(filamentous) I.
Filaroviridae Chap. 30 p. 484 a. General properties (1) morphology -Long pleomorphic viruses - filamentous or convoluted forms - See Fig. 30-1 p. 485. -80nm diam; length 0.5-14um (particles as long as 14,000nm seen). -linear ssRNA single molecule; helical symmetry with envelope. (2) viral replication -7 proteins in genome - See Fig. 30-2 p. 486. -viruses multiply in cytoplasm, forming large inclusion bodies from aggragated -bud from plasma membrane.
nucleocapsids.
b. Pathogenesis and clinical features -Two important human pathogens (1) Marburg Virus - 25% fatality (2) Ebola Virus - 4 strains Ebola-Zaire or Z - 90% mortality Ebola-Sudan or S - 60% mortality Ebola-Reston strain (in monkeys) - humans only get subclinical disease; no mortality Ebola-Ivory Coast - no mortality -these filoviruses cause the most severe of the hemorrhagic fevers with the highest fatality rates even though they are not arboviral. -Found in Africa - rare. - Clinical symptoms similar to arbovirus hemorrhagic fevers. Very rare and pathogenic - Class 4 pathogens - must be handled at maximum security containment units (CDC) -Rapid onset with fever, diarrhea, severe hemorrhages, vomiting, abdominal pain, myalgia, pharyngitis, conjunctivitis and proteinuria. c. Lab diagnosis -*Class 4 pathogen (P4). Specimens must be taken with great care and shipped to one of only 6 P4 facilities. See Fig. 32-3 p. 503 - at CDC -Isolated on Vero cells (monkey kidney cells) and identified by EM. -Infected cultures can be gamma irradiation sterilized and stained with FAB. -Patients serum tested for Ab to virus using virus-infected Vero cells sterilized by gamma irrad. (FAB or RIA) d. Epidemiology, prevention and control
Ebola Hemorrhagic Fever Table Showing Known Cases and Outbreaks, in Chronological Order
Year Ebola subtype Country No. cases % Mortality
1976 1976 1976 1977 1979 1989 1990 1992 1994 1994 1995
Ebola-Zaire Ebola-Sudan Ebola-Sudan Ebola-Zaire Ebola-Sudan Ebola-Reston Ebola-Reston Ebola-Reston Ebola-Zaire Ebola-Ivory Coast Ebola-Zaire
1996 1996 1996 1996 1996 20002001 20012002
Ebola-Zaire Ebola-Zaire Ebola-Zaire Ebola-Reston Ebola-Reston EbolaSudan Ebola-Zaire
Zaire [Congo (DRC)] 318 Sudan 284 England 1 Zaire 1 Sudan 34 USA 0 USA 0 Italy 0 Gabon 49 Ivory Coast 1 Democratic 315 Republic of the Congo (formerly Zaire) Gabon 31 Gabon 60 South Africa 2 USA 0 Philippines 0 Uganda 425 Gabon and The Republic of the Congo 122
88% 53% 0% 100% 65% 0% 0% 0% 59% 0% 81%
68% 75% 50% 0% 0% 53% 79%
J. Arenaviridae (Sand) Chapter 32 p. 500 a. General properties (1) Morphology -helical symmetry with envelope - pleomorphic -2 segments of ambisense (some + and some-) circular ssRNA in gneome (complementary H bonding at ends forms circles) -one of segments is small (S segment -3.4kb), and one is large ( L segment -7.2kb). -Each of the 2 circular segments has a separate helical nucleocapsid and both are enclosed in a lipid envelope from budding. -See Table 32-2 and Fig. 32-1 p. 501 and 502. -*Contains nonfunctional ribosomes (sand) acquired when budding through plasma membrane. (2) viral replication See Fig. 32-2 p. 502 -Cytoplasmic multiplication -mature by budding from plasma membrane -usually produce carrier cell cultures with DI particles -ribosomes accidently enveloped in budding -heteroploidy is common -genetic reassortment between the 2 segements is very common. b. Viral classification See Table 32-1 p. 501 -only 1 genus - Arenavirus -the genus is divided into 2 serotypes or groups: (1) Old World serogroup or complex [a] Lymphocytic choriomeningitis (LCM) [b] LAS - Lassa fever (2) New World serogroup or complex [a] Tacaribe complex Junin Machupo Guanarito Sabia c. Pathogenesis and clinical features -Table 32-1 shows arenavirus diseases of man.
