D&D3.1 Flashcards
Viruses
composed of DNA or RNA genomes in small proteinaceous partices (capsid). The genome contains all the information to initiate and complete an infectious cycle. They establish a relationship in a variety of hosts that ranges from benign to lethal. They have the property of self assembly. They are metastable structures subject to conformational changes to promote delivery of the genome to the appropriate host cell. Viral assembly and disassembly are targets for anti-viral drugs.
Conventions to viruses genome
mRNA containing a translatable open reading frame is always + strand; it is ribosome ready and ready to be translated into protein. The complementary strand is – strand.
Virus classification
they are grouped according to nature of genetic material (DNA or RNA, symmetry of the capsid (helical vs icosahedral), naked vs enveloped, and the dimensions of the virion and capsid.
basic methods for studying viruses.
Electron microscopy, animal models, sequence analysis, cell culture, serology, and other molecular techniques.
One-step growth curve
an experiment done in cultured cells where every cell is infected with virus. Viruses do not grow exponentially, like bacteria, but are released in bursts (this is due to the fact that viruses are assembled from preformed components. The growth curve is composed of two phases, the eclipse period and the latent period.
Eclipse period
between 0 and 12 hours after virus absorption where no infectious virus is detectable inside or outside the cell. This is the time when virus particles have broken down after penetrating cells, releasing their genomes for replication. They are no longer infectious and cannot be detectable as plaque forming units (PFU) in assay.
Latent period
the time it takes from the initiation of infection to the release of new infectious virus particles from the cell and is on the order of 16 hours for the adenovirus. In this period, the virus attaches to the cell, enters and uncoats the viral genome, express and replicate the genome, and assemble new viruses and egress from the cell.
Functions of virion proteins
1) protection of the genome: assembly of a stable, protective protein shell, recognition of viral genome and packaging, and sometimes interact with host cell membrane to form an envelope. 2) delivery of the genome: specific binding to host cell receptors, transmission of specific signals that induce uncoating of the genome, induce fusion with host cell membrane, and interact with internal component of host cell to direct transport of genome to required site. 3) mediate interactions with the host: with host components to ensure efficient viral replication, with cellular components for transport to sites of assembly, and with the host immune system.
Virus particles
are created by symmetrical arrangement of many identical or highly similar proteins in order to provide maximal contact and non-covalent bonding between them. Capsid proteins of different viruses have very highly conserved motifs, although the protein sequence may not be conserved. This allows for genome delivery because the structure is not permanently bonded together. They therefore have very stable interactions during assembly, egress and transmission, but are also reversal for entry and un-coating. The protein coats of animal viruses are mostly either helical or icosahedral symmetry (symmetric because of self assembly of subunit proteins). Regular structures form when identical bonds are made between identical subunits, but when non-identical bonds form it results in aggregates.
Helical capsids
it is the simplest way to arrange multiple identical subunits is to use rotational symmetry and arrange irregularly shaped proteins around a circumference of a circle to form a disk. This formation is very common in a wide variety of viruses.
Icosahedral capsids
an arrangement of protein subunits in the form of a hollow, quasi-spherical structure, with the genome within. This is accomplished by using the triangle as the repeating unit.
Icosahedral symmetry
it is a solid shape consisting of 20 triangular faces with 12 vertices and faces with 2-, 3-, and 5- fold axis of symmetry. These structures may not actually be icosahedrons, but have more complex arrangement of facets within the triangular faces. The smallest closed shell is constructed of 60 identical subunits- 3 per face. Larger volumes are attained by using more subunits. These subunits interact in quasi-equivalent ways, with non-covalent interactions occurring in slightly different structural environments.
Envelopes
they are lipid bilayers acquired during assembly of viral particles and typically have viral glycoproteins embedded in the membrane. Most are acquired by budding through a membrane of the host cell into some extra-cytoplasmic compartment; either from the cell membrane or the endoplasmic reticulum or the golgi apparatus. It is the last step in viral assembly and allow the virus to escape the cell. Non-enveloped viruses usually escape by lysis of the cell and is terminal. Therefore enveloped viruses do not necessarily kill the cell
Viral glycoproteins
can play roles in multiple facets of the virus lifecycle including entry and host range determination, assembly and egress, evasion from the vertebrate immune system. They are integral membrane proteins, typically with one or two membrane-spanning domains. Often occur in oligomeric, non-covalent assemblies specifying a myriad of functions.
Seven classes of viral genome configuration
dsDNA, gapped circular dsDNA, ssDNA, dsRNA, ss(+)RNA, ss(-)RNA, and ss(+)RNA with DNA intermediate.
DNA viruses
double stranded, gapped genomes or single stranded genomes must transcribe mRNA using the (-) strand of DNA genome as a template. This means that the gaps must be filled (or the genome replicated in the case of ssDNA) before the genes can be transcribed. For most DNA viruses, it is the host’s RNA polymerase II that transcribes the genome. This take place in the nucleus, where this enzyme is located and produces regular mRNA that is capped and poly-adenylated by the host’s machinery for translation by the host ribosomes. An exception is the poxviruses, which replicate in the cytoplasm of infected cells and encode their own RNA polymerase.
RNA viruses
all RNA viruses make use of RNA-dependent RNA polymerase (RdRp), which is not found in host cells. This enzyme is used both for production of mRNA and the replication of the genome.
(+) stranded RNA viruses
the genomes can be translated directly by cellular ribosomes. Amplification of mRNA copy number or production of sub-genomic mRNAs is mediated by RdRp.
(-) stranded RNA viruses and double stranded RNA viruses
(+) sense mRNA must be transcribed from the genome in order to have gene expression. Because animal cells do not contain RdRp, it is not ribosome ready and the viruses must bring this enzyme with them into the infected cell.
Retroviruses
these are (+) stranded RNA viruses with DNA intermediate. Before gene expression, these viruses must copy their single stranded RNA genome into dsDNA, which is accomplished by reverse transcriptase (it needs to be packaged in the virus). Animal cells do not have this enzyme. The dsDNA copy of the virus genome then integrates into the host cell’s DNA. Once integrated, mRNA is transcribed from the virus genome using host cell-encoded RNA polymerase II.
Viral attachment
involves specific binding of a virus attachment protein with a cellular receptor molecule. The target may be proteins (usually glycoproteins) or carbohydrates (found on glycoproteins or glycolipids). Carbohydrate receptors tend to be less specific than protein receptors because the same configuration of carbohydrate side-chains may occur on many different glycosylated membrane bound molecules.
