2.病原生物學(xué)-大二下第29章逆轉(zhuǎn)錄病毒

1、Retrovirus 1CharacteristicsRNA viruses that convert their RNA to DNA : RetrovirusIntegrate into host cell DNA during replication2RetroviridaeRNA virus contain reverse transcriptasesubfamilycharacteristicsexamplesOncovirinae(RNA腫瘤病毒亞科)(正逆轉(zhuǎn)錄病毒亞科）cancers、human T-cell leukemia virus(HTLV) Lentivirus (慢病

2、毒屬)immunosuppressionhuman Immunodeficiency virus(HIV)Spumavirinae(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). They were

3、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 promised patient)5AIDS1982 disease was officially named AIDS. First isolated in 1983 from the lymph node of a patient wit

4、h lymphadenopathy in Paris1984 blood test developed 6Classification HIV-1 worldwide pandemicHIV-2 in west Africa 7 Structure and CompositionP17P248P7HIV Genome Two +ss RNA 2 LTR (long terminal repeat region)Three structure genes: gag, pol, env 9Structure GenesGeneEncoded ProteinFunction of Proteinga

5、gP24, p7Capsid Nucleocapsidp17MatrixpolReverse 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

6、nucleusnef downregulates 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 H

7、IV ( 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 Source of infection patients or carriers16Tran

8、smission Routes 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 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 millio

9、n 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 2013TotalAdultsWomenChildren (15 years)TotalAdultsChildren (15 years)TotalAdultsChildren (15 years)Global summary of the AIDS epidemic 2013 18

10、EpidemiologyTotal: 35.0 million 33.2 million 37.2 millionMiddle East & North Africa230 000160 000 330 000Sub-Saharan Africa24.7 million23.5 million 26.1 millionEastern Europe & Central Asia1.1 million 980 000 1.3 millionAsia and the Pacific4.8 million4.1 million 5.5 millionNorth America and Western

11、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 estimated to be living with HIV2013 19Estimated number of adults and children newly infected with HIV2013 Middle East & North Africa25 00014 000 41

12、000Sub-Saharan Africa1.5 million1.3 million 1.6 millionEastern Europe & Central Asia110 000 86 000 130 000Latin America94 00071 000 170 000Caribbean12 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

13、 44 000 160 00020Estimated adult and child deaths from AIDS2013 Middle East & North Africa15 00010 000 21 000Sub-Saharan Africa1.1 million1.0 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

14、.7 millionAsia and the Pacific250 000210 000 290 000North America and Western and Central Europe 27 000 23 000 34 00021Middle East & North Africa23001500 3400Sub-Saharan Africa210 000180 000 250 000Eastern Europe & Central Asia1000 1000 1200Latin America18001000 7400Caribbean1000500 1000Estimated nu

15、mber of children (15 years) newly infected with HIV2013 Total: 240 000 210 000 280 000 Asia and the Pacific22 00018 000 32 000North America and Western and Central Europe 500 200 50022PathogenesisThe typical course of untreated HIV infection spans about a decade stages include :Primary infection: 2-

16、4 weeks after infection; actue monomucleosis-like syndrome in many patients (50%-75% ).Clinical latency: asymptoms infection (10years)AIDS related complex(ARC）AIDS: opportunistic infection, neoplasmas23Time course and stages of HIV infection24Primarylatency 1. Primary infection 25 50%-90% people hav

17、e the symptoms like flu. Last for 2 weeks. 26Primary infection Rash : 20-50% last 1-2 weeks26272. Clinical latency PGL 27 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 shorte

18、r (months to 1-2 years) in children3. AIDS related complexlow-grade feverweak,chronic diarrhea, Lymph node enlargementOpportunistic infectionProtozoal: toxoplasmosis (弓形蟲病), cryptosporidiosis (隱孢子蟲?。〧ungal: 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: My

19、cobacterium Viral：CMV, HSV, EBV.HIV associated cancerKaposis a (HHV-8)Non-Hodgkins lymphoma (some are EBV)Neurological symptoms：Aseptic meningitis; Neuropathies; AIDS dementia complex 4. AIDS29Neurological symptomsAseptic meningitis(無菌性腦炎）Neuropathies（神經(jīng)病變）AIDS dementia complex（癡呆）30Kaposis aVery ra

