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Micro Chapter 42: Beta and Gammaherpesviruses: CMV and Epstein-Barr Virus Beta and gammaherpesviruses show differences in their viral genomes and the phenotype of infections they cause The main betaherpesvirus is human cytomegalovirus (CMV) The main gammaherpesvirus is Epstein-barr virus (EBV) On average, over half of people int eh US are infected with CMV, and most are infected with EBV - This is self-limited and rarely leads to disease in healthy people, but can cause big problems in immunosuppressed A hallmark of all herpesvirus infections is persistent infection - CMV and EBV persist for the lifetime of the infected host EBV establishes persistent infection of B cells, & can go from latency to a lytic productive infection CMV can establish latent infection of hematopoietic cells of myeloid lineage Intermittent excretion of both viruses on mucosal surfaces with no symptoms is common and likely responsible for their spread Acquisition of CMV and EBV infection in the community happens after exposure of mucosal surfaces, including the oropharynx and genital tract, to the virus Early in life, CMV is easily transmitted in breast milk, the most common way infants get it - In developed countries, catching CMV is more common in adolescence, from intimate exposure to oropharyngeal secretions or sexual contact CMV is considered an STI CMV also easily crosses the placenta and infects a developing fetus, causing congenital CMV infection o CMV is the most common viral infection of the fetus, and can lead to permanent neuro damage and hearing loss EBV is transmitted similar to CMV - One exception is EBV is found in breast milk, but not transmitted that way Almost all adults in the developing world have been infected with EBV, while in the developed world EBV only is seen in populations with risk factors, like being poor In populations that don’t see EBV much in childhood, infection in adolescence and young adulthood can cause acute infectious mononucleosis o Primary infection with CMV or EBV rarely causes symptomatic disease in kids, but causes symptoms in adolescents o Mono symptoms are pharyngitis, fever, lymphadenopathy, hepatitis, and lymphocytosis with reactive lymphocytes Immunocompromised people in hospitals can also catch EBV or CMV in blood transfusions or transplants, and this form can often be more severe CMV and EBV attach to target cells by low-affinity interactions with cell-surface glycosaminoglycans, followed by high-affinity interactions with specific receptors - - 2 ways they enter: o Interaction with a receptor/coreceptor and fusion at the plasma membrane o Interaction with a receptor/coreceptor at the plasma membrane, followed by internalization, acid-dependent fusion, and release of the nucleocapsid and tegument proteins from endocytic vesicles EBV infects B cells by attaching its envelope glycoprotein to complement receptor 2 (aka CR2 or CD21) Both CMV and EBV use glycoproteins B, H, and L to fuse the viral envelope to the endosome membrane o EBV does this to infect B cells o In epithelial cells though, EBV enters at a neutral pH, and doesn’t need endocytosis CMV and EBV replicate their nucleic acids in the nucleus of infected cells – page 431 - - - - They will sequentially express immediate-early viral proteins, then early, and then late proteins o These are all needed to make progeny virus After fusion and penetration, nucleocapsids containing infectious DNA are translocated to the nucleus Once the virion DNA is in the nucleus, transcription is initiated by virion tegument proteins and cell factors that activate expression of viral immediate-early genes o Tegument proteins also disarm some host cell-intrinsic antiviral responses Expression of viral immediate-early genes leads to sequential expression of viral genes needed to make viral nucleic acid, including viral DNA-dependent DNA polymerase, and genes for virion structural proteins Assembly of CMV or EBV virions includes nucleocapsid formation, viral DNA packaging, and envelopment, just like in all herpesviruses Viral DNA is made as long chains of genome-length DNA copies (concatemers), and then cleaved into unit-length genomes during packaging and capsid maturation Newly replicated viral DNA is then encapsidated in the nucleus, and then nucleocapsids exit the nucleus by budding through the nuclear membrane, acquire the tegument layer of protein in the cytoplasm, and eventually become enveloped The virions are then released by exocytosis or by death of the infected cell The envelope glycoproteins can elicit antiviral antibodies that neutralize it Latent viral infections – characterized by restricted viral gene expression and no progeny are made - - CMV can persist as a latent infection in CD34+ myeloid progenitor cells, and these undifferentiated but committed cells spread to organs and differentiate, leading to reactivation of latent infection o Latency CMV transcripts are made, but we don’t know what they do Latent EBV infection shows persistence of the viral genome with no lytic infection, and expression of specific viral genes o At first, viral genes like EB nuclear antigen 1 are expressed, to ensure maintenance and partitioning of the viral genome as a replicating episome during expansion of infected cells o Expression of latent membrane proteins LMP1 and LMP2a, provides growth signals to infected cells that drive cell proliferation o A small # of viral genes and small RNAs are expressed in long-lived nondividing B cells, which serve