *Diagnosis*: Detection of virus in respiratory secretions; serology *Treatment*: Supportive Albuterol, aerosolized ribavirin (severe cases) Synagis (F antigen vaccine) to prevent infection in high-risk infants (e.g. premature, lung disease, heart disease) *Quick facts*: The virus is named respiratory syncitial virus (RSV) because viral fusion (F) surface proteins cause infected cells to fuse and form syncytia RSV is the major respiratory pathogen in young children, infecting virtually everyone by age 3. Infections in adults are milder. Worldwide outbreaks of RSV occur every winter, unlike outbreaks of other cold viruses, which occur every few years Asthma and RSV bronchiolitis both present with wheezing, but the mechanisms of disease probably differ: whereas asthma involves smooth muscle constriction, RSV bronchiolitis can occur before smooth muscle has formed in the bronchioles (at age 2-8 mo). Human metapneumovirus (hMPV), also in the genus Paramyxoviridae, is very similar to RSV in structure and function. It is a common respiratory pathogen.

Clinical case: A woman presents with a runny nose, sneezing, an irritable throat, and a slight fever. She suffers similar symptoms every year, often at the same time as other members of her family. Her symptoms go away within a week, except for the nasal discharge that persists for a few more days.

*RHINOVIRUS* RNA virus -> icosahedral nucleocapsid -> nonenveloped -> SS+ nonsegmented -> Picornaviridae -> Rhinovirus *Clinical presentation*: common cold *Pathobiology*: Only has a human reservoir Spreads by contact or aerosol => binds ICAM-1 on upper respiratory tract epithelial cells => extends locally without killing cells => local inflammation leads to exudate and increased ICAM-1 expression => further viral binding and infection Exudate may block passageways, leading to a secondary bacterial sinusitis or otitis media Patient acquires IgA immunity to the particular serotype following an infection *Diagnosis*: clinical presentation *Treatment*: supportive care; no vaccine due to too many viral serotypes *Quick facts*: 50% of colds are due to rhinoviruses Rhinovirus preferentially replicates at the cooler 33C of the nose and upper airways (the warmer 37C of the lungs is why you don't get a pneumonia from the virus)

Clinical case: A mother brings her 3-year-old son to the doctor after severe bouts of vomiting and diarrhea for the past 2 days. The diarrhea is watery, although the mother denies seeing any blood in it. The doctor makes a diagnosis by an ELISA on the child's stool and assures the mother he will be fine with good rehydration.

*ROTAVIRUS* RNA virus -> icosahedral nucleocapsid -> nonenveloped -> DS segmented -> Reoviridae -> rotavirus *Clinical presentation*: gastroenteritis *Pathobiology*: Fecal-oral transmission => infects villus cells of proximal small intestine => replicates within and lyses cell => impaired absorption of carbohydrates and other nutrients => vomiting followed by water diarrhea *Diagnosis*: stool specimen - immunoassay for virus *Treatment*: rehydration Rotavirus vaccine = oral, live-attenuated virus *Quick facts*: Because rotaviruses don't cause any inflammation, the diarrhea is non-bloody! Infection before 6mo of age is uncommon due to passive IgA immunity from the mother's colostrum. However, by age 3, almost every individual worldwide has been infected & develops lifelong immunity "Reo"virus = "respiratory enteric orphan" because we used to think it didn't cause any diseases NOTE that reoviruses (rotavirus and colorado tick virus) are the only double-stranded RNA viruses!

Clinical case: A woman goes to her doctor complaining of a red rash on her face. She reports having a fever that resolved just before the rash appeared. During a physical exam, the doctor notes that the rash has spread to the arms. Swollen lymph nodes are felt in the cervical region and behind the ears. The doctor inquires about the woman's vaccination record and makes a diagnosis to be confirmed by serological studies. The doctor also makes sure that the woman is not pregnant. The woman is relieved to know the rash will go away in several days, although she may experience arthritis for some time thereafter.