Viral entry
penetration of the target cell normally occurs a very short time after attachment of the virus to its receptor in the cell membrane. Unlike attachment, entry is generally energy-dependent process (the cell must be metabolically active for this to occur). Penetration may involve endocytosis of the virus into intracellular vesicles (endosomes), which the virus must escape. For enveloped viruses, fusion of the virus envelope with a cellular membrane requires the presence of specific fusion protein in the virus envelope and occurs at the plasma membrane or endocytic membrane.
Viral uncoating
the viral capsid is completely or partially removed and the virus genome is exposed.
Viral genome replication
exact copies of the viral genome must be produced to be packaged into progeny virions.
dsDNA virus genome replication
replication is exclusively nuclear. The replication of these viruses is relatively dependent on cellular factors, but may involve viral polymerases and accessory factors. Another strategy is replication in the cytoplasm (poxvirus) and have all the necessary factors for replication of their genomes and are therefore largely independent of the cellular machinery.
ssDNA virus genome replication
replication occurs in the nucleus, involving the formation of a ds intermediate that serves as a template for the synthesis of ssDNA.
Gapped circular dsDNA virus genome replication
uses a virally encoded reverse transcriptase to copy viral genomes from mRNAs transcribed from the template genome.
Viruses with RNA genome replication
transcription and genome replication is integrated. Replication uses anti-genome as the template. Production of the anti-genome, as well as the replicated genomes is performed by RdRp.
Assembly of virion
for icosahedral capsids packaging of the genome can either be accomplished by assembling the capsid around the virus genome or by feeding the genome into preformed capsids. For helical nucleocapsids, viral genome is usually coated with nucleocapsid protein during its synthesis. Assembly often results in significant cytopathic effect (CPE) because capsid proteins are produced in very high numbers. The abundance can result in the appearance of either cytoplasmic or nuclear inclusions (depending on the cellular location). These inclusions can be detected by electron microscope and the size and location is often highly characteristic of particular viral infections.
Viral egress
exit from the infected cell for naked viruses often occurs with lysis of cell due to the volume of the virus in the cell. Viruses with envelopes can acquire their envelopes from budding. Viruses that bud into the plasma membrane are released into the extracellular environment directly. Viruses that bud into the membranes of golgi apparatus or ER are secreted from the infected cell.
Tissue tropism with viruses
when a certain virus is likely to infect specific tissues and not others. Enterotropic viruses replicate in the gut and neurotropic viruses in the nervous system tissue. Tropism is determined by a combination of factors including access to the tissue in which it can replicate, receptors required for binding and entry, expression of host genes required for virus infection and production of new progeny virus, and a relative failure of host defenses. Tropism can drive virus population variants among or within individuals particularly in viruses with highly error prone replication systems.
Transmission and shedding of viruses
for local infections, shedding occurs at initial site of infection. For disseminated or systemic diseases, shedding could take place from multiple or distant site. Viral transmission may be in a single host or in multiple hosts as in insect to human transmission. The means of transmission depends on the site of viral replication/release and the stability of virus particle in the environment. Enveloped viruses are fragile and sensitive to many environmental stresses, such as pH, and are often transmitted by close contact. Non-envoloped viruses are hardier and can sustain drying, low pH, detergents, and high temperature and therefore can be transmitted via virus associated objects or formites and use respiratory or fecal/oral routes. Most transmission is horizontal, but vertical (parent/child) and germ-line transmission does sometimes occur. Some viruses are seasonal or geographical, which may indicate the need for particular animal or vector host or may indicate a susceptible or naïve population.
Host factors in susceptibility to viral diseases
these factors include expression of appropriate receptors for virus entry, accessibility and permissively (ability of cells to support viral replication) of infected cells, age of host, genetic background, and immune status.
Immune mediated pathology
some viral diseases are mediated by host immune response, which can include antibody (immune complex diseases), cell mediated response (rash, fever, and malaise), autoimmunity (possibly due to cross-reactivity with virus), and transient immune modulation such as immune suppression.
Acute viral diseases
is characterized by a high viral replication rate and production of a large number of progeny. Replication is transient in a specific host and is limited by either death of the host (and/or cell death) or by the host immune responses. Local or systemic depends on initial events of infection and viral tropism.
Acute local viral infection
usually infections of epithelial cells at body surface (gut, respiratory tract, eyes). Often have short incubation times and many are serotypes (rapidly mutating). This results in short lived immunity primarily via secretory IgA. Re-infections are common. E.g. colds and diarrheal disease.
Acute systemic viral infection
primary infection site is also often epithelial cells but viremia and systemic infection leads to secondary replication at various sites. Immune response includes both IgA and IgG and leads to lifelong immunity. E.g. measles and smallpox.
Chronic viral infection
ongoing virus infection and/or replication, usually with mild or unapparent disease in host. Manifestation of disease is often a result of immune suppression or other complications. Chronic infections can be persistent, latent, or slow.
Persistent viral infection
usually refers to virus infections that continue to produce new viruses over a long period of time. Last for longer periods of time and may be the result of an acute primary infection that never clears and the ability of the virus to spread to other organisms or offspring of the host.
Latent viral infections
involve substantial periods in which the host produces no detectable viruses. They are different from dead end infections in that they retain their ability to re-initiate transcription and replication to produce new virus. This is reactivation or recrudescence. (VZV in nerves)
Slow viral infections
no symptoms on initial infection, long incubation period, may or may not induce an immune response, and eventual disease is followed by progressive deterioration and death. (AIDS and cancer)
Transforming viral infection into cancer
some retroviruses integrate into host genome and activate viral or host oncogenes. Other viruses may integrate to cause host DNA breakage and oncogene activation or inactivation of tumor suppressor. Finally, some infections (in particular persistent infections) may cause ongoing inflammation and so contribute to tumorigenesis.
Three general outcomes of viral infection of a cell
1) abortive infection or failed infection (no virus produced/ no apparent effects on the cell). 2) lytic infection resulting in production of virus and death of the infected cell. 3) persistent infection- chronic (production of virus), latent (no virus produced), and transforming (may produce virus). These outcomes are characteristic of certain viruses in their target tissues, however they are not hard-wired and are dependent on virus, host, target tissue, and immune status at time and site of virus entry. A virus that is cytolytic in epithelial cells may be latent in neurons (tissue dependent). A latent virus in neurons may be reactivated upon immune suppression and resume productive lytic infection (dependent on immune status).
