Virus Replication PDF
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HADI YASSINE
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These notes provide an overview of virus replication, covering topics such as origins, replication mechanisms, genomic maps, and antiviral drugs. The document is geared towards an undergraduate-level understanding of virology.
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Virus Replication Medical Virology HADI YASSINE 1 Objectives After completion of this session you should be able to define the following: Origins of Viruses Replication: Testable viral properties General steps of viral replication Mode...
Virus Replication Medical Virology HADI YASSINE 1 Objectives After completion of this session you should be able to define the following: Origins of Viruses Replication: Testable viral properties General steps of viral replication Mode of entry of viruses Genomic maps of certain DNA an RNA viruses Viral genetic and evolution Viral replication and antiviral drugs 2 Origins of Viruses How did these become independent genetic entities? The only absolute requirement is an origin of replication in the nucleic acid. Regressive theory: viruses are degenerate forms of intracellular parasites. (e.g. leprosy bacillus, rickettsiae and chlamydia) Cellular origin: Viruses evolved from bits of RNA or DNA that escaped from genes of larger organism Co evolution theory: Viruses coevolved or adapted with life. What are transposons? In contrast to other microbes and multi-cellular organisms, the origin and evolution of viruses is mostly unknown. Our knowledge concerning their origin is lost in a sea of conjecture and speculations, hardly supported at all with precise scientific evidences. For example, viruses have never been detected as fossil particles, probably because they are too small and too fragile to succumb to fossilization processes. Due to the fact that the genome of viruses underlies mutation and genetic recombination, viruses probably evolve according to a form of natural selection, very similar to that governing other living things. Currently, there are three hypotheses. Regressive theory Viruses may have once been small cells that parasitised larger cells. Over time, genes not required by their parasitism were lost. The bacteria rickettsia and chlamydia are living cells that, like viruses, can reproduce only inside host cells. They lend credence to this theory, as their dependence on parasitism is likely to have caused the loss 3 of genes that enabled them to survive outside a cell. Cellular origin theory Some viruses may have evolved from bits of DNA or RNA that "escaped" from the genes of a larger organism. The escaped DNA could have come from plasmids—pieces of DNA that can move between cells—while others may have evolved from bacteria. Coevolution theory Viruses may have evolved from complex molecules of protein and DNA at the same time as cells first appeared on earth and would have depended on cellular life for many millions of years. 3 Replication (Virus growth cycle) For a virus to multiply it must obviously infect a cell. Viruses usually have a restricted host range (Tropism) i.e. animal and cell type in which this is possible. Other than the receptor specificity, all must make proteins with 3 sets of functions. -Ensure replication of the genome - Package the genome into virus particles -Alter the metabolism of the infected cell so that viruses are produced. 4 Replication (Virus growth cycle 6-8 hours) Testable viral properties Virus Replicate in nucleus Most DNA viruses (not poxviruses) Orthomyxoviruses (influenza), retroviruses Replicates in cytoplasm Most RNA viruses, pox viruses Encodes DNA polymerase Hepadnaviruses & poxviruses Encodes RNA polymerase RNA viruses (except retroviruses), poxvirus Encodes reverse transcriptase Retroviruses, hepatitis B virus Carries RNA-dependent RNA polymerase (-) RNA viruses; dsRNA viruses: reoviruses Segmented genome: reassortment Orthomyxoviruses (influenza), reoviruses, also arenaviruses and bunya viruses Fusion viruses (Syncytia forming) RSV, VZV, retrovirus, paramyxoviruses 5:31 PM Associated with human cancer Medical virology HTLV, EBV, HPV, HBV, HCV 5 The replication of poxvirus is unusual for a virus with double-stranded DNA genome (dsDNA) because it occurs in the cytoplasm, although this is typical of other large DNA viruses. Poxvirus encodes its own machinery for genome transcription, a DNA dependent RNA polymerase, which makes replication in the cytoplasm possible. Most dsDNA viruses require the host cell's DNA-dependent RNA polymerase to perform transcription. These host DNA are found in the nucleus, and therefore most dsDNA viruses carry out a part of their infection cycle within the host cell's nucleus. Influenza virus replicates in the nucleus because it can get primers to make its RNA via cap snatching where it destroys the RNA of the host cell by snatching the 7meGTP to make