*RUBELLA VIRUS (GERMAN MEASLES)* RNA virus -> icosahedral nucleocapsid -> enveloped -> SS+ nonsegmented -> Togaviridae -> Rubivirus *Clinical presentation*: Rubella = fever followed by descending rash Congenital rubella = congenital malformations (deafness, PDA, pulmonary artery stenosis, cataracts, microcephaly) *Pathobiology*: Transmitted by aerosol => virus infects nasopharynx and replicates in local lymph nodes => systemic hematogenous spread (viremia) => Antibody-mediated reaction leads to a maculopapular rash beginning in the face and spreading to the extremities => Antibody complexes may result in arthritis in women If the virus infects a pregnant woman in the first trimester => may cross placenta to fetus => infects fetal cells & promotes mitotic arrest, necrosis, or chromosomal damage => congenital defects in brain, heart, or eyes Lifelong IgG-mediated immunity following infection *Diagnosis*: Detection of anti-rubella antibodies (IgM for recent infection; IgG if immune) Blocks cytopathic effect (CPE) of ECHOvirus in culture Amniocentesis detection of virus indicates congenital rubella *Treatment*: Self-limiting (no antiviral treatment available) Vaccine: live attenuated virus; part of MMR vaccine *Quick facts*: Pregnant women are screened for rubella immunity. However, the rubella vaccine is not administered until after delivery for fear of fetal infection. An infant with congenital rubella may transmit the virus up to the age of 2, complicating the control of infection UNLIKE other Togaviridae (i.e. EEE/WEE/VEE), rubella is NOT an arbovirus (no arthropod vector) MMR (measles, mumps, rubella) vaccine is the only live viral vaccine that can be given in HIV-positive individuals.

Clinical case: A physician interested in medical history comes across a narrative recorded in Africa about a group of patients plagued by 'vesicles all over their bodies.' The vesicles are described as 'oozing' and 'viscous', causing body surfaces to stick together. Even more dramatic, the story describes how the disease started with a few but soon engulfed an entire village. little more than supportive care could be offered to these patients, most of who soon died.

*Smallpox (Variola) Virus* DNA virus -> icosahedral nucleocapsid -> enveloped -> DS linear -> Poxviridae -> Orthopoxvirus *Clinical presentation*: Rash (beginning as macules, evolving to vesicles) *Pathobiology*: Inhaled via aerosols => infects upper respiratory epithelium => penetrates mucosa and enters bloodstream => primary viremia => infects and multiplies within internal organs => large number of virions released into bloodstream => secondary viremia => virus spreads throughout the body, giving focal infections in skin, lungs, intestines, kidneys, brain When skin is infected: viral particles collect and replicate in epidermis => collections form macules, first in the head and later in the extremities => virus replicates and generates host immune response => macules become pus-filled vesicles => crusts form in 2-3 weeks => infectious particles are released *Diagnosis*: (past) detection in vesicular fluid *Treatment*: Vaccines: -Cowpox virus (antigenically similar but benign virus), discovered by Edward Jenner and used in the US and Europe beginning in the 1800s -Vaccinia virus (live-attenuated virus) used in developing countries during the WHO's 1967 successful campaign to eradicate smallpox (Because the virus has been eradicated, vaccinations are now only given to those in the military) *Quick facts*: Vaccinia virus may someday serve as vaccine for many different pathogens, with strains now engineered to carry antigens of various other viruses and bacteria The last case of smallpox was reported in Somalia in 1977; now, only a few vials of the virus exist, including some secured by the US government The WHO's eradication effort worked because 1) only one smallpox serotype existed; 2) no smallpox carrier state existed; & 3) no animal reservoirs of the virus existed Another Poxviridae causes molluscum contagiosum, small pink tumors with a central dimple often on trunk and anogenital regions. It is most often seen in AIDS patients.

Clinical case: A 72-year-old woman complains to her doctor of a burning, painful rash on her chest. A physical exam reveals fever and a vesicular, erythematous rash limited to the right side of her chest and overlapping the dermatomal area of T7-T8. The physician confirms a diagnosis by a Tzanck smear of the lesions showing multinucleate giant cells with intranuclear inclusion bodies. The physician administers acyclovir and explains that though the rash will likely ameliorate, the regional pain may last longer.