Cytopathic effects of virus infection
includes any detectable morphological change in host cell. Retroviruses do not generally cause cell death, being released by budding and causes persistent infections. Conversely, picornaviruses cause lysis and death of cells, leading to fever and increased mucous secretions in rhinoviruses and paralysis or death for poliovirus.
Direct cell damage and death from viruses
may result from diversion of cell’s energy, turning off of cell marcromolecular synthesis, competition of viral mRNA for cellular ribosomes, competition of viral promoters and enhancers for cellular factors and inhibition of the interferon defense mechanisms.
Indirect cell damage from viruses
can result from integration of viral genome, induction of mutations in the host genome, inflammation, and host immune response. The immune response has the greatest effect on the outcome of infection and the pathological effects. Cellular immunity plays the major role in clearing virus infection and humoral immunity protects against reinfection.
Permissive vs non-permissive cells for particular viruses
permissive cells provide machinery and components required for replication, non- permissive do not and does not always result in efficient production of virus. It can also result in a latent or transforming infections. There is a continuum between the two.
Intracellular restriction factors against viruses
cellular proteins that can block post-entry steps of certain virus infections. They are not apart of the adaptive immune response but there is specificity for certain viruses. These factors are potent, widely expressed, and intracellular blocks to viral replication. These exists due to evolutionary pressures but viruses evolve faster than the host. E.g Trim5 blocks retroviruses and APOBEC blocks HIV and HCV.
Toll-like receptors (TLRS)
recognize PAMPs and induces signaling pathways which lead to activation of innate immunity and instructs development of antigen specific acquired immunity
TLR3
ligand is dsRNA (viruses)
TLR4
ligand is LPS, fusion protein (respiratory syncytial virus), and envelope protein (mouse mammary- tumor virus)
TLR7
imidazoquinoline (synthetic compounds) and ssRNA (viruses)
TLR8
imidazoquinoline (synthetic compounds) and ssRNA (viruses)
TLR9
CpG containing DNA (bacteria and viruses)
Retinoic acid inducible gene 1 (RIG-1)- like helicase (RLHs)
recognize viral nucleic acids within infected cells. RLH proteins coordinate many of the same signaling pathways as TLRs.
Type I IFNs
include alpha-IFN and beta-IFN. Antiviral cytokines transiently produced and secreted by most infected cells within hours. They induce resistance to viral replication in all cells, increase MHC class I expression and antigen presentation in all cells, and activate NK cells to kill virus-infected cells.
Type II IFNs
gamma-IFN. Produced by T cells and NK cells, and some others (but more restrictive than type I).
Jak/Stat pathways
respond to IFN binding to IFN receptors and control genes whose transcription is regulated by interferon-stimulated response elements (ISREs) for the type 1 IFNs and by gamma activated site (GAS) elements for type II IFN.
Antiviral state
a cells response to IFN in order to block viral replication by altering transcription of over 100 genes. dsRNA activates a number of IFN responsive genes. Results in temporary blockade of cell proliferation, reduces cellular metabolism, potentiates NK cell activity including gamma-IFN production, increases expression of antigen presentation molecules, and may lead to apoptosis. Most viruses can induce IFN production resulting in “flu-like” syndrome. Large amounts of IFN can have severe physiological effects but have been used in treatment against hep C as well as tumors.
Protein kinase R (PKR)
phosphorylates and inactivates a cellular translation initiation factor, resulting in decreased protein synthesis.
2’-5’ Oligoadenylate synthesis (OAS)
activates a cellular ribonuclease that degrades mRNA.
Mononuclear phagocytes
apart of innate defense. Phagocytosis, release of inflammatory mediators, antigen presentation
Dendritic cells
apart of innate defense. Migratory cells found in every tissue except the brain, present antigens to T cells, stimulate B cell differentiation and proliferation. They are key modulators in the development of that adaptive immune response during viral infections and secrete a large variety of antiviral and immunoregulatory cytokines. They are important in initiating T cell response to viruses, which fail to induce co-stimulatory activity in other types of antigen presenting cells. Pathogens that escape recognition receptor specific phagocytosis, get taken up by tissue DCs through macropinocytosis allowing their peptides to be presented to T cells.
Natural killer cells
apart of innate defense. Are activated in response to IFNs or macrophage dependent cytokines and serve to contain virus infections while adaptive immunity response generate antigen-specific cytotoxic T cells that can clear the infection.
Granulocytes
are also called PMNs, include neutrophils, basophils, eosinophils, and mast cells.
Chemokines
chemoattractant for leukocytes, recruiting monocytes, neutrophils, and other effector cells from blood to site of infection. E.g IL-8, IP10, MIP1-alpha.
progression of host response to viral infection
Viral pathogens are recognized by the cells in which they replicate, leading to the production of interferons that serve to inhibit viral replication and to activate NK cells. The induced innate responses either succeed in clearing the infection or contain it while an adaptive response develops. Adaptive immunity harnesses many of the same effector mechanisms used in the innate system, but is able to target them with greater precision. Thus antigen-specific T cells activate the microbicidal and cytokine-secreting properties of macrophages harboring pathogens, while antibodies activate complement, act as direct opsonins for phagocytes, and stimulate NK cells to kill infected cells. In addition, the adaptive immune response uses cytokines and chemokines, in a manner similar to that of innate immunity, to induce inflammatory responses that promote the influx of antibodies and effector lymphocytes to sites of infection.
Humoral response
B lymphocytes are the effectors of the humoral response and produce Ig, both surface bound and secreted. When their receptors are bound that cell divides and there is amplification and competition for antigen, promoting antibody affinity maturation (selection of B cells with the highest affinity antibody) and differentiation of those cells into plasma cells. Stimulation also leads to isotype switching (IgM to IgG, IgE, or IgA). Antibodies produced during primary virus infection are usually lower affinity than those produced later on. IgA inhibits virion/host attachement, neutralizes toxins and enzymes. IgG inhibits fusion of enveloped viruses with host membranes. IgG and IgM opsonize virions to enhance phagocytosis and can facilitate complement lysis of enveloped viruses. IgM can coat and agglutinate some virions. Neutralizing antibodies binds to virus and prevents it from budding or fusion. Abs can also target infected cells for complement-mediated lysis or for enhaced killing of KN and phagocytes as in antibody-dependent cell mediated cytotoxicity (ADCC).