a plus stranded RNA Hepadnavirus: Hepadnaviruses have very small genomes of partially double- stranded, partially single stranded circular DNA. The genome consists of two strands, a longer negative-sense strand and a shorter and positive-sense strand of variable length. The polymerase enzyme functions to repair the gap in the double- stranded DNA molecule that is created by the presence of the segment of single- stranded DNA. The activity of the polymerase is essential for the virus’s replication. This enzyme is unique among viral polymerases in that it has reverse transcriptase activity to convert RNA into DNA to replicate the genome (the only other human-pathogenic virus family encoding a polymerase with this 5 capability is Retroviridae), RNAse activity (used when the DNA genome is synthesized from pgRNA that was packaged in virions for replication to destroy the RNA template and produce the pdsDNA genome), and DNA-dependent-DNA- polymerase activity (used to create cccDNA from pdsDNA in the first step of the replication cycle). I.E. IT IS MULTIFUNCTIONAL DNA POLYMERASE 5 General steps of viral replication 1. Adsorption: receptor, 37ºC (slowly at -4ºC), Mg++ or Ca++ 2. Entry: by endocytosis (pinocytotic vacuole= viropexis) or by fusion 3. Uncoating: release virus genome, cell enzymes (from lysosomes) remove virus protein. 4. Transcription: Production of virus mRNA or replicative intermediates from viral genome (REMEMBER BALTIMORE CLASSIFICATION!) Carried out either by host cell or virus-specified enzyme Patterns of transcription differ before (early) and after (late) virus nucleic acid replication, Transcription sometimes overlaps with different starting and/or termination points within one gene to produce different proteins from the same nucleic acid sequence (Multiple start codons; or splicing mechanism). What is more transmissible HBV (Billion copies per 1 ml) HCV HIV 6 5. Synthesis of virus components: Virus protein synthesis: mRNA translated on cell ribosomes into two types of virus protein: a. Non-structural viral protein (mainly enzymes for virus replication) b. Structural-virus particle protein Virus nucleic acid synthesis: template either the parental genome or with single strand nucleic acid genomes, newly formed complementary strands, by using either virus-coded polymerase or with some DNA viruses a cell enzyme carries out 6. Assembly: new virus particle are assembled in cell nucleus, cytoplasm or (with most enveloped virus) at the plasma membrane which invests the new particle to form the virus envelope. 7. Release: either by sudden rupture (lyses) or by gradually extrusion (budding) of enveloped viruses through the cell membrane 5:31 PM Medical virology 7 7 Major Steps for Virus Replication are All the Same 8 Terminologies Endemic: Outbreak: Epidemic: Pandemic: 5:31 PM Medical virology 9 Endemic: a disease that exists permanently in a particular region or population. Malaria (not a virus!) is a constant worry in parts of Africa. Outbreak: happens when a disease occurs in greater numbers than expected in a community or region or during a season. An outbreak may occur in one community or even extend to several countries. It can last from days to years (Gastroenteric viruses). Epidemic: An outbreak of disease that attacks many peoples at about the same time and may spread through one or several communities. Infectious disease spreads rapidly to many people. (SARS-1). Pandemic: When an epidemic spreads throughout the world (H1N1; SARS-2). For example, in 2003, the severe acute respiratory syndrome (SARS) epidemic affected several thousands around the globe. A pandemic is a global disease outbreak. HIV/AIDS is an example of one of the most destructive global pandemics in history. Spanish influenza killed 40-50 million people in 1918. 9 Lentiviruses Replication AND HAART Treatment https://www.youtube.com/watch?v=odRyv7V8LAE HAART is a customized combination of different classes of medications that a physician prescribes based on such factors as the patient’s viral load (how much virus is in the blood), the particular strain of the virus, the CD4+ cell count, and other considerations (e.g., disease symptoms). Because HAART cannot rid the body of HIV, it must be taken every day for life. HAART can control viral load, delaying or preventing the onset of symptoms or progression to AIDS, thereby prolonging survival in people infected with HIV. HAART has been in use since 1996 and has changed what was once a fatal diagnosis into a chronically managed disease. Nucleoside reverse transcriptase inhibitors (NRTIs) Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Protease inhibitors (PIs) Integrase inhibitors (INSTIs) Fusion inhibitors (FIs) Chemokine receptor antagonists (CCR5 antagonists) 10 Mode of entry of viruses a. Viropexis-endocytosis b. Fusion pH change c. Some viruses enters the nucleus via the nuclear pore Viropexis is the process by which different classes of viruses— particularly picornaviruses and papovaviruses—enter the host cell in which they will be able to replicate. The hydrophobic structures of the capsid proteins may be exposed after viral binding to the cell (see viral attachment protein). These structures help the virion or the viral genome slip through the membrane. It can be juxtaposed with viral endocytosis, which is receptor mediated, and doesn't involve direct penetration of the virion. 