-Diagnosis by rising Ab titer in serum using indirect FAB. [b] LAS - Lassa fever -1969, Arenavirus killed several hospital personnel in Lassa, Nigeria -Blood samples from autopsy sent back to Yale University for viral analyses. -One Yale lab technician contracted the virus and died. [1] Clinical symptoms - Class 4 pathogen. -Incubation period 1-2 wks. -Symptoms variable. Can start with headache, fever and malaise. This progresses to sore throat, abdominal chest and muscular pains, vomiting and/or diarrhea. Any organ can be involved. -In severe cases, many organs affected - pharyngitis, conjunctivitis, pneumonitis, carditis, hepatitis, encephalopathy, proteinuria, facial edema and hemorrhages. Death is caused by cardiovascular collapse. -Mortality rate is 20% in hospitals (nosocomial), but only 2% in natural cases. [2] Lab diagnosis -Few labs set up to handle diagnosis. Very dangerous P4. Nigerian outbreak in 1969 - nosocomial infections killed medical personnel. Specimens sent to Yale University. Lab researchers died. -Recover virus from blood (urine or throat less frequent). -Grows in Vero cells. Produces CPE. -Immunofluroescence on infected tissue. CAREFUL! - Gamma sterilize if possible. -Look for IgM in patient's serum using indirect FAB with gamma sterilized lassa virus infected Vero cells. [3] Epidemiology, prevention and control -Lassa virus enzootic in the West African peridomestic mouse. -now endemic in rural West Africa - >100,000 new infections/yr and 1000-3000 deaths -virus carried by mouse, shed in urine, transmitted vertically (milk, eggs) to offspring and horizontally (zoonotic) to humans by contaminating the house with infected urine (aerosols) -virus not spreading from endemic areas, so person-to-person transmission not as strong as mouse-toperson. -person-to-person transmission only common nosocomially, but nosocomial spread in hospitals most dangerous.. -Only control is rigorous precautions with hospital specimens and destruction of rhodent carriers. (2) New World serogroup or complex [a] Tacaribe complex Junin
4) Sabia virus (from Brazil) -First isolated in Brazil in 1990. -Only 2 cases in Brazil. One naturally infected Ag engineer (from infected rodent) One lab tech working with the virus. -First case in U.S. in Aug 1994; lab infection of virologist working in biosafety level-3 lab. Centrifuge bottle with specimen cracked at high-speed and aerosoled virus. Was working in Connecticut DPH. (MMWR September 1994, Vol 43(34)635-636.
K. Retroviridae (Reverse Transcriptase) Chapter 35, p. 531 1. General Properties Table 35-1 p. 534 a. Morphology Fig. 35-4 and 35-5 p 540 -2 strands of linear + ssRNA (diploid) in helical symmetry with additional icosahedral capsid and outer envelope. The two strands of +ssRNA (diploid) are linked by H bonds at the 5'end. 5' end has 7meG cap and 3' end has poly A tail and t-RNA- like structure at 3'OH terminus. -Core contains two molecules of reverse transcriptase -Most retroviruses contain only 3 genes (gag, pol and env). HIV-1 contains 9 genes (vif, vpu, vpr, tat, rev and nef in addition to 3 above). These additional 6 genes contribute to extreme pathogenicity of HIV-1. See Fig. 35-6 p. 541. From: www.Wong's virology
-important viral proteins are: ( Fig. 35-5 p.540 and other figs. from Talaro & Talaro 2004 Ed.McGraw Hill and Wong's virology) 1) p24 gag protein - icosahedral capsid proteins 2) p17 gag protein - inner envelope protein 3) gp-41 and gp-120 - stalk and knob of envelope peplomer or spike (72 of them on outer envelope viral attachment molecules that react with CD4 receptors) 4) p9 gag and p7 gag - associated with inner core of virus - part of nucleoprotein core. 5) reverse transcriptase - 2 molecules of RT associated with each of the genomes (diploid genome)
From WWW Wong's Virology
F r o m : T al ar o & Talaro 2004, Foundations in Microbiology. McGraw Hill
b. Viral replication Will only look at replication of HIV1 below. 2. Endogenous and Exogenous Retroviruses i. Endogenous -Transmitted vertically as an integrated provirus (DNA). -Most never produce disease. In 1999 Science News: -30 mill. yr. old human endogenous retrovirus K (HERV-K) may have infected germ cells of Old World monkeys (ancestors of humans). -Humans have > 50 copies of HERV-K in genome. -Also, HERV-K generally dormant, but found a gene in it similar to HIV gene REV used to shuttle copies of HIV genomes out of nucleus to cytoplasm for assembly. -Think ancient ancestor of HIV picked up REV from HERV-K ii. Exogenous -Transmitted horizontally by normal portals. -may cause slow transformation of cells; but weakly ongogenic -acute transforming may be highly oncogenic Table 11-3 p. 176 has comparison of Endogenous and Exogenous retroviruses.