Cytotoxic CD8 T cells
necessary for getting virus after it is inside the cell. They need to be powerful and accurate to minimize damage to healthy tissue. T helper cells generally bind to class II and produce cytokines that regulate proliferation and activity of other cells. T cytotoxic cells generally bind peptide with class I and can kill virus infected cell.
Important effector functions of T cells with virus infections
secretion of IFN by helper and cytotoxic T cells and activated NK cells. CTLs lyse virus infected cells. NK cells and macrophages kill infected cells directly or by antibody-dependent cell mediated cytotoxicity (ADCC).
Protective immunity
consists of preformed immune reactants (cells, Ab, and cytokines) and immunological memory. Antibody levels and effector T-cell activity gradually decline after an infection is cleared. An early reinfection is rapidly cleared by these immune reactants. There are few symptoms but levels of immune reactants increase. Reinfection at later times leads to rapid increases in antibody and effector T cells owing to immunological memory (the anamnestic response), and infection can be mild or even inapparent. Viral infections may be controlled by the host immune system with or without clearance of the virus.
Humoral response
is critical for recognition of virions. Cell-mediated response is critical for recognizing and eliminating virally infected cells. Th1 cells skews immune response towards cell mediated immunity and Th2 cells favor humoral response.
Antigenic variation
includes point mutation in antigenic drift (HIV and influenza A) and genome shuffling in antigenic shift (influenza). These rapid changes allow viruses to be unrecognizable to the immune system.
Immune tolerance
molecular mimicry or infection prior to competent immune system. Virus proteins that resemble host proteins may escape the immune system.
Restricted expression of viral genes
going invisible to the host defenses as in latent infections (HIV).
Production of viral molecules that act as inhibitors or decoys of host defense molecules
such as cytokines, receptors, and Ab’s (pox and herpesviruses). Viruses produce proteins which can bind and block cellular mediators or can mimic cellular mediators. Those mimics have evolved to omit certain functions of their cellular counterparts (such as stimulatory) and retain only those functions which benefit them (such as suppressive functions).
Down regulation of host proteins
such as MHC class I or adhesion molecules (pox and herpesviruses). Since class I is required for CTL recognition, down regulation protects virus infected cells from detection. Class I down regulation however, is also a trigger for NK cell detection, so some sophisticated viruses also express a viral homolog of class I molecules to avoid NK recognition.
Infection of immune-privileged sites
such as the brain (HSV)
Direct infection of the immune system
HIV and EBV
Inhibition of apoptosis and cell cycle control
(e.g. SV40 large T antigen and Adenovirus E1A). Many viruses affect these two pathways, and these two pathways are also often involved in tumorigenesis.
Herpesvirus family
envelope, linear dsDNA that is protected by an icosahedral capsid, includes HSV-1 (oral and some genital lesions, spontaneous temporal lobe encephalitis, keratoconjunctivitis), HSV-2 (genital and some oral lesions), VSV (HHV-3, chickenpox, zosters- shingles), EBV (HHV-4, mononucleosis, burkitt lymphoma, hodgkin lymphoma, nasopharyngeal carcinoma), CMV (HHV-5, infection in immunosuppressed patients- AIDS retinitis, especially transplant recipients, congenital defects), HHV-6 (roseola- exanthema subitum), HHV-7 (less common cause of roseola), HHV-8 (Kaposi sarcoma). In this family there is latency after initial infection and may reactivate later and is sometimes but not always associated with further disease. Tends to occur during immunosuppression. Herpesviruses are classified into three subfamilies based on their site of latency.
Herpesviruses in the a subfamily
(HSV-1, HSV-2, VZV) establish latency in sensory ganglia.
Herpesviruses in the b subfamily
(CMV, HHV-6, HHV-7) establish latency in monocytes and lymphocytes.
Herpesviruses in the g subfamily
(EBV, KSHV) establish latency in B cells.
Herpes simplex type 1 (HSV1)
targets mucosal epithelium, latency in neuron ganglia, transmitted by respiratory secretions and saliva, can cause gingivostomatitis, keratoconjunctivitis, herpes labialis, temporal lobe encephalitis (most common cause of sporadic encephalitis, can present with altered mental status, seizures, and/or aphasia), Herpes whitlow, neonatal herpes.
Herpes simplex type 2 (HSV2)
target mucosal epithelium, latent in sacral neuron ganglia, transmitted by sexual contact and perinatally. Clinical manifestations include herpes genitalis and some orofacial lesions, neonatal herpes, encephalitis, herpes whitlow, herpes keratitis.
Varicella zoster virus (VZV)
varicella-zoster (chicken pox and shingles), encephalitis, pneumonia. Targets mucosal epithelium, latency in dorsal root or trigeminal ganglia. Most common complication of shingles is post-herpetic neuralgia. Transmitted by respiratory secretions.
Epstein-Barr virus (EBV)
mononucleosis. Characterized by fever, hepatosplenomegaly, pharyngitis, and lymphadenopathy (especially in posterior cervical nodes). Transmitted by respiratory secretions and salivia, also called kissing disease since is common in teens and young adults. Infect B cells through CD21. Atypical lymphocytes seen on peripheral blood smear that are not infected B cells but are reactive cytotoxic T cells, detect by positive monospot test- heterophile antibodies detected by agglutination of sheep or horse RBCs. Associated with lymphomas (endemic Burkitt lymphoma), and nasopharyngeal carcinoma. Targets both B lymphocytes and epithelia. Latency in B lymphocytes. In immunocompromised patients it can cause central nervous system lymphoma.
Cytomegalovirus (CMV)
congenital infection, mononucleosis (negative monospot). Targets Epithelia monocytes, lymphocytes and others. Latency in monocytes, lymphocytes and possibly others. Transmitted congenitally and by transfusion, sexual contact saliva, urine, and transplant. In immunocompromised patients, can cause retinitis, pneumonia, colitis. In newborns, can cause congenital CMV.
Herpes lymphotropic virus-6 (HHV- 6) and Human Herpes virus 7 (HHV-7)
targets and latency in T lymphocytes and other. HHV-6 is transmitted through contact and respiratory route transmission for HHV-7 is unknown. Can cause roseola-high fevers for several days that can cause seizures, followed by a diffuse macular rash.
Human herpes virus-8 (HHV-8)
targets endothelial cells, latency in B lymphocytes. Transmitted by sexual contact (exchange of body fluids?). clinical presentation includes Kaposi sarcoma- a neoplasm of endothelial cells. Seen in HIV/AIDS and transplant patients. Can also cause dark/violaceous plaques of nodules representing vascular proliferations. Can also affect GI tract and lungs.