11 Example of virus Ligands and cellular receptors Virus Viral protein Target cell Cell receptor containing ligand (RBD) EBV gp350/220 B & epithelium cell CD21 Vaccinia virus VGF Various cell types ICAM-1 Poliovirus VP1 Intestinal epithelium immunoglobulin Corona virus Spike (S1) Respiratory and Human amino intestinal epithelium peptidase Influenza A Heamagglutinin Respiratory Sialic acid- virus epithelium containing glycoprotein HIV gp 120 T cell, macrophage CD4 Measles Hemagglutinin (H) Various Cell types CD46 or CD150 CD: Cluster of differentiation (markers on cells) VGF: Virus growth factors. a polypeptide with amino acid sequence homology to epidermal growth factor (EGF) and transforming growth factor alpha and is present twice RBD: Receptor binding domain 12 Growth curve Shortly after infection and for a time period of minutes to hours depending on the virus being studied only low amounts of parental infectious material can be identified, this is the eclipse phase. Genome replication has been initiated but progeny virus have not yet formed. There is then a maturation phase when viral material accumulates in the cell or surrounding medium. After a few hours cells infected with lytic viruses become metabolically disordered and then die, viral production ceases. Titers then slowly drop. Cells infected with non lytic viruses can continue to produce viral particles indefinitely. Typical growth curve of a virus compared with that of bacterium Incubation Period! 13 14 Different strategic method to overcome short genetic information: 4 reading frames Surface ag vpg Open reading frame encode for polyprotein Virion associated poly. Transcribe 5 genes arranged Sequentially each with cap and poly A tail 1. Multiple ORF Core ag 2. Polyadenylated (AAA) at the 3’ end 3. Associated polymerase 4. Translational frameshifting 5. Alternative RNA splicing 5:31 PM Medical virology 15 the whole genome of hep b is 3, smth kb Ristriction enzymes Sequence? the virus has to accomdate the short genome it has to make multiple proteins starts multiple Different strategic method to overcome short genetic information: 1. Multiple ORF diff start codons 2.Polyadenylated (AAA) at the 3’ end viral genome acts as mrna RNA viruses that replicates in cytoplasm has its own 3. Associated polymerase polymmerase 4. Translational frameshifting RNA will shift to another segment o be translated 5. Alternative RNA splicing RNA will be spliced into diff segment producing diff proteins 15 Replication strategy of positive RNA virus (poliovirus). Replication strategy of positive RNA virus (poliovirus). The genomic RNA acts directly as mRNA and is translated to give a polyprotein which is rapidly cleaved by two virus-coded proteases into 12 or more smaller proteins. At later stage during replication the number of positive RNA strands increases and these are used either as mRNA or are packaged into virion. By contrast with poliovirus, other positive strand viruses, e.g. coronaviruses also use translational frame shifting to extend the information encoded on certain of the mRNAs 16 CoV (+ve sense RNA) Replication Translation of the positive-strand genomic RNA gives rise to a large polyprotein does not transcribe the whole genome , coronaviruses only part of it also use which will translational full-length, antisense negative-strand template generate the polymerase frame Subgenomic which will shifting to make rna’s which will extend the make information proteins encoded on certain of the mRNAs Summary of mouse hepatitis virus coronavirus (MHV) replication. MHV binds to the host-cell receptor CEACAM-1 through interaction of the spike (S) glycoprotein. Virus entry into the host cell can occur through fusion with the surface of the host cell, with the subsequent release of the genomic RNA into the cytoplasm. Alternatively, MHV can enter the host cell through the formation of endocytic vesicles, and genomic RNA is released into the cytoplasm following fusion with the vesicle membrane (not shown). Translation of the positive-strand genomic RNA gives rise to a large polyprotein that undergoes proteolytic processing to generate an RNA- dependent RNA polymerase. Through the action of the RNA polymerase, a full- length, antisense negative-strand template is generated. Subgenomic mRNAs are synthesized, presumably from subgenomic negative-strand templates. Translation of subgenomic mRNAs gives rise to structural viral proteins. S glycoprotein is expressed on the surface of the host cell and this