*Varicella-Zoster virus (VZV) or Herpesvirus 3* DNA viruses -> icosahedral nucleocapsid -> enveloped -> DS linear -> Herpesviridae -> Varicellovirus *Clinical presentation*: Varicella (chickenpox); zoster (shingles) *Pathobiology*: Highly contagious from respiratory secretions or ruptures varicella vesicles => virus infects respiratory tract => 2-week incubation period => viremia => flu-like symptoms and widespread vesicles with red base appearing as 'dew on a rose petal' (varicella) => rash spreads centrifugally => mild in children; severe and may progress to pneumonia or encephalitis in adults Varicella resolves within 2 weeks => virus enters local sensory nerve endings => axonal transport proximally to sensory ganglion cell bodies => latent infection of dorsal root ganglion Stress or immune-compromise => viral reactivation => axonal transport of virus from ganglia to nerve endings => recurrent painful vesicular rash over sensory dermatome (zoster) *Diagnosis*: Detection of virus Multinucleate giant cells on Tzanck smear of skin lesions Eosinophilic Cowdry intranuclear inclusion bodies on skin biopsy *Treatment*: Supportive Acyclovir, famciclovir (severe) anti-VZV immunoglobulin (for immunocompromised) Vaccine: attenuated VZV *Quick facts*: The VZV vaccine is controversial for two reasons: a) Immunity may wane, allowing more serious adult varicella infections, & b) A latent state from prior infection is not eliminated, so zoster can still occur Reye's syndrome (liver damage, encephalitis): associated with aspirin treatment for chickenpox in children

Clinical case: A 75-year-old man from New York is brought to the ED after reporting 1 week of fever, headache, nausea, and muscle ache. On exam, he appears confused and has a course (coarse?) tremor in his hands. CT and MRI are unrevealing. A lumbar puncture is performed, and CSF analysis demonstrates elevated protein, normal glucose, and lymphocytosis. His family reports that he was visiting them for the summer, but they have avoided the outdoors after several dead crows were found in their neighborhood.

*WEST NILE VIRUS* RNA virus -> icosahedral nucleocapsid -> enveloped -> SS+ nonsegmented -> Flaviviridae -> Flavivirus *Clinical presentation*: Most infections are asymptomatic West Nile fever: fever, fatigue, headache, myalgia, anorexia, eye pain, nausea, vomiting, diarrhea, rash West Nile encephalitis: neuroinvasive disease causing encephalitis (more typical in elderly) or meningitis (more typical in children); symptoms range from mild confusion to tremor, extrapyramidal symptoms, flaccid paralysis, or severe encephalopathy that may progress to coma or death (particularly in elderly/ immunocompromised) *Pathobiology*: Virus maintained in cycle between birds and mosquitos => spreads to incidental human host by mosquito bite => replicates in Langerhans cells of skin, which migrate to regional lymph nodes => viremia and infection of multiple organs including the CNS *Diagnosis*: IgM antibody in serum or CSF PCR of CSF *Treatment*: supportive; prevention via mosquito control *Quick facts*: WNV named after the West Nile province of Uganda where it was first isolated; it first appeared in N. America in 1999, causing several deaths in NY Crows and other birds are the hosts for WNV. Clusters of dead crows have heralded human cases Rare transmission of WNV has been reported via transfused blood products, donated organs, and breast milk.

Clinical case: A diplomat plans to make a trip to Central America. However, just before leaving, his doctor receives a CDC report of jungle log cutters that have fallen ill with jaundice, instances of hemorrhage, and liver dysfunction. He insists that the diplomat be immunized against this infectious agent before traveling to the area. For a summer trip, a woman visits the tropics for a short time. One week upon returning, she shows signs of fever, headache, and pain behind the eyes and in the back and joints. She also notices a generalized rash forming. The doctor explains that the illness will pass but that a second infection by a similar agent might lead to more devastating symptoms.