HSV identification
viral culture for skin.genitalia. CSF PCR for herpes encephalitis. Tzanck test- a smear of an opened skin vesicle to detect multinucleated giant cells commonly seen in HSV1 and 2 and VZV infection. Intranuclear inclusions also seen with HSV-1 and 2 and VZV
Herpesvirus replication
entry occurs through binding to surface receptors-> fusion. Nucleocapsid enters cytoplasm and is transported to nucleus via microtubules where genome enters through pores. Herpesviruses replication occurs in an organized, temporal manner. Immediate early (IE) genes are expressed prior to protein synthesis (brought in with the virus). IE genes are required for the expression of the early (E) and late (L) genes, which are de novo synthesized. Many IE genes encode transcriptional activators. E genes encode proteins involved in DNA replication, such as viral DNA polymerase, thymidine kinase (TK), helicase, etc. Many drug targets are to these virally-encoded proteins. For example, acyclovir and ganciclovir act on TK, and foscarnet acts on viral DNA polymerase. Finally, L genes encode structural proteins, such as capsid and glycoproteins. Virus assembly occurs in the nucleus. Capsids self-assemble and newly synthesized DNA gets packaged. Nucleocapsids assembled in the nucleus bud through the nuclear membrane and acquire their glycoprotein-rich envelope as they pass through the Golgi complex. Virions leave the cell through exocytosis or cell lysis.
Clinical HSV disease
HSV 1 and 2. Lesions are infectious. It penetrates through cracks in the skin. Washing with soap and water readily inactivates HSV. Incubation period is 2-12 days (average is 4 day). Primary infection has no serum antibody present when symptoms first appear. Most HSV infections are asymptomatic. If they are symptomatic, primary disease is likely to be more severe than recurrences. After primary infection, the virus spreads from infected epithelial cells to nearby sensory nerve endings and travels to the nerve cell body in the sensory ganglion. For facial HSV it is the trigeminal ganglion. For genital, it is the sacral ganglion. The virus then enters the nucleus, where it lies latent. With reactivation, it travels from the infected ganglion or neuronal body down the axons to cause recurrence of disease in skin or mucous membrane supplied by that nerve. Lesions occur on face, cornea or perineum. Reactivation can be triggered by illness, sunlight, stress, menstruation, and immunosuppression. Reactivation is commonly asymptomatic, but the virus still sheds and is transmissible. If lesions do develop they are less in number and heal more quickly than primary lesions and may go unnoticed. Primary HSV-1 usually occur in childhood and are often asymptomatic.
Gingivostomatitis
most common primary infection with HSV-1, wide spectrum of severity. The child develops painful mouth vesicles and ulcerations of the gums, lips and tongue. These ulcers are usually in the anterior part of the mouth. Fever is common and can be quite high. There is often swelling of the lips and drooling. Cervical lymph node swelling is commonly seen.
Herpetic whitlow
occurs from inoculation of HSV from oral secretions onto the fingers. The virus gains entry into the skin via small cut or abrasion. This is an occupational hazard for doctors, nurses, and dentists. Wearing gloves whenever there is the potential to get oral secretions on your hands is necessary. This includes suctioning tracheostomies, obtaining nasal specimens from patients etc. This entity is also sometimes seen when a child injures his/her finger and mother (who has a cold sore or who is asymptomatically shedding HSV from her oral secretions) kisses it. Often the area of entry is near the fingernail but does not have to be. The area of virus entry develops erythema, swelling and grouped vesicles on an erythematosus base. The vesicles quickly evolve into pustules, with cloudy fluid. The finger is tender to touching. Frequently, a whitlow is mistaken for a bacterial infection and the patient is given antibiotics.
Genital herpes
is a sexually transmitted infection that is usually caused by HSV-2, but HSV-1 causes about 30% of infections. Primary HSV genital infections are most commonly asymptomatic. However, if symptoms occur, painful vesicles and ulcers develop in the genital and sometimes perianal region. These lesions are quite painful and last 10-14 days. In women with primary lesions, swelling of the vulva and perineal tissues is often seen. Urinating may be very painful as the more acidic urine irritates the lesions. In some women, urinating is so painful, acute urinary retention develops requiring placement of a catheter.
Herpes keratitis
is a condition where HSV infects the cornea of the eye. Herpes keratitis can be the result of a primary infection or from reactivation. It can be caused by HSV-1 or HSV-2, but HSV-1 is the more common pathogen. HSV-2 may rarely infect the eye by means of orofacial contact with genital lesions and occasionally is transmitted to neonates as they pass through the birth canal of a mother with genital HSV-2 infection. HSV produces dendritic lesions of the cornea, which can cause scarring and blindness. HSV keratitis is one of the leading causes of blindness in the US. Topical and sometimes systemic antivirals are used for therapy.
Encephalitis
can be caused by primary disease or reactivation. This is an extremely serious manifestation of herpes disease. Herpes encephalitis can occur either through blood-borne (hematogenous) spread or neuronal transmission of the virus. Herpes infection of the brain results in a fulminant and hemorrhagic, necrotizing encephalitis. There is a strong predilection for the temporal lobes of the brain. As a consequence, it is common to observe altered mental status. Mortality is about 30% with treatment. HSV-1 causes most cases of childhood and adult encephalitis. HSV-2 is the more common cause of neonatal herpes encephalitis, which is associated with maternal genital herpes infections.
Neonatal herpes
is a primary infection of the neonate that can be acquired intrauterine (in utero), peripartum (perinatal) or postpartum (postnatal). The majority of transmissions occur during the peripartum period, e.g. during birth from exposure to maternal secretions with HSV 1 or 2 present (active lesions or asymptomatic viral shedding). Since most genital herpes lesions are caused by HSV-2, most (but not all) neonatal HSV is caused by HSV-2. Because maternal infections can be asymptomatic and because asymptomatic viral shedding can occur, neonatal herpes frequently is diagnosed in babies whose mothers have no history of a known herpes infection. There are three forms of disease: 1) skin, eye and mucous membrane (SEM), 2) CNS, and 3) disseminated, with disseminated being the most severe. Because of the morbidity and mortality associated with neonatal herpes disease, finding a vesicle in a neonate less than 4 weeks of age (without a definitive alternative explanation) is a medical emergency. Herpes should be high on the differential and treated until proven otherwise.
reactivation of HSV infections
in many, viral shedding may occur 1-3 days prior to development of a symptomatic outbreak. Herpes labialis (cold sores) most common with HSV-1.