might contribute to fusion with neighboring uninfected cells by binding to CEACAM-1. Virus assembly occurs within vesicles, followed by virus release by fusion of virion-containing vesicles with the plasma membrane. Released virus can infect other cells and can replicate within the parent cell through binding to CEACAM-1. E, envelope protein; ER, endoplasmic reticulum; M, membrane protein; N, nucleocapsid protein; ORF, open reading frame. Credit: Cornelia C. Bergmann, et al / Nature Reviews Microbiology. Why translation frameshifting occur: 17 1. Secondary and tertiary structure of the RNA 2. Certain codons take longer to translate; because there are not equal amounts of tRNA of that particular codon in the cytosol i.e. lag phase 17 Replication strategy of a negative-stranded RNA virus (influenza). Diff ORF Replication strategy of a negative-stranded RNA virus (influenza). The viral genome is in the form of eight loosely linked single-stranded RNA segments. Most transcribed mRNAs and code for a single protein. However, the mRNAs of genes 7 and 8 have undergone alternative splicing and each now codes for 2 viral proteins. The mode of transcription of influenza virus is unique since both host and virus RNA polymerase are utilized. through alternative splicing 8 segments can make 11 proteins 18 Replication strategy of a negative-stranded RNA virus (Rabies). Negative sense ssRNA viruses need RNA polymerase to form a positive sense RNA. The positive- sense RNA acts as a viral mRNA, which is translated into proteins for the production of new virion materials. With the newly formed virions, more negative sense RNA molecules are produced Genome goes into making the new virions Negative sense ssRNA viruses need RNA polymerase to form a positive sense RNA. The positive-sense RNA acts as a viral mRNA, which is translated into proteins for the production of new virion materials. With the newly formed virions, more negative sense RNA molecules are produced. 19 episomal-a latent state in which the virus does not integrate into the host genome and exists as an episome inside the host cell's nucleus. in a way its similar to plasmid (ex: herpes virus HSV 1) What happens in herpes after the cold sores go away it does not mean the virus itself went away, the virus is there hidden in the ganglia and they do so in the episomal form Replication strategy of positive DNA virus (adenovirus). Protein P/5’end Linear DNA throughout replication both segments of the gene are utilized to express mRNA Protein P/5’end Linear vs. Episomal vs. Integrated? What is the difference between linear or episomal? they are both not integrated but linear are also not circularly enclosed as opposed to the episomal https://www.youtube.com/watch?v=QM5kOHRQuQc The adenovirus life cycle is separated by the DNA replication process into two phases: an early and a late phase. In both phases, a primary transcript that is alternatively spliced to generate monocistronic mRNAs compatible with the host’s ribosome is generated, allowing for the products to be translated. The early genes are responsible for expressing mainly non-structural, regulatory proteins. The goal of these proteins is threefold: to alter the expression of host proteins that are necessary for DNA synthesis; to activate other virus genes (such as the virus-encoded DNA polymerase); and to avoid premature death of the infected cell by the host-immune defenses (blockage of apoptosis, blockage of interferon activity, and blockage of MHC class I translocation and expression). Once the early genes have liberated adequate virus proteins, replication machinery, and replication substrates, replication of the adenovirus genome can occur. A terminal protein that is covalently bound to the 5’ end of the adenovirus genome acts as a primer for replication. The viral DNA polymerase then uses a strand displacement mechanism, as opposed to the conventional Okazaki fragments used in mammalian DNA replication, to replicate the genome. The late phase of the adenovirus lifecycle is focused on producing sufficient quantities of structural protein to pack all the genetic material produced by DNA replication. Once the viral components have successfully been replicated, the virus is assembled into its protein shells and released from the cell as a result of virally induced cell lysis. 20 The strand displacement is a mechanism opposes the conventional Okazaki fragments. means it is not okazaki fragments rather smth else called strand displacement : as you are synthesising the strand is displaced through ssDBP Early and late mRNA. Encoded by both strands. Could be alternatively spliced. A terminal protein that is covalently bound to the 5’ end of the adenovirus genome acts as a primer for replication. Adenovirus replication properties: Encode genes from both strands. Alternative splicing of mRNA Early mRNA from the original strand: Cell regulators (DNA synthesis and inhibiting apoptosis) Strand displacement. 