20、re, Pre-AIDS: mainly in older Mediterranean men20 000 times more common in untreated AIDS patient Infection with HHV-8 is necessary for development of KS3132Obstacle to HIV EradicationLatent reservoir Loss of CD4 help Latent reservoirImmunodeficiencyAIDSEscaping immune control: Latent reservoir (imm

21、une-privileged) Mutation druing RT Nef, down regulate the MHC-I. Loss of CD4 T cell help 33Laboratory Diagnosis Anti-HIV antibodyRoutine use for HIV screeningAb develops after 4-6 weeks, remains detectable for lifeInitial test by ELISAConfirmed by Western blotp24 viral antigen (capsid, CA) for blood

22、 screening by ELISA developed before the Abviral RNA for blood and for babies born by infected moms by RT-PCR34Anti-HIV antibody test ELISAWestern blotIF: ELISA test postiveHIV + diagnosis ConfirmedWindow periodA combination of three tests are used to screen blood.Anit-HIV strategiesNo vaccines agai

23、nst HIV Health education Antiviral drugs3738 .au Treatment of HIV 38FDA approved about 30 drugsRT inhibitorsProtease inhibitorsFusion inhibitorIntegrase inhibitor (2007)CCR5 inhibitor (2008)HAARTHighly Active Anti-Retroviral Therapy (HAART)Combination of two RT inhibitors and 1 protease inhibitor.Re

24、duce viral load to nearly zeroHas allowed immune responses to recover and protect from other infectionsStrong side effectsExpensivedrug resistanceHIV is not completely cleared39HIV在中國的傳播1. 1982-1984 VIII因子2. 1985 輸入性病例3. 1989 靜脈吸毒者和性傳播4. 1992 血液污染病例中國遏制與防治艾滋病“十二五”行動計劃當(dāng)前艾滋病流行形勢仍然嚴(yán)峻，社會歧視廣泛存在，局部地區(qū)和高危行為

25、人群疫情嚴(yán)重，還有相當(dāng)數(shù)量的感染者和病人未被發(fā)現(xiàn)，梅毒等性病疫情上升，艾滋病傳播的危險因素廣泛持續(xù)存在，感染者陸續(xù)進入發(fā)病期，病人明顯增多，死亡增加。防治工作面臨一些新的挑戰(zhàn)：性傳播已成為主要傳播途徑，傳播方式更加隱蔽，男性同性性行為人群疫情上升明顯，配偶間傳播增加，未開展預(yù)防母嬰傳播項目地區(qū)的母嬰傳播率處于較高水平；抗艾滋病病毒治療耐藥增多加大了治療的壓力和難度。同時，一些地區(qū)和部門對艾滋病防治工作重視不夠，政策落實不到位，防治措施覆蓋面不足；現(xiàn)有的防治技術(shù)、手段和能力尚不能滿足工作需求，防控工作的針對性和有效性有待進一步提高，基層基礎(chǔ)工作有待加強。防治工作出現(xiàn)的新問題與原有問題以及難點問題交織并存，情況更加復(fù)雜，防治任務(wù)十分艱巨。 。防控措施“中國遏制與防治艾滋病“十二五”行動計劃（一）擴大宣傳教育覆蓋面，營造良好社會氛圍。 （二）擴大綜合干預(yù)覆蓋面，提高干預(yù)工作質(zhì)量。 （三）加強血液安全管理，預(yù)防醫(yī)源性傳播。 （四）擴大監(jiān)測檢測覆蓋面，最大限度發(fā)現(xiàn)感染者。 （五）擴大治療覆蓋面，提高治療水平和可及性。 （六）加強對感染者和病人的服務(wù)和管理，全面落實關(guān)懷措施。 （七）實施分類指導(dǎo)，全面推進艾滋病防治工作。防控措施切斷傳播途徑任何與單一固定的HIV陰性伴侶以外的性行為都應(yīng)該使用安全套保護；不共用未經(jīng)滅菌處理的