3. Classification of Retriviruses Ref: "All the Virology on the WWW" -Seven genera Retroviridae Classification
Retrovirus Genus 1. Mammalian type B retroviruses 2. Mammalian type C retroviruses
Subgenus
Ex -Virus Name
Mouse mammary tumor virus (MMTV)
"Mammalian type C retrovirus group" Reticuloendotheliosis virus group
Murine Leukemia Virus Feline Leukemia Virus Reticuloendotheliosis virus
3. Avian type C retroviruses 4. Type D Retrovirus group
Avian leukosis virus
Mason-Pfizer monkey virus
(MPMV) 5. BLV-HTLV retroviruses
Bovine leukemia virus Human T Cell lymphotrophic virus Bovine lentivirus group Equine lentivirus group bovine immunodefic virus Equine infectious anemia virus (Coggins test in horses) Feline lentivirus group Primate lentivirus group feline immunodefic virus human immunodeficiency virus 1 (HIV1)** human immunodefic. virus 2 (HIV2)
*6. Lentivirus
A-type: Immature viruses in process of assembly. Also known as 'intracisternal particles'. Non-enveloped, (non- infectious???) immature particles only seen inside cells, believed to result from endogenous retroviruslike genetic elements. 1. B-type: Enveloped, extracellular particles with a condensed, acentric core and prominent envelope spikes, e.g. MMTV. 2.-3. C-type: As B-type, but with a central core and barely visible spikes - e.g. most mammalian (2.) and avian (3.) retroviruses (MLV, ALV, HTLV, HIV). 4. D-type: Usually slightly larger (to 120nm) and spikes less prominent, e.g. MPMV. By and large, molecular genetic studies have borne out these morphologic differences, but have also largely replaced them - most comparisons now made on the basis of sequence conservation. Pathogenesis - Diseases caused by Human Retroviruses 5. BLV-HTLV retrovirus a. BLV is bovine leukemia virus. b. HTLV Human T-Cell lymphotrophic virus (1) HTLV-1- Human T-Cell lymphotrophic virus type 1 -adult T-cell leukemia/lymphoma -HTLV-1 first human retrovirus discovered in 1980. Transmitted horizontally inside infected CD4+ lymphs in semen or blood and vertically in breast milk or even transplacentally. -HTLV-1 enters T helper cells and integrates into the cellular genome. -It does not contain oncogenes or "turn on" cellular oncogenes. -It turns on the growth-promoting genes and the transformed cells proliferate as leukemic cells. -T4 helper/inducer T cells are transformed to malignant blast cells. -Highly malignant disease of young adults; prevalent in Japan and the Caribbean. -Characterized by hepatosplenomegaly, lymphoadenopathy and occasional skin lesions of malignant T cell infiltrates. -Hypercalcemia also occurs. -Death from explosive proliferation of T cells, or loss of immunity and opportunistic infections. -No effective treatment at this time. (2) HTLV-2 -No known disease - prevalent in IV drug users.