21 ORF 5:31 PM Medical virology 22 STOP CODONS: UAG UAA UGA Start codon: AUG Why translation frameshifting occur: 1. Secondary and tertiary structure of the RNA 2. Certain codons take longer to translate; because there are not equal amounts of tRNA of that particular codon in the cytosol i.e. lag phase 22 example of multiple ORF the overlap is in terms of genetic material the HBV genome integrates sometimes and sometimes it does not, based on what does it integrate? the development of the disease 23 5:31 PM Medical virology 24 http://csmbio.csm.jmu.edu/biology/virology/Viral%20growth%20cycle/Viral%20Growth%20Cycle.htm (IMPORTANT) HOW DOES THE CELL RECOGNIZE VIRUS? 24 What Does Ambisense means? from both ways 5:31 PM Medical virology 25 An ambisens genome is a genome which both nucleic acid strands encode for proteins. This expression strategy is found in four genera of segmented negative stranded RNA viruses: Arenavirus, Phlebovirus, Tospovirus, and Tenuivirus. It depends on solid transcription termination signals to avoid creating dsRNA, a pattern recognized by all cells to trigger antiviral response. All the ambisens negative standed RNA viruses indeed encode a hairpin to stop transcription. Non- segmented negative stranded RNA viruses, and orthomyxoviridae have leaky termination signal, preventing them to use this transcription strategy 25 In RNA replication, the genome is copied into a complete positive-sense encapsidated intermediate called the ANTIGENOME (Negative sense RNA virus). It is the complementary strand of RNA from which the genome of a virus is constructed; i.e. The ANTIGENOME is the template for the synthesis of progeny genome. 1. What is post-translational modification? 2. Give an example for post translational cleavage of protein? 3. Haploid, diploid, polyploid Viruses? 1 copy-2copy ex HIV -multiple copies https://www.nature.com/articles/s41579-020-00501-8 In RNA replication, the genome is copied into a complete positive-sense encapsidated intermediate called the antigenome. The antigenome is the template for the synthesis of progeny genome. Retroviruses that contain two copies of their RNA genome in each viral particle are also said to be diploid. Replication of the genome produces a positive-sense antigenome known as a complementary RNA (cRNA) for sNSVs (Box 2), which is encapsidated by nucleoprotein into a complementary RNP (cRNP). The antigenome serves as the template for genome synthesis. 26 Viral genetic and evolution Accurate estimates of virus mutation rates are important to understand the evolution of the viruses and to combat them. https://jvi.asm.org/content/84/19/9733 Mutation rate variation across viruses. a Range of variation of mutation rates for the seven Baltimore classes of viruses (ss single- strand, ds double-strand; +/− genome polarity, RT retroviruses, pRT para-retroviruses). In the RT group, all mutation rates fall in the non-hatched arrow region except the HIV-1 mutation rate measured in cellular DNA, which is orders of magnitude higher than the rate measured in plasma. This is because many APOBEC-edited viral genomes fail to produce viable progeny and hence do not reach plasma (see text for details). b Negative correlation between genome size and mutation rate in viruses. Baltimore groups are indicated. The observed correlation can be explained in terms of differences between RNA and DNA viruses and between ss and ds viruses. In the RT group, the extremely high mutation rate of HIV-1 in cellular DNA is indicated with an arrow. In contrast, the HIV-1 mutation rate measured in plasma falls within the usual RT range RNA virus are less prone to proof reading Mutation frequency describes the amount of sequence variation seen in a virus population, generally after a given amount of time, but often with no knowledge of the number of generations the virus has undergone, or the forces of selection and drift that have affected the population. Accurate measurement of either is difficult. Studies done for animal viruses in vitro or in cell culture have estimated rates of 10−3 to 10−5 substitutions per nucleotide per round of replication. Despite these uncertainties, it can be inferred that viral mutation rates roughly range between 10−8 and 10−4 substitutions per nucleotide per cell infection (s/n/c), with DNA viruses occupying the 10−8–10−6 range and RNA viruses the 10−6–10−4 range The APOBEC3 enzymes are deaminases that edit single-stranded DNA (ssDNA) sequences by transforming deoxycytidine into deoxyuridine [1,2,3]. APOBEC3s are involved in the mechanisms of innate defense against exogenous viruses and endogenous retroelements 27 Viral genetic and evolution Mapping viral genome: Is the complete sequence of viral DNA or RNA, partial mapping or fingerprinting of oligonucleotides produce by enzymatic cleavage are simpler and still useful for identification of viruses with large genomes. Oligonucleotides mapping: Several hundred bacterial