病原微生物學教學課件：18-Retrovirus-英五

1、Retrovirus 1CharacteristicsnRNA viruses that convert their RNA to DNA : RetrovirusnIntegrate into host cell DNA during replication2RetroviridaenRNA virus contain reverse transcriptasesubfamilycharacteristicsexamplesOncovirinae(RNA腫瘤病毒亞科腫瘤病毒亞科)cancershuman T-cell leukemia virus(HTLV)Lentivirinae(慢病毒亞

2、科慢病毒亞科)immunosuppressionhuman Immunodeficiency virus(HIV)Spumavirinae(泡沫病毒亞科泡沫病毒亞科)no clinical diseaseHuman foamy virus3HUMAN IMMUNODEFICIENCY VIRUS（HIV） Acquired immunodeficiency syndrome（AIDS）4AIDS1981, In California Los Angeles, CDC reported 5 young men die from pneumocystis pneumonia (卡氏肺孢菌肺炎).

3、They were all the male homosexual population.There were very few cases of opportunistic infection pneumocystis pneumonia that was caused by a fungal pneumosystis carinii. (in very severely immunocompromised patient)5AIDS1982 disease was officially named AIDS. First isolated in 1983 from the lymph no

4、de of a patient with lymphadenopathy in Paris1984 blood test developed 6Classification HIV-1HIV-27http:/ and CompositionP17P248HIV Genome nTwo +ss RNA n2 LTR (long terminal repeat region)nThree structure genes: gag, pol, env 9Structure GenesGeneEncoded ProteinFunction of ProteingagP24, p7Capsid Nucl

5、eocapsidp17MatrixpolReverse transcriptaseTranscribes RNA genome into DNAProteaseCleaves precusor polypeptidesIntegraseIntegrates viral DNA into host cell DNAenvgp120Attachment to CD4gp41Fusion with host cell10Six regulate genestat transcriptional activatorsrev viral RNA export of nucleusnef downregu

6、lates surface expression of MHC class I11Replication12Attachment of the virus Primary: CD4 Co-receptor: CCR (chemokine receptor) 13Co-receptor14 Co-receptor: CCR (chemokine receptor) CCR5 (R5 virus) or CXCR4 (X4 virus) people with CCR5-delta32 mutation are naturally resistant to

7、HIV ( Caucasian高加索人 1-2%突變)15HIV fusion Conformational change in gp120. gp41 are exposed and inserted in to the cellular membrane. gp41 undergoes significant conformational change, pulls the viral and cellular membranes together, fusing them.Transmission vHIV is not a particularly infectious virus,

8、not contagious like measles virus vNot spread by respiratory, alimentary, or vector routesvSource of infection patients or carriers16Transmission vRoutes of transmission1735.0 million 33.1 million 37.2 million 31.8 million 30.1 million 33.7 million16.0 million 15.2 million 16.9 million 3.2 million 2

9、.9 million 3.5 million2.1 million 1.9 million 2.4 million1.9 million 1.7 million 2.1 million 240 000 210 000 280 0001.5 million 1.4 million 1.7 million1.3 million 1.2 million 1.5 million 190 000 170 000 220 000Number of people living with HIVPeople newly infected with HIV in 2013 AIDS deaths in 2013

10、TotalAdultsWomenChildren (15 years)TotalAdultsChildren (15 years)TotalAdultsChildren (15 years)Global summary of the AIDS epidemic 2013 18EpidemiologyTotal: 35.0 million 33.2 million 37.2 millionMiddle East & North Africa230 000160 000 330 000Sub-Saharan Africa24.7 million23.5 million 26.1 milli

11、onEastern Europe & Central Asia1.1 million 980 000 1.3 millionAsia and the Pacific4.8 million4.1 million 5.5 millionNorth America and Western and Central Europe 2.3 million 2.0 million 3.0 millionLatin America1.6 million1.4 million 2.1 millionCaribbean250 000230 000 280 000Adults and children es

12、timated to be living with HIV2013 19Estimated number of adults and children newly infected with HIV2013 Middle East & North Africa25 00014 000 41 000Sub-Saharan Africa1.5 million1.3 million 1.6 millionEastern Europe & Central Asia110 000 86 000 130 000Latin America94 00071 000 170 000Caribbe