a. HIV-1 -HIV-1 first named LAV (lymphocyte adenopathy virus). -Then given name HTLV-3 -Finally changed to Human Immunodeficiency Virus (HIV). - Cytocidal for lymphocytes; not oncogenic. - causes AIDS. Replication of HIV-1: O'Brien, S.F. and M. Dean. 1997. In Search of AIDS-Resistance Genes. Sci Am 277(3):44-50 Sequence of Events of HIV infection in humans: 1) Virus changes tropism over time 2) Starts out as M-tropic (infects macrophages (MP). -Gp120 protein on HIV envelope has tropism for dual receptors on MP: -CCR5 protein receptor + CD4 Receptor 3) Virus is taken into MP and reproduces, producing new HIV (productive infection). -diploid +ssRNA genomes uncoat in cytoplasm and use RT to produce ds DNA provirus. -ds DNA provirus goes to nucleus and integrates in latent infections. -activation of DNA provirus causes replication and a productive cycle resulting in death of the infected cell. New infected virus particles are assembled in the cytoplasm and released by budding 4) Over time, the virus gp120 receptor protein changes its tropism from the CCR5 + CD4 receptors on MP to a new dual receptor on Th cells: -As is changes, the HIV is dual tropic for both MP and Th cells. 5) Finally, HIV becomes T-Tropic: -The CXCR4 receptor + CD4 receptors of Th become recognized receptors. Sequence: M-Tropic -----> Dual Tropic ----> T-Tropic (CCR5 + CD4) (Both) (CXCR4 + CD4)
Resistance to HIV in 1% of caucasians due to homozygous mutant CC5 gene. HIV is contracted in this state,
The virus initially infects a type of m a crop hag es (de ndritic ce lls) w ith C D 4 re cep tors and C C R -5 corec eptors o n the c ell m em bra ne, a nd repro duc es virus particles in these cells w ith out killin g them .
Th e virus, over a p erio d o f m o n th s o r years, ch an g es its affin ity fro m m acrop h ag es to T h elp er lym p h o c ytes (TH o r T4 cells) w ith C D 4 recep to rs an d C XC R /4 co recep to rs o n th e cell m em b ran e.
226
Fig 25.15 p. 772
The general multiplication cycle of HIV
From: Fig. 25.15 in Talaro and Talaro 2004 Introduction to Microbiology McHill
www.Wong's Virology HIV attaching to lymphocyte
From Flint 2002
Disease: Acquired Immunodeficiency Syndrone (AIDS) -Caused by Human Immunodeficiency Virus types 1 and 2; mainly type 1; type 2 mainly in Africa; not as severe [a] Pathogenesis and Clinical symptoms -Causes AIDS (Acquired Immuno Deficiency Syndrome) -Exogenous cytocidal, productive infection. -Discovered in 1983 at Pasteur Institute by Montagnier et-al. -A year later Gallo at NCI claimed discovery. Caused investigation by ethics committee. -First seen as rare complex of symptoms in male homosexuals in late 1970's in clusters in Las Angeles, New York and San Francisco. -Initial symptoms described- Pneumocystis carinii pneumonia by harmless protozoan and Kaposi's sarcoma (very rare). - First called GRID (gay-related immunodeficiency disease) STAGES OF INFECTION: Four main stages I Initial infection with acute symptoms in 2 weeks -Targets cells are the CD4+ macrophages, and even monocytes. -Initial infection may have vague mono-like symptoms of fever, myalgia, adenopathy, arthralgia and myalgia and even rash. These symptoms disappear quickly. II HIV + antibodies in serum in 2 months after initial infection III Incubation period of 2-20 years; virus growing in macrophages and beginning to switch affinity to T4 helper cells and killing them. IV Full AIDS symptoms as T4 helper cell levels drop to<200 cells/ul blood and opportunistic infections and
Initial Infection of Target Cells and seroconversion illness
From Talaro & Talaro 2004
From: Talaro & Talaro 2004. McGraw Hill
Clinical definition: A severe immunodeficiency disease arising from infection with HIV, having Ab to HIV, and accompanied by some of the following symptoms: Life-threatening opportunistic infections from: 1) protozoa: Pneumocystis carinii pneumonia; toxoplasmosis of the brain; Cryptosporidium diarrhea. 2) fungi: Cryptococcus meningitis; Candidiasis; lung infections with Aspergillis. 3) viruses: VZV; HSV; 4) bacteria: Mycobacteria (grow in massive numbers in bone marrow, liver, spleen and lymph nodes). Other AIDS related pathological syndrones: -persistent fever -unusual cancers -Kaposi's sarcoma (HHV8) is main one; epithelial carcinomas of the skin, mouth and rectum; -B cell lymphomas. -chronically swollen lymph nodes -weight loss -diarrhea -neurological disorders -lesions in the brain, meninges, spinal column and peripheral nerves; withdrawal, persistent memory loss, spasticity, and progressive dementia; numbness, tingling, loss of reflexes and pain in the extremities.