Keratitis
(inflammation/infection of the cornea)- Primary infection of any of the 3 (ophthalmic, maxillary, mandibular) branches of cranial nerve V leads to latent infection of nerve cells in the trigeminal ganglion. When keratitis occurs as a result of reactivation, the virus, which has been latent in the trigeminal ganglion, migrates down the nerve axon to cause corneal disease. Interneuronal spread of HSV within the ganglion can occur and this allows patients to develop subsequent keratitis without ever having had a primary ocular HSV infection. HSV produces dendritic lesions of the cornea, which can cause scarring and blindness. These lesions are usually dendritic in appearance. HSV keratitis is one of the leading causes of blindness in the US. Topical and sometimes systemic antivirals are used for therapy.
Recurrent Genital Herpes
Women or men may reactivate and shed HSV virus from their mucous membranes, anus or perineum. In some cases, recurrent lesions may be so small and trivial that they are not noticed. Recurrences of genital herpes cause terrible psychological stress on patients and their partners. Regular condom use and daily antiviral suppressive therapy will decrease transmission to uninfected partners. In many patients, symptomatic recurrences will become less frequent with time and may disappear. But most patients continue to shed virus asymptomatically intermittently, even if their symptomatic outbreaks disappear. Up to 70% of new genital HSV infections are transmitted by asymptomatic reactivation and shedding.
Encephalitis
In encephalitis due to reactivation, neuronal spread of the latent virus occurs in retrograde fashion to the brain, usually through the trigeminal tract. Presentation is similar to that seen during primary infection.
Diagnosis of HSV infections
Herpes gingivostomatitis and herpes labialis can often be diagnosed clinically, without laboratory testing. Laboratory testing may be desired in some cases to confirm the diagnosis. Genital herpes can also often be diagnosed clinically, but there are issues to consider that make obtaining a definitive diagnosis a good idea. Specifically, patients that are diagnosed with genital herpes feel stigmatized. There are issues with potential transmission to partners. Consideration should be given to regular condom use and/or antiviral suppressive therapy (in some patients). Definitive diagnosis for herpes simplex viruses can be obtained by: Viral culture of lesions (easiest and best bet for oral or genital lesions), Direct fluorescent antibody stain of lesions (fluorescent stain adheres to HSV antigens in a sample indicating their presence), and PCR of lesions (most expensive). None of these tests can distinguish between a primary or recurrent infection.
Treatment of HSV
There are a group of nucleoside analog drugs used to treat herpes infections, some of which have high specificity since they take advantage of activation of the drug by a viral enzyme, thymidine kinase (remember HSV encodes a viral thymidine kinase).
acycloguanosine (acyclovir)
The most common nucleoside analog for HSV treatment, but there are other similar agents. Severe HSV infections are treated with intravenous acyclovir. The following groups should be treated with intravenous acyclovir therapy: Patients with neonatal herpes, Herpes infections in immunocompromised hosts, and Patients with encephalitis or meningoencephalitis. Oral antiviral therapy (acyclovir or a related antiviral) can be used for oral or genital HSV outbreaks.
HSV Prophylaxis
In certain patients who will be compliant, oral antiviral suppressive therapy is considered for patients with frequent painful oral or genital herpes recurrences. It is also considered for those patients who have genital herpes and are sexually active with an uninfected partner (or do not have a stable sexual partner). For successful viral suppression, patients must be willing to take medicine once or twice daily and not miss days.
Chickenpox
is primarily transmitted by the respiratory route via droplet or aerosolized secretions (coughing, sneezing). Chickenpox can also be acquired from direct contact with lesions or aerosolization of virus from skin lesions. A person with chickenpox is contagious 1-2 days before the rash appears and until all blisters have formed scabs. Incubation period: It takes from 10-21 days after exposure for someone to develop chickenpox. Symptoms start with fever, malaise, headache and sometimes cough. The rash appears in “crops” or waves. The initial lesions might be flat and rose colored, but they quickly mature into the classic “dew drop on a rose petal” which is a vesicle on an erythematosus base. The rash first appears on the face or trunk, then spreads to the extremities. As successive crops appear, lesions will be noted to be in various stages of development. Vesicles mature to pustules (with cloudy centers), which then rupture and scab. A hallmark of chickenpox is the finding of lesions in multiple stages of evolution (vesicles, pustules, crusts and scabs). The rash is described as itchy. The distribution of the rash is notable in that there are more lesions on the trunk and face then on the arms and legs. It takes about 7 days for all lesions to scab—at the time all lesions are scabbed the patient is no longer infectious. If the patient does not pick at the lesions and they don’t become secondarily infected, there is usually no scarring. Adolescents and adults often have much more severe disease than do young children. Pregnancy is a special situation. Pregnant women who contract chickenpox are at high risk for development of severe disease including varicella pneumonia and death. Many need intensive care and mechanical ventilation.
Pathogenesis of Chickenpox
The virus gains entry via the respiratory tract and spreads to the regional lymphoid system. Viral replication takes place in regional lymph nodes over the next 2-4 days and is followed by a primary viremia occurring 4-6 days after initial infection. The virus then replicates in the liver, spleen, and possibly other organs. A secondary viremia, spreads viral particles to the skin 14-16 days after initial exposure, and causes the typical vesicular rash.
Complications of Chickenpox
includes secondary infection or cellulitis, pneumonia, necrotizing fasciitis, encephalitis or encephalomyelitis, hepatitis, and congenital varicella syndrome
Secondary infection or cellulitis
this is the most common complication seen with chickenpox. Group A Streptococcus is the most common bacteria to cause secondary skin and soft tissue infections (cellulitis) after chickenpox. While keeping lesions clean certainly decreases risk of secondary infection, we see this complication even in children whose families have been meticulous with wound care.
Pneumonia
Bacterial pneumonia-This is the second most common complication that occurs with chickenpox. Group A streptococcal infections and Staphylococcus aureus are the most common pathogens responsible. While usually treatable, this can be a fatal complication in some individuals. Viral VZV pneumonia-usually occurs only in immunocompromised patients and pregnant women. This is a serious development and often requires intensive care management. This is a potentially fatal complication.
Necrotizing fasciitis
a rare but very serious complication where the infection extends deeper into the fascia. As the infection progresses along fascial planes, it shears off nerve endings and blood supply to the skin causing necrosis of the overlying skin. This is sometimes a fatal complication and when necrotizing fasciitis occurs as a complication of varicella, it is usually due to Group A Streptococcus.