13、an12 0009400 14 000Total: 2.1 million 1.9 million 2.4 millionAsia and the Pacific350 000250 000 510 000North America and Western and Central Europe 88 000 44 000 160 00020Estimated adult and child deaths from AIDS2013 Middle East & North Africa15 00010 000 21 000Sub-Saharan Africa1.1 million1.0

14、million 1.3 millionEastern Europe & Central Asia53 000 43 000 69 000Latin America47 00039 000 75 000Caribbean11 0008300 14 000Total: 1.5 million 1.4 million 1.7 millionAsia and the Pacific250 000210 000 290 000North America and Western and Central Europe 27 000 23 000 34 00021Middle East & N

15、orth Africa23001500 3400Sub-Saharan Africa210 000180 000 250 000Eastern Europe & Central Asia1000 1000 1200Latin America18001000 7400Caribbean1000500 1000Estimated number of children (15 years) newly infected with HIV2013 Total: 240 000 210 000 280 000 Asia and the Pacific22 00018 000 32 000Nort

16、h America and Western and Central Europe 500 200 50022PathogenesisThe typical course of untreated HIV infection spans about a decade stages include :nPrimary infection: 2-4 weeks after infection; actue monomucleosis-like syndrome in many patients (50%-75% ).nClinical latency: asymptoms infection (10

17、years)nAIDS: opportunistic infection, neoplasmas23Time course and stages of HIV infection24Primarylatency 1. Primary 25 50%-90% people have the symptoms like flu. Last for 2 weeks. 261.Primary infection Rash : 20-50% last 1-2 weeks26272. Clinical latency PGL27

18、Immune system response CD4 500 cells/mm3 Lower viral load Asymptomatic infection or a persistent generalized lymphadenopathy (PGL) May last 10 years in adults usually much shorter (months to 1-2 years) in childrennOpportunistic infectionProtozoal: toxoplasmosis (弓形蟲病), cryptosporidiosis (隱孢子蟲?。〧unga

19、l: pneumocystis carinii (卡氏肺孢菌感染)， candidiasis (白假絲酵母菌病), crytococcosis (新生隱球菌感染), Bacterial: Mycobacterium Viral：CMV, HSV, EBV.nHIV associated cancerKaposis sarcoma (HHV-8)Non-Hodgkins lymphoma (some are EBV)nNeurological symptoms：Aseptic meningitis; Neuropathies; AIDS dementia complex 3. AIDS28Neu

20、rological symptomsAseptic meningitisNeuropathiesAIDS dementia complex29Kaposis SarcomaVery rare, Pre-AIDS: mainly in older Mediterranean men20 000 times more common in untreated AIDS patient Infection with HHV-8 is necessary for development of KS3031Obstacle to HIV EradicationLatent reservoir Loss o

21、f CD4 help Latent reservoirImmunodeficiencyAIDSEscaping immune control: Latent reservoir (immune-privileged) Mutation druing RT Nef, down regulate the MHC-I. Loss of CD4 T cell help 32Laboratory Diagnosis nAnti-HIV antibodyRoutine use for HIV screeningAb develops after 4-6 weeks, remains detectable

22、for lifeInitial test by ELISAConfirmed by Western blotnp24 viral antigen (capsid, CA) for blood screening by ELISA developed before the Abnviral RNA for blood and for babies born by infected moms by RT-PCR33Anti-HIV antibody test ELISAWestern blotIF: ELISA test postiveHIV + diagnosis ConfirmedLabora

23、tory Diagnosis nAnti-HIV antibodyRoutine use for HIV screeningAb develops after 4-6 weeks, remains detectable for lifeInitial test by ELISAConfirmed by Western blotnp24 viral antigen (capsid, CA) for blood screening by ELISA developed before the Abnviral RNA for babies born by infected moms to evalu

24、ate the efficacy of treatment35Window periodA combination of three tests are used to screen blood.Anit-HIV strategiesnNo vaccines against HIV nHealth education nAntiviral .au Treatment of HIV 38nFDA approved about 30 drugsRT inhibitorsProtease inhibitorsFusion inhibitorIntegrase inhibitor (2007)CCR5 inhibitor (2008)HAARTlHighly Active Anti-Retroviral Therapy (HAART)Combination of two RT inhibitors and 1 protease inhibitor.Reduce viral load to nearly zeroHas allowed immune responses to recover and protect from other infectionsStrong side effectsExpensivedrug resistanceHIV is not completely cle