See Figure below from Talaro & Talaro 2004. McGraw Hill
S
Opportunistic infections and other diseases used in the expanded case definition of AIDS
233
[b] Lab Diagnosis p. 550 -Patient's history (high risk?) -HIV + Ab in serum by EIA using recombinant HIV Ag; or -PCR for actual viral Ag in blood in earliest stages. -secondary infections and unusual cancers and symptoms related to AIDS. [d] Epidemiology -Origin of AIDS In 1999 Science News: -30 mill. yr. old human endogenous retrovirus K (HERV-K) may have infected germ cells of Old World monkeys (ancestors of humans). -Humans have > 50 copies of HERV-K in genome. -Also, HERV-K generally dormant, but found a gene in it similar to HIV gene REV used to shuttle copies of HIV genomes out of nucleus to cytoplasm for assembly. -Think ancient ancestor of HIV picked up REV from HERV-K -Not conclusive. Thought to be mutant of simian AIDS. However, too genetically different. -Serological tests on stored samples show mainly African samples + before 1970. From CDC's EID SIV
-First officially reported in 1980. -May have begun in central Africa in early 1950's. -AIDS is now the commonest cause of death in young adusts in large cities of U.S. -At risk groups in U.S. (order of risk) 1) male homosexuals -50% 2) IV drug users - 25% (60% in New York City) 3) heterosexual partners of HIV carriers - 8% 4) unknown - 8% 5) blood transfusions and organ transplants - 2% 6) coagulation factors transfusions for hemophiliacs - 1% 7) congenital and neonatal infections; 1 in 3 infected mothers infect fetuses or newborns. 8) healthcare workers - very low risk. From Talaro & Talaro. 2004. Introduction to Microbiology. McGraw Hill
Fig. 25.13 p. 769
[e] Control & Treatment -AIDS second in worldwide mortality only to acute respiratory disease. - Must have prevention and cure. 1) Vaccine Development -Major effort at NIAID to bring vaccines from basic research to clinical trials. Some include: a) Killed HIV vaccines ( undergoing clinical trials) b) Live recombinant virus vaccines. HIV Ag genes are spliced into vaccinia virus. First human immunizations (volunteers in Zaire and France) used recombinant vaccinia virus expressing the HIV envelope glycoprotein gp160. It induced only low levels of humoral and cell-mediated immunity. Now using adjuvants with purified recombinant vaccines. c) Other envelope proteins used include gp120 and gp41. 2) AIDS chemotherapy: See : www.immunet.org/immunet/atn.nsf/page/a-294-03 FDA approved drugs: 1. Nucleoside analog reverse transcriptase inhibitors *a) Ziduvudine (AZT) RetrovirR -Thymine analog - inactivates reverse transcriptase. First drug approved by FDA for AIDS. Now given in combination with about 2 others. -Major side effect was bone marrow suppression - used smaller doses. b) Other nucleoside analogs -All inhibit reverse transcriptase. ddI (2nd to get FDA approval), ddC, sttvudine (d4T), AZdU, Abacavir, and 3TC. 2. Non-nucleoside Reverse Transcriptase Inhibitors - Nevirapine, Delavirdine, Efavirenz (DMP-266) 3. Nucleotide Reverse Transcriptase Inhibotors -Adefovir; Zidovudine (Retrovir, AZT, ZDV) 4. Protease Inhibitors
A. Unclassified diseases - Prions - subacute spongiform encephalopathies p. 27 and Chapter 10 p. 160 Prusiner, S.B. 1984. Prions. Sci. Am. 251(4):50-59. 1. The spongiform encephalopathies -Very slow encepthalopathies found in both man and animals with extremely long incubation periods months, years and decades. It slowly progresses to complete destruction of the CNS. a. Pathogenesis and Clinical Symptoms (1) Kuru (2) Creutzfeldt-Jakob disease (CJD) (3) Scrapie - sheep *prototype of the encephalopathies (4) Bovine spongiform encephalopathy (BSE - mad cow disease)- in England; beef were fed sheep patties from scrapie infected sheep. -General Symptoms of encephalopathies: (kuru, CJD, scrapie, BSE) -Difficulty in walking. -Loss of motor coordination. -Functional disorder in cerebellum. -Progress slowly to total demential and death. -CJD generally starts with dementia. -No immune response. -Ab's have been prepared to prions. -Forms vacuoles in brain (spongiform).