Encephalitis or encephalomyelitis
these are rare but serious complications of VZV. If they are due to acute infection with spread of virus to the CNS, they usually occur in immunocompromised hosts with chickenpox. A more common form of encephalitis occurs during the convalescent stage of varicella and is thought to be antibody mediated. It may occur up to 2-3 weeks after the illness and is likely due to antibodies to VZV that cross react with certain brain antigens. This antibody mediated form of the disease does not involve any replicating virus in the brain.
Hepatitis
Mild elevations of liver function tests are sometimes seen with chickenpox but significant abnormalities or fulminant liver failure may occur. Severe hepatitis and/or fulminant liver failure usually occur only in immunocompromised hosts.
Congenital varicella syndrome
Rare disorder that occurs when varicella is contracted by a pregnant woman in her first 8-20 weeks of pregnancy. The fetus can exhibit multiple tissue and organ abnormalities, such as microcephaly, mental retardation, hypoplasia of extremities, microphthalmia and hypopigmentation.
Treatment of Varicella
Varicella in normal children is usually a benign self-limited disease that does not mandate therapy. However, if therapy is instituted within the first 48-72 hours of onset, antiviral therapy can shorten the course. Acyclovir can be given orally to outpatients. For those patients sick enough to require inpatient management, acyclovir can be given intravenously. All patients who are immunocompromised, pregnant, or have severe varicella disease should be treated with antiviral therapy. Most immunocompromised and pregnant patients will require hospitalization and intravenous therapy. Teenagers and adults who develop varicella should be considered high risk for severe disease, and most physicians would start acyclovir even if beyond the 48-72 hour period from onset of disease.
Prophylaxis of Chickenpox
Live attenuated varicella zoster virus vaccine (chickenpox vaccine) is currently recommended for prevention of chickenpox. It is given to children as part of the routine immunization schedule as a 2-dose series. The vaccine is given by subcutaneous injection: Initial dose at 12-15 months of age and Booster dose given at 4-6 years of age. Live attenuated vaccines may cause disease in patients who are immunocompromised. In general, the varicella vaccine is contraindicated in immunocompromised patients.
VZV Latency and Reactivation
The virus remains in the ganglia during the latent period, which for many people is life-long. In 1/3 of infected individuals, virus reactivation results in shingles. The virus may be reactivated by stress, immune suppression, or other unknown factors. Once the virus reactivates in the ganglion it tracks down the sensory nerve to the area of the skin that nerve innervates, producing a varicella-form rash in the distribution of a dermatome. Inflammation and necrosis of cells in the ganglion occurs, and neuropathic pain (sometimes excruciating) is felt in the dermatome of the sensory nerve. VZV is the only Herpesvirus (Herpesviridae virus) that does not exhibit asymptomatic viral shedding in normal hosts that experience reactivation. Other members of the Herpesvirus family may manifest reactivation only by asymptomatic viral shedding. During VZV reactivation in normal hosts, virus is shed only from the shingles lesions.
Clinical Manifestations of Shingles
The first symptom of shingles is often radicular pain in the area innervated by the nerve in which the latent infection has now reactivated. Pain may precede development of lesions by several days. Once, the lesions emerge, they are grouped vesicles on an erythematous base. They are confined to the single involved dermatome and do not cross the midline of the body. Lesions usually heal in about 2 weeks. Reactivation can affect the eye via the trigeminal nerve.
post-herpetic neuralgia
The major complication of shingles is chronic burning, itching, or shooting pain, which is seen primarily in the elderly. The pain may last weeks to months after the rash has healed. Often associated with post-herpetic neuralgia is increased sensitivity to touch (hyperesthesia). Post-herpetic neuralgia is a neuropathic pain which is sometimes severe and can last weeks to months. Pain control is often needed.
Diagnosis of Shingles
Usually chickenpox and shingles can be diagnosed clinically. If the diagnosis is unclear (i.e. differentiation between shingles and herpes) there are ways to distinguish the viruses: Direct fluorescent antibody (swab the base of the lesion and look for antigens by way of a fluorescent tagged antibody), VZV polymerase chain reaction (PCR) , and Viral culture (HSV grows readily, VZV grows slowly so culture is usually used to “rule in” herpes)
Treatment of Shingles
Acyclovir (or an acyclovir-like drug) given within 48-72 hours of onset may decrease lesions and pain.
Shingles Prophylaxis
A shingles vaccine (Zostavax) is approved for individuals 50 years of age or older. It is a live-attenuated vaccine and is given as 1 dose. This vaccine effectively “boosts” the immune response to VZV and decreases likelihood of developing shingles. Studies show Zostavax reduces risk for developing shingles by 70% in those greater than 50 years. In those who were vaccinated but who developed shingles, it reduced the risk of postherpetic neuralgia by 66%.
Understand the importance of T-cell mediated immunity to VZV infection.
There is evidence that lowered cell-mediated immunity to varicella is the critical piece that puts people at risk for shingles. The fact that shingles is more common in the elderly may reflect declining cell mediated immunity in old age. Declining cell-mediated immunity may also be due to fewer exposures to naturally occurring chickenpox in the community (now that most children are vaccinated). Routine exposures used to serve to “boost immunity” in persons regularly.
Pregnancy with CMV
Primary infection in the mother leads to viremia and possible transplacental infection of the fetus. Two thirds of the infants whose mothers contract primary CMV during pregnancy will NOT be infected in utero—1/3 are infected. Fortunately, most of those infected will be asymptomatic. Only 10-15% of the infected infants will have symptoms at birth –this is about 3-5% of the infants born to mothers with primary infections. These babies have congenital CMV. Infection of the fetus can also occur if a pregnant women reactivates CMV, but the risk is much lower (<1% of babies will become infected and even fewer are symptomatic).
Signs of Congenital CMV
The following signs are seen in infants with congenital CMV syndrome: Low birth weight, Microcephaly, Hearing loss, Mental impairment, Hepatosplenomegaly, Skin rash (blueberry muffin spots)-due to extramedullary hematopoiesis in the skin, Jaundice, Chorioretinitis. CMV may also be transmitted perinatally. Travel through the birth canal may result in infection by aspiration of CMV infected cervical/vaginal secretions. Or the infant may be infected by breastfeeding. More than 50% of infants fed with breast milk that contains infectious virus become infected with CMV. Infants that are infected during the birth process or after delivery (breast milk) do not have the congenital CMV syndrome. These infants usually have asymptomatic infection.