*YELLOW & DENGUE FEVER VIRUSES* *ST. LOUIS & JAPANESE ENCEPHALITIS VIRUSES* RNA virus -> icosahedral nucleocapsid -> enveloped -> SS+ nonsegmented -> Flaviviridae -> Flavivirus *Clinical presentation*: a. Yellow fever virus: Yellow fever (=hepatitis, jaundice) b. Dengue fever virus: -Dengue fever: "breakbone fever" (=flu-like + severe joint/muscle pain) -Dengue hemorrhagic fever: =dengue fever + hemorrhage, shock c. St. Louis, Japanese Encephalitis viruses: encephalitis *Pathobiology*: Normal reservoir in monkeys, birds, or humans => transmitted by mosquito bite => enters bloodstream with transient viremia Infects: a. Hepatocytes (Yellow fever) => necrosis => hepatitis, jaundice b. Macrophages (Dengue fever) => acute inflammation => pyrogens and pain mediators released => "breakbone fever" i. IF SECOND INFECTION by different serotype => antibodies against first serotype increase => cross-react to form immune complexes => type III hypersensitivity reaction => hemorrhage, shock (Dengue Hemorrhagic Fever) c. CNS (St. Louis or Japanese Encephalitis) => direct damage to neurons, inflammation => neurological abnormalities *Diagnosis*: Isolate virus from infected tissue (e.g. CNS in encephalitis); serology *Treatment*: Prevention - monitor mosquito count in an area Vaccine: => Yellow fever virus: live attenuated vaccine => Japanese encephalitis: formalin-killed vaccine *Quick facts*: Epidemics have geographic specificity: -Yellow fever in tropical South America & Africa -Dengue fever in tropics worldwide -Dengue hemorrhagic fever in southern Asia -St. Louis encephalitis in southeastern U.S. -Japanese encephalitis in Japan Two forms of yellow fever exist: 1) JUNGLE (reservoir in tropical monkeys) and 2) URBAN (reservoir in humans); each transmitted by a different mosquito Fun fact: Yellow fever plagued many workers in the Panama Canal project, and only after its control was the canal completed.

Most common causes of conjunctivitis?

1. H influenza 2. Adenovirus 3. S. pneumoniae

Break down the classification of arboviruses.

Arboviruses (= arthropod-borne virus): A. Togaviridae -EEE -WEE -VEE B. Flaviviridae -West Nile virus -Yellow fever -Dengue fever -St. Louis encephalitis -Japanese encephalitis C. Bunyaviridae -California encephalitis -Rift valley fever -Sandfly fever

Most common viral cause of intellectual disability in the US?

CMV

Most common causes of aseptic meningitis?

Coxsackievirus Echovirus Mumps virus (see "coxsackievirus A & B" card)

Most common human disease caused by an arbovirus?

Dengue fever (see "yellow and dengue fever viruses, St. Louis and Japanese encephalitis viruses" card)

Contrast HAV/HEV with HBV/HDV/HCV.

HAV/HEV (versus the other hepatitis viruses) have: Oral transmission No chronic carrier state No cirrhosis No risk of hepatocellular carcinoma

Most common cause of epidemic encephalitis?

Japanese encephalitis virus (see "yellow and dengue fever viruses, St. Louis and Japanese encephalitis viruses" card)

Five most common pediatric diseases with a rash?

Measles (measles virus) Rubella (rubella virus) Scarlet fever (S. pyogenes) Roseola (HHV 6) Erythema infectiosum (Parvovirus B19)

Most common causes of pneumonia in young children?

RSV Parainfluenza virus (see "parainfluenza virus" card)

Causes of the common cold?

Rhinovirus Coronavirus Adenovirus Influenza C virus Coxsackievirus (see "coxsackievirus A & B" card)

Most common cause of infectious diarrhea in infants (>6 months) and young children?

Rotaviruses (see "rotavirus" card)

Causes of a palm and sole rash?

Syphilis Rocky Mountain spotted fever Coxsackievirus (see "coxsackievirus A & B" card)

Infections that can be transmitted from pregnant mother to fetus?

TORCHES = *TO*xoplasma gondii *R*ubella *C*ytomegalovirus *HE*rpes, *H*IV *S*yphilis Note that all of these organisms can cross the placenta which is the pathophysiologic basis for the vertical transmission of infection.

HSV-1 versus HSV-2?

Typically, HSV-1 infects ABOVE the waist (eye and mouth lesions) & HSV-2 infects BELOW the waist (genital lesions) Note that oral-genital sex can lead to HSV-1 below and HSV-2 above. See "HSV-1" card