From Talaro & Talaro 2004. McGrawHill
normal brain
spongiform encephalopathy
From Talaro & Talaro 2004
McGraw Hill
(1) Kuru p. 160 -Confined to a single tribe in New Guinea highlands. -Unknown until 1920. -First studied and described in 1957; responsible for 80-90% of deaths in the women. Older males executed as kuru socerers. -1965 Gajdusek and Gibbs at NIH determined cause to be filterable agent (no virus found). Transmitted in brains of infected individuals. Got Nobel Prize in 1976. -5-30 year incubation period (Avg. 20 yrs.). -Affected women and children participated in ritualistic cannabalism of organs (brain) of dead relatives in funeral ceremonies. - 100% fatal. -Disease now extinct except for rare case of child who participated 20-30 years earlier. (2) Creutzfeldt-Jakob disease (CJD) p. 160 -Similar to Kuru in clinical symptoms. -1 case /million worldwide. -Strikes middle aged - Libyan Jews have highest incidence. -Transmitted by corneal transplantation; neurosurgery; implantation of electrodes into the brain. -Requires sterilization of equipment and instruments by incineration. (3) Scrapie - sheep *prototype of the encephalopathies -Resembles kuru. (4) Bovine spongiform encephalopathy (BSE - mad cow disease) - in England; beef were fed sheep patties from scrapie infected sheep. b. Prions -etiological agent of these spongiform encephalopathies See Fig. 10-3 p. 161
-the infectious prion protein recovered from scrapie brains and experimental animal encephalopathies has been designated PrPSc (scrapie prion protein). -PrPSc has the same amino acid sequence as a normal protein found in the cell membrane of normal neurons of the host. The normal prion protein is called PrPC. -PrPSc is an isoform of PrPC - it only differs in the 3-D or tertiary configuration. -The formation of the PrPSc isoform after translation of the normal PrPC is a spontaneous event of 1/1million persons per year in CJD. c. Replication of PrPSc prions to cause encephalopathies p. 163 (1) Abnormal isoform PrPSc forms dimer with normal cellular PrPC and acts as template for the abnormal 3-D (tertiary) folding of the normal prion to the abnormal shape. -The different tertiary shape is what makes the PrPSc so resistant to normal agents which inactivate viruses (many physical and chemical inactivating treatments, nucleases, uv irradiation, formalin proteiolysis and boiling). (2) the process cascades with newly altered PrPSc acting as templates to alter the final
B. Oncogenic viruses (Chapter 11) Table 11-1 p. 171 shows viruses associated with malignant tumors in humans 1. Families of viruses that are ongogenic a. Retroviridae b. Papovaviridae c. Hepadnaviridae d. Herpesviridae e. Flaviviridae 2. Mechanisms of viral oncogenesis Two main mechanisms of oncogenesis in cells: (1) Oncogenes -The cellular oncogenes (c-onc) are essential genes that play key roles in the normal regulation of cell growth, division, and differentiation. -*Of main importance in cancers caused by viruses. (2) Tumor suppressor genes (inactivation of these initiates cancer) -half of all cancers due to altered function of these genes. -However only indirectly involved in cancers caused by viruses (1) Oncogenes -Oncogene hypothesis -By Huebner & Todaro - 1969 "Every normal cell contains viral oncogenes (v-onc) transmitted vertically. They can be activated by carcinogens (chemical, biological or physical)." -We now know that cellular oncogenes (c-onc) are not of viral origin. -Viral oncogenes (v-onc) apparently are of cellular origin and were acquired by viruses via transduction from cellular oncogenes -Approximately 60 viral oncogenes (v-onc), which were first found in Retroviruses, are identified to
