Transcript 11mb ppt
Viral Tropism and Cellular Receptors Viral Tropism A specific pathologic “signature” left by a viral infection, usually related to its ability to replicate only in specific cell types Samllpox (scarring from recovered scabes) Polio (paralytic attack) Yellow Fever (acute jaundice) Rhinovirus (common cold) Mechanisms of tropism Cellular receptors; differential expression limits viral entry into specific cell types that express the cellular receptor Post-entry factors; cell type must be permissive for viral replication Transcription and translation machinery compatible with viral life cycle Innate anti-viral defenses can be overcomed by viral encoded proteins or these defenses do not affect viral life cycle For lipid enveloped viruses, a specific viral envelope Attachment Protein (usually glycosylated) interacts with the cognate cell surfcae receptor to bring about fusion of the virus membrane and the host-cell membrane Varieties of Viral Receptors Attachment and entry are distinct events, and may be mediated by different receptors Varieties of Viral Receptors For some viruses, attachment and entry receptors are complementary but distinct Herpes Simplex Virus 1 (“cold sores”) Herpes Simplex Virus 2 (genital lesions) Cellular attachment is primarily via heparan sulfate, but productive entry into the cell requires a coreceptor and interaction with a different envelope glycoprotein Herpes Virus has 11 membrane glycoproteins, four of which are involved in attachment and entry gB, gC (attachment--interacts with heparan sulfate) gD, gH/gL (entry--interacts with coreceptor) Expression of these receptors in the right place and combination can account for some of HSV tropism Many coreceptors have been described Entry receptors for Herpes Simplex Viruses Name Alternate Desig nati on HSV-1 HSV-2 hTR2 Hve A + + hNectin1 Hve C + + 3-O-sul phated HS hNectin2 CD1 55 Hve B Hve D + - - +/- - + Tis sue Express ion Lun g, L iver, kidn ey, Heart, Brain , Pla cen ta Brain , Spi nal Co rd, Pro state, Placenta, L iver Liver, Placenta, Hea rt, Kidn ey, Pan crea s Placenta, Pro state, Endo thel ial cel ls Brain , In testine, Peyer's Patche s, T-cells Varieties of Viral Receptors For some viruses, attachment and entry receptors are complementary but distinct HIV-1 (only one envelope glycoprotein) Requires a primary receptor (CD4) and a coreceptor (chemokine receptor) for viral entry Sequential interaction of the virus envelope glycoprotein with CD4 and coreceptor results in fusion between the virus and host cell membrane Use of Different Coreceptors Largely Accounts for Viral Tropism (HIV) T-tropic M-tropic CD4+ CD4+ CD4+ CCR5+ CXCR4+ Primary T cells CCR5+ CXCR4+ Macrophages T cell Line Use of Different Coreceptors Largely Accounts for Viral Tropism (HIV) T-tropic M-tropic CD4+ CD4+ CD4+ CCR5+ CXCR4+ Primary T cells CCR5+ CXCR4+ Macrophages T cell Line ccr5/ccr5 81% of Caucasian Get infected normally Progress to AIDS normally ccr5/Dccr5 15-18% of Caucasians Get infected normally But progress to AIDS 2-4 years more slowly Dccr5 /Dccr5 1% of Caucasians Highly Resistant to Infection Loss of CCR5 function but otherwise normal (no side effects) This makes CCR5 an attractive drug target Varieties of Viral Receptors For some viruses, attachment and entry receptors are the same, but membrane fusion is not at the cell surface, membrane fusion is triggered by low pH in endosomes Influenza HA glycoprotein binds to sialic acid receptor on cell surface Virus and receptor are endocytosed Low pH in endosomes trigger conformational changes in HA which results in membrane fusion Fusion Peptide Viral Receptors: Some Principles A variety of molecules, including glycoproteins, glycolipids, and glycosaminoglycans, can serve as viral receptors. Different viruses employ different cellular receptors. A given virus isolate may employ several alternate cellular molecules as receptors. In some instances, viral entry requires two or more different coreceptors on the cell surface. Usually, both co-receptors are necessary and neither alone is sufficient. Different isolates of the same virus may prefer different receptors. A specific virus isolate may alter its receptor preference by selection of a mutant VAP during serial passage in animals or cell cultures. The domain of the receptor that binds the virus may be either a polypeptide sequence or a carbohydrate moiety, often located at the external tip of