endonulease, called restriction endonulease, have been identified and purified from various bacteria. Different virus, yield characteristically different restriction endonulease fragment patterns, sometimes called fingerprints or restriction fragment length polymerase (RFLPs), usually 4-6 nucleotide pairs 5:31 PM Medical virology 28 28 Viral genetics and evolution DNA Sequence analysis Much more information can be obtained by determining the complete sequences of nucleotides in a viral genome by either the Maxam-Gilbert method or dideoxy method (Sanger). ORFs are translatable sequences starting with codon for methionine (AUG) and uninterrupted by stop codons (UAA, UAG, UGA). Recombinant technology Molecular cloning 5:31 PM Medical virology 29 29 Uses of genetic engineering: Complete sequencing of the genome of viruses representing all DNA virus and cDNA corresponding to the entire genome of RNA virus; (We can then modify the genome & use the virus (e.g. adeno) as a deliveray system. Production of labeled nucleic acid probes for viral diagnosis Recognition of the copy number and sequences of viral or proviral DNAs that are integrated into the DNA of transformed cell Marker rescue by transfection with gene fragment, as method of genetic mapping and of site-specific mutagenesis Production of proteins coded by specific viral genes using bacterial, yeast, insect, and animal cell expression systems, or by cell-free translation Synthesis of peptides based on DNA sequences data Making Stable cell lines using lentiviruses for expression purposes Study virus it self Use virus to generate continues cell lines Use virus for drug delivery (cancer therapy) Use virus for vaccine delivery Use virus to express proteins and identify mAb (phage display) 30 USE of Viral Vectors to Express Protein of Interest for Vaccination or Treatment non- infectiou s because of the deletion if we want to talk covid they take the covid protien this is used a way to just send the genome Ebola virus vaccine as an example it does not repilcate because we removed this gene HBV vaccine is a recombinant protein meaning you allow the gene to express the protein and use the protein for the vaccine 31 Example of genetic mechanisms that have affected viral evolution Mechanisms Example Point mutation Lethal chicken influenza Genetic reassortment Pandemic human influenza A subtypes H1N1 (1918,)H2N2(1957) & H3N2(1968) because of the segmented genome Recombination and Change in polio vaccine following mutation vaccination (Recombination between the live vaccine virus and other enteroviruses) Hyper mutation Evolution of subacute sclerosing pancephalitis virus from measles virus (mutation in M gene causing neurological diseases) https://www.youtube.com/watch?v=b9ejT4doIlM https://www.youtube.com/watch?v=QGSpYWfb1b8 https://www.youtube.com/watch?v=a4dvVa4L2-s Ques Ten outbreaks of poliomyelitis caused by pathogenic circulating vaccine-derived polioviruses (cVDPVs) have recently been reported in different regions of the world. Two of these outbreaks occurred in Madagascar. Most cVDPVs were recombinants of mutated poliovaccine strains and other unidentified enteroviruses of species C. Atype 2 cVDPV isolated during an outbreak in Madagascar was co-circulating with coxsackieviruses A17 Recombination between Poliovirus and Coxsackie A Viruses of Species C: A Model of Viral Genetic Plasticity and Emergence (Picornaviruses Subacute sclerosing panencephalitis (SSPE) is a serious disorder of the central nervous system. It is a slow virus infection caused by defective measles virus. The term subacute sclerosing panencephalitis has been used since Greenfield suggested it in 1960 to designate a condition due to a persistent infection by a virus involving both grey matter and white matter.1 Pathogenesis A large number of nucleocapsids are produced in the neurons and the glial cells. In these cells the viral genes that encode envelope proteins have restricted expression. As a result, infectious particles like the M protein are not produced, and the virus is able to survive persistently without evoking an immune response. 32 Eventually the infection will lead to SSPE. https://www.msdmanuals.com/home/children-s-health-issues/viral-infections-in- infants-and-children/subacute-sclerosing-panencephalitis-sspe 32 Viral replication and antiviral drugs 33 Open book reading activity Chapter 3 (page 19) 2-The molecular biology of the mammalian cell: - 2.4 - Processing of primary RNA transcripts - 2.5 - Translation of mRNA into proteins - 2.6 -Control of gene expression 5- Genetic variation of viruses: - 5.1 -Low fidelity of reverse transcriptases and RNA replicases - 5.2 -Recombination - 5.3 -Gene reassortment 5:31 PM Medical virology 34 34 Thank you for your attention Reference and reading recommendations: 1. Your text book: part 1, Viral replication and genetics, Page 18 2. www.cdc.gov( Centers for Disease Control and Prevention) ASMA Altani 35 35