C. Viral syndrones (Chapter 36 p. 563) Review only 1. respiratory Table 36-1 p. 566 2. gastroenteritis Table 36-2 p. 570 3. central nervous system Table 36-3 p. 573 4. skin rashes Table 36-4 p.578 5. hemorrhagic fevers Table 36-5 p. 579 6. genitourinary Table 36-6 p. 581 7. optic Table 36-7 p. 582 8. arthritis Table 36-8 p. 583 9. carditis Table 36-9 p. 584 10. hepatitis Table 36-10 p. 585 11. congenital & perinatal Table 36-11 p. 587 XI. Control and Prevention of Viral Disease A. Host Immune Responses Chapters 7, 8, 13, 15, 16 See Biology 203 Blackboard Power Point from Micro. 1. Natural resistance or Natural Immunity (non-specific immunity) (Chapter 7) a. genetic determinants of host resistance p. 111 b. specific immune response genes and other immune response genes c. cell membrane receptors for specific viruses d. physiologic factors in host resistance p. 114 (1) age (2) malnutrition (3) hormones and pregnancy (4) fever (5) state of cell differentiation
-Three main types (Antigenic and chemical differences) a) alpha-IFN -(Le- IFN; from leukocytes) b) beta-IFN - (F-IFN; from fibroblasts and epithelial cells) c) gamma-IFN* - (Immune IFN; from T lymphs and NK cells) -Mechanism of IFN action: a) Viral nucleic acid derepresses or turns on the IFN gene in the host cell nucleus. The host cell produces and secretes IFN. b) The IFN reacts with receptors on the membranes of adjacent cells to trigger a cascade of biochemical reactions. c) The IFN reacting with its receptor on the cell membrane induces the cell to produce a group of antiviral proteins (at least 3 enzymes). d) The AVP (RNase L) inhibits translation of viral m-RNA into viral proteins by destroying the viral m-RNA. From Talaro and Talaro 2004
2. Active Immunity -Specific immunity (Chapter 8) a. Components of the specific immune response Fig. 8-1 p. 121 (1) Antigen (Ag) processingcells - APC - dentritic macrophages -the antigen is the virus or viral cell surface antigens -concentrates Ag on surface and "presents to B cells and Th cells. (2) B cell immunity (humoral mediated immunity -HMI) (3) T cell immunity (cellular mediated immunity -CMI) HI and CMI are the two main branches of the immune system.From Talaro and Talaro 2004 Humoral Immunity (B Cell) and Cellular Immunity (T Cell)
(2) B cell immunity (humoral mediated immunity -HMI) for virus infected cells a] mature B lymphs or plasma cells are Ab producing cells - secrete into blood. b] virus neutralization; serum IgG and secretory IgA main virus neutralizing Ab c] C' dependent cytotoxicity (lysis) of cells with viral Ag-Ab on suface (CDC) d] Natural Killer Cells - NK cells - large granular lymphocytes that do not have the characteristic molecules found on B lymph and T lymph surfaces. They can kill a variety of tumor, virusinfected cells, bacterial cell, and other cells in a non-specific manner (They don't produce specific Ab to virus). Antibodies bind to virus Ag on infected cells via their Fab (Ab attaching) region. NK cells, attach via Fc (Ab tail) receptors, and kill virus infected cells or other cells with Ab attached - not by phagocytosis but by release of toxic substances called perforins. a] mature B lymphs or plasma cells are Ab producing cells - secrete Ab into blood (IgM and IgG) or onto mucous membranes (secretory IgA).