the receptor molecule. Not all cells that express the viral receptor are capable of supporting the complete cycle of viral replication. Viral Tropism & Pathogenesis Viral receptor expression is the primary but not the only determinant of viral tropism Polio virus Parvovirus B19 Paralysis Exanthem subitum Pure red cell aplasia LCMV Poliovirus Family:Picornaviridae (small (+) RNAvirus); Genus: Enterovirus Infects only primates (human & non-human) PVR--CD155 (Ig Superfamily) Virus bind more avidly to homogenates from primate vs nonprimate tissues Viral RNA infectious for single round in non-primate tissue (by passing the entry block) High conservation amongst Primates Replicates in gut, excreted in feces Fecal-oral transmission; hygiene issues; swimming pools Viral invasion of CNS; also replicates preferentially in anterior horn cells--lower motor neurons of spinal cord; results in flaccid paralysis Receptor expression is necessary but not sufficient to explain viral tropism Polivirus Receptor Expression and Viral RNA expression Tissue Cells PVR exp ression Poliovi rus Replic ation Cellular destruc tion Central nervous system Neurons Anterior horn sp inal co rd Posterior ho rn spinal cord Medulla Cerebellum Midbrain Forebrain High High High High High High High High High Moderate Moderate Moderate Seve re Minim al Moderate Minim al Minim al Minim al Thymu s Kidney Lung Adrena l T lymphocy tes Epithelial, tubule cell s Alveo lar cell s Endroc rine cell s High High High High None None None None None None None None Intestine Spleen Skeletal muscle Many Lympho cytes Myo cytes Low Low Low None None Moderate None None None Parvovirus B19 Family: Parvoviridae (ssDNA virus) Tropism for red cell progenitors in bone marrow Receptor is a glycoshingolipid on the erythrocyte P antigen--also present on cells of mesenchymal origin Virus replicates only in actively dividing cells, not in terminally differentiated RBCs Therefore, tropism is limited to actively dividing cells with high receptor expression (erythrocyte precursors) RBCs Platelets Macrophages Granulocytes Lymphocytic Choriomeningitis Virus Family: Arenaviridae (minus-strand RNA virus) Different strains of LCMV exhibit different tropism Armstrong strain--neurotropic Clone13 strain--hepatotropic (liver) and spleen-tropic Both strains use the same receptor (-dystroglycan), but differ by one amino acid in the viral envelope glycoprotein One amino acid change confers high or low affinity binding of viral envelope to cellular receptor Other determinants of viral tropism Cellular protease requirement Temperature of replication Acid Lability Transcriptional control Cellular protease requirement Virulent (NCD Virus) Fusion Competent Avirulent (NCD Virus) Secreted protease Fusion Incompetent Fusion Competent Plasma membrane protease cleavage Temperature of replication Optimal temp. for rhinovirus (common cold) replication is 33º C Restricts replication to respiratory epithelium (e.g. lining of the nose and throat) Acid/Protease lability Enteric (gut) viruses must be able to survive low pH (acidic) of stomach, high pH of intestine and actions of digestive enzymes Some viruses exploit presence of digestive enzymes to “activate” viral envelope protein Reovirus Transcriptional Control --retroviruses LTR Transcription (tat) DNA Binding Motifs for various transcription factors Pappilomavirus Replication in Epidermis Mature virions and viral shedding Transcription of late Structural genes, virion assembly Primary Infection, Permissive for genome replication, but transcription of late structural genes is blocked Tropism, Viral Variation and Pathogenesis/Virulence Avian Influenza Virus H5N2 serotype circulates in domesic fowl Virulent serotype occurred in domestic poultry (1983 in Penn., 1995 in Mexico) Virulence is due to single amino acid change in envelope--deleted a glycosylation site close to Env cleavage site Mutant Virus --replicate to higher titers, in wider range of tissues --mild disease becomes rapidly fatal Fusion Competent Plasma membrane protease cleavage HIV tropism and Pathogenesis T-tropic M-tropic VIREMIA (RNA COPIES PER ML) CD4+ CCR5+ CXCR4+ Primary T cells CCR5+ CXCR4+ Macrophages T cell Line CD4:CD8 RATIO CD4+ CD4+ MACROPHAGE-TROPIC SHIV SF162P LPL DEPLETED LYMPHOCYTE-TROPIC SF33A LN DEPLETED 7 7 6 6 5 5 4 4 3 3 0 6 12 18 24 30 36 42 48 2.0 2.0 1.5 1.5 1.0 1.0 0.5 0.5 0.0 0.0 0 6 12 18 24 30 36 WEEKS AFTER INFECTION 42 48