as a reservoir for EBV in the normal host o By restricting expression of its genome, EBV can maintain its genetic material, while also limiting its recognition by antigen-specific lymphocytes o Reactivation of EBV from latency is sporadic B cells that reactivate release infectious virus that can infect epithelial cells, leading to periods of shedding of EBV during the person’s lifetime Reactivation of EBV is most often in people with a defect in virus-specific T cell responses, and those being immunosuppressed Small noncoding RNAs called microRNAs (miRNAs) work in post-transcription gene regulation, and serve as a major regulatory mechanism in development, homeostasis, and stress responses, including viral infections - - Both CMV and EBV encode lots of miRNAs, that are critical in virus replication, including interference with cell antiviral responses, and establishment and maintenance of latent infection Both viruses can also turn on host cell miRNAs o EBV can turn on host cell ones that can lead to cancer CMV infects lots of cells, including epithelial and endothelial cells, blood mononuclear cells, neural progenitor cells, and CNS support cells EBV infects less cells, just B cells and epithelial cells NK cells and TC cells are very important in limiting replication of CMV and EBV - These responses control virus replication during primary infection, and provide surveillance during viral latency to limit reactivation Loss of these responses leads to reactivation, virus spread, and disease So an immunodeficiency that affects TC cells or NK cells, like HIV, put them at risk for developing severe disease CMV has proteins that downregulate and degrade MHC1 and MHC2s, and regulate NK cell receptors and function - CMV can also encode for cytokines like Il-8 and Il-10, and chemokine receptors, that regulate inflammatory response to favor virus persistence Ways CMV and EBV evade the host response – page 433 Most acute CMV and EBV infections are asymptomatic, especially in young kids Primary infection in young adults causes acute mononucleosis syndrome, which shows fever, fatigue, pharyngitis, cervical lymphadenopathy, splenomegaly, and peripheral blood monocytosis with atypical or reactive lymphocytes - Usually EBV, but CMV causes 1/5 of cases with these symptoms, called heterophile-negative This is self-limited in otherwise healthy people Once the symptoms show up, it’s cause the host immune response is already in “full swing” Atypical lymphocytes seen in the blood are mostly activated CD8+ T cells directed against viral antigens on infected cells o Critical to control viral infection, and may be responsible for many of the symptoms of mono Newborns infected in utero with CMV can develop significant disease - It’s acquired from mom infection, which is almost always unrecognized int eh pregnant woman Congenital CMV infection shows multiorgan disease with unrestricted virus replication and direct viral toxic effect, due to immature fetal immune response Congenital CMV can show CNS issues, hepatitis, hematologic problems o CNS disease includes hydrocephalus, retinitis, encephalomalacia, and hearing loss o Hearing loss from congenital CMV is the most common nonfamilial cause of hearing loss o The hearing loss can be delayed till they’re 3-4, due to waiting on virus replication CMV can be associated with atherosclerosis and coronary artery disease Chronic CMV and EBV infections are associated with chronic inflammatory diseases and cancers In immunocompromised people, CMV and EBV infection can cause organ failure and death - They can start as mono symptoms that progress to life-threatening diseases like hepatitis, colitis, and pneumonia For transplants, CMV cause organ rejection Posttransplant lymphoproliferative disease (PTLD) – EBV reactivates after a transplant EBV is an oncogenic virus that is associated with Hodgkin lymphoma, Burkitt lymphoma, nasopharyngeal carcinoma, and gastric carcinoma - EBV is found in almost half of Hodgkin lymphomas also if you’ve had mono you’re at a higher risk to Hodkin lymphoma Burkitt lymphoma is common in Africa, so it’s thought malaria-caused immunosuppression actives B cells allowing opportunities for reactivation of EBV To diagnose, one way is to look for large inclusions called owl eye inclusions - - - Can also diagnose CMV with an antigenemia assay – uses immunofluorescence to detect CMV antigen in circulating WBCs o Finding CMV antigen in blood WBCs means actively replicating CMV PCR is great for CMV and EBV Seroconversion – a standard to detect primary infection of CMV and EBV o Finding IgM anitbodies specific for either CMV or EBV suggests a recently acquired infection o Detection of IgG antibodies specific for either CMV or EBV doesn’t give you any info on the duration of the infection o These tests are only good for otherwise healthy people, and don’t help any in immunocompromised people There is high incidence of preexisting infection in them The underlying immune dysfunction can lead to inconsistent serum finding Heterophile antibodies - antibodies that aren’t specific for EBV, and instead recognize antigens on RBCs o They’re induced by EBV infections, and are what you’re looking for in a heterophile antibody (aka “monospot”) test CMV and EBV in immunocompetent people is almost always self limited and usually doesn’t need treatment - Immunocompromised people need antiviral meds The viral polymerases are targeted Ganciclovir and foscarnet inhibit CMV replication o Ganciclovir inhibits viral DNA-dependent DNA polymerase