Cytomegalovirus (CMV)
is another common pathogen that is a double-stranded DNA virus. This pathogen also infects the majority of people by adulthood. Transmission may occur in utero, perinatally or postnatally. In developed countries (i.e. US) with a high standard of hygiene, 60% of adolescents have been infected and ultimately 80% of the population is infected. In developing countries, over 90% of people are ultimately infected.
Transmission of CMV
A person can become infected with CMV when they come in contact with infected body fluids: Saliva, breast milk, sexual contact, blood, tears, respiratory secretions, contact with urine, stool etc.; Blood transfusions and organ transplantations; Infected pregnant women can pass the virus to their unborn babies
Incubation period of CMV
2 weeks to 2 months
Pathophysiology of CMV
Upon initial infection, CMV infects the epithelial cells of the salivary gland or the genital tract, resulting in a persistent infection and intermittent viral shedding. There is likely viremia causing wide distribution of the virus to other organs and tissues. Infection of the genitourinary system leads to CMV being shed in the urine.
Primary infections
in persons with normal immune systems are usually asymptomatic. If symptoms occur, the illness can take 2 forms: 1) a mild febrile illness or 2) mononucleosis- like illness (similar to Epstein-Barr virus) with fever, swollen nodes and a mild hepatitis. Primary infections in immunocompromised persons are serious and CMV can infect most organs including causing pneumonia, colitis, hepatitis, encephalitis, retinitis, etc.
Latency and Reactivation of CMV
Once infected, the virus remains latent for life (latent infection) and may be reactivated from time to time, during which infectious virions appear in the urine and the saliva. Reactivation can lead to vertical transmission (mother to baby in utero), but vertical transmission is more common in mothers with primary CMV infections. Reactivation in persons with normal immune systems is asymptomatic. The virus is shed in body secretions, typically the saliva and the urine. Reactivation in immunocompromised individuals may produce serious disease including pneumonia, colitis, hepatitis, encephalitis, and retinitis.
Immunocompromised Individuals with CMV
The severity of CMV disease in immunocompromised patients parallels the degree of impairment of cell-mediated immunity. Patients with organ transplantation, bone marrow transplantation, or HIV (with very low CD4 counts) are most likely to have severe disease. CMV can affect most organs, but the most frequent clinical manifestations include CMV pneumonia, colitis, retinitis and hepatitis.
Treatment of CMV
in persons with normal immune systems is not indicated- resolution without sequelae is expected. Immunocompromised persons with CMV infections are treated with an antiviral, Ganciclovir. CMV-IG, an immunoglobulin preparation with high titer of CMV antibodies, together with Ganciclovir are sometimes used to treat CMV pneumonia. Ganciclovir treatment of infants with congenital CMV is being studied in a clinical trial to see if outcomes are improved, but currently there is no recommendation to treat those infants.
Prophylaxis with CMV
There is no available vaccine. CMV-IG is given intravenously once monthly to some severely immunocompromised patients who are at very high risk for CMV to prevent CMV disease.
Diagnosis of CMV
Viral culture , PCR, Fluorescent antibody staining, serology, and histology
Serology for diagnosing CMV
For primary CMV disease (mononucleosis-like syndrome or pregnant woman with febrile illness), serology can establish the diagnosis. Unlike the previous tests, this one can distinguish between primary and recurrent infection. In persons with a primary CMV infection, the CMV IgM will be positive and there will be a negative CMV IgG. Serology is also useful in establishing whether a person has EVER had a CMV infection. CMV IgG is positive for life, once the person has been infected. The following can be used to interpret serology: Positive IgM, negative IgG = acute CMV disease. Negative IgM, negative IgG= patient has never been infected with CMV. Negative IgM, positive IgG= patient has previously been infected with CMV at some time in their life. Positive IgM, positive IgG = recent CMV reactivation.
Histology in immunocompromised patients with CMV
with organ involvement (i.e. hepatitis, pneumonia, colitis), a tissue biopsy is sometimes done for diagnostic purposes. CMV-infected cells will have a characteristic “owl’s eye” appearance, which is diagnostic for CMV infection. The owl’s eye is a dense, dark nuclear body surrounded by a halo. These represent intranuclear inclusions (accumulation of viral proteins or virions). There may also be smaller intracytoplasmic inclusions noted.
Influenza virus
an RNA virus with a segmented genome made up of eight different pieces of ssRNA, which encode several different viral proteins. Surrounding the core is a lipid envelope, with a lining of matrix protein on the inner side of the envelope, the two most common viral proteins are hemagglutinin (H) and neuraminidase (N) glycoproteins. Both H and N are surface proteins and different types are designated by numbers (e.g. H1, H2, N1, and N2). Influenza viral subtypes are identified by the combination of H and N proteins on the viral coat (e.g. H1N1). There are three types. Type A and B strains circulate in the population every year. Type C strains cause mild or clinically-insignificant illness. Type A strains cause both epidemics and pandemics and can infect other animals. With the nomenclature, the first letter says the type (e.g. A). this is followed by the strain number, the year the strain was isolated and the virus subtype. For non-human strains, the animal is listed between the virus type and the geographic origin. Influenza epidemics continue to persist because the type A and B viruses undergo constant and rapid change due to antigenic drift.
Respiratory syncytial virus (RSV)
cause respiratory infections and contains an F-protein that causes formation of multicunleated giant cells (syncytial cells). This virus differs from the rest of its kin by lacking bot the HA and NA glycoproteins. It is the number one cause of pneumonia in young children, especially in infants less than 6 months of age. It is highly contagious with outbreaks occurring in the winter and spring. It is hard to treat and efforts focus on prevention. Can be prevented in many cases with palivizumab, a monoclonal antibody against RSV that is produced by a recombinant DNA method. Previously infected individuals are not completely immune but the subsequent infections are usually limited to the upper respiratory tract. Spreads through large droplets. It lives on surfaces for 1 hour and 40-60% of attacks are in children under the age of two. Yearly epidemics, with both A and B subtypes, can circulate during one season, but also in alternative seasons. Usually one of the subtypes in dominant. Even when there are two strains circulating, there is often temporal and geographic clustering. It is the most common cause of bronchiolitis. It can result in severe disease requiring hospitialization, usually in children less than a year of age but can be severe in anyone, particularly high-risk groups (immunocompromised, elderly). RSV infection in a child may predispose children to wheezing as adults.