b] virus neutralization; serum IgG and secretory IgA main virus neutralizing Ab
Secretory IgA
c] C' mediated lysis of cells with viral Ag-Ab on suface
Complement (C') lesions on cell membrane
d] Natural Killer Cells - NK cells - large granular lymphocytes that do not have the characteristic molecules found on B lymph and T lymph surfaces. They can kill a variety of tumor, virus-infected cells, bacterial cell, and other cells in a non-specific manner (They don't produce specific Ab to virus). Antibodies bind to virus Ag on infected cells via their Fab (Ab attaching) region. NK cells, attach via Fc (Ab tail) receptors, and kill virus infected cells or other cells with Ab attached - not by phagocytosis but by release of toxic substances called perforins. From http://www.tulane.edu/~dmsander/WWW/MBChB/3b.html
Fab
Fc
NK Cell
http://www.tulane.edu/~dmsander/WWW/MBChB/3b.html
(3) T cell immunity (cellular mediated immunity -CMI) -populations of T cells Table 8-1 p. 123 -Th cells (T helper cells) -Tc cells (cytotoxic T cells) Td cells (delayed hypersensitivity - subpopulation of Tc cells) -Ts cells (suppressor T cells - moderate immune response)
From Talaro & Talaro 2004
Summary of the general development and functions of B and T lymphocytes
[a] B lymphs [b] T lymphs
b. mechanisms of virus destruction by immune responses Fig. 8-4 p. 129 (1) B Cell Humoral Immunity -See above a] neutralizing Ab from B cells with help of macrophages and CD4+ Th cells (serum IgM and IgG and sIgA) b] virus neutralization; serum IgG and secretory IgA main virus neutralizing Ab c] C' dependent cytotoxicity (lysis) of cells with viral Ag-Ab on suface (CDC) d] Natural Killer Cells (2) T Cell Cell Mediated Immunity (CMI) by Tc cells a] Cellular destruction of virus infected cell by Tc cell populations with help of Th cells.
From Talaro and Talaro 2004.
a. artificial passive immunity -immune gamma globulin therapy - injection of immune serum from animal or human to person already exposed or as prophylactic.
b. natural passive immunity -sIgA from mother to child in colostrom -IgG transplancental from mother to fetus
B. Immunization against viral diseases (Chapters 13 and 15) 1. human viral vaccines Table 13-6 p. 231 a. live attenuated b. inactivated dead c. synthetic and DNA vaccines 3. immunization schedules Table 15-1 p. 261 4. effects of viral vaccines on control of infections Fig. 15-1 p. 260 C. Chemotherapy of viral diseases (Chapter 16) -An ideal chemotheurapeutic agent (synthesized in laboratory) has: 1) Selective toxicity 2) High chemotheurapeutic index (ratio of minimum cell-toxic dose to minimum virus-inhibitory dose) - should be 100 - 1000 and 3) Broad spectrum activity None of the antiviral chemotherapeutic agents available to date meet these criteria. 1. targets for antiviral chemotherapy Table 16-1 p. 267 2. groups of antiviral drugs Fig. 16-1 p. 273 a. inhibitors of viral DNA polymerase - nucleoside analogs -acyclovir and homologs (gangciclovir) - first developed in 1977 - herpes -ribovirin - 1972 aerosol for servere influenza and parainfluenza b. inhibitors of reverse transcriptase -zidovudine and homologs - AZT; 1986; treatment of AIDS c. ion channel blockers - prophylactic for Influenza A -adamantadine
g. inhibitors of regulatory proteins - none licensed -many viruses have regulatory proteins that control viral replication; inactivate these and virus can't replicate. h. interferons p. 82; discussed above. -alpha INF gene engineered and cloned in E. coli in 1980; all others since then. -modest success only as anti-viral (HCV) or anti-cancer drug. -possible future in combination therapy with other drugs.
FINAL TEST