2.病原生物学-大二下第29章逆转录病毒

1、Retrovirus 1CharacteristicsRNA viruses that convert their RNA to DNA : RetrovirusIntegrate into host cell DNA during replication2RetroviridaeRNA virus contain reverse transcriptasesubfamilycharacteristicsexamplesOncovirinae(RNA肿瘤病毒亚科)(正逆转录病毒亚科）cancers、human T-cell leukemia virus(HTLV) Lentivirus (慢病

2、毒属)immunosuppressionhuman Immunodeficiency virus(HIV)Spumavirinae(泡沫病毒亚科)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%突变)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 (弓形虫病), cryptosporidiosis (隐孢子虫病）Fungal: pneumocystis carinii (卡氏肺孢菌感染)， candidiasis (白假丝酵母菌病), crytococcosis (新生隐球菌感染), 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(无菌性脑炎）Neuropathies（神经病变）AIDS dementia complex（痴呆）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在中国的传播1. 1982-1984 VIII因子2. 1985 输入性病例3. 1989 静脉吸毒者和性传播4. 1992 血液污染病例中国遏制与防治艾滋病“十二五”行动计划当前艾滋病流行形势仍然严峻，社会歧视广泛存在，局部地区和高危行为

25、人群疫情严重，还有相当数量的感染者和病人未被发现，梅毒等性病疫情上升，艾滋病传播的危险因素广泛持续存在，感染者陆续进入发病期，病人明显增多，死亡增加。防治工作面临一些新的挑战：性传播已成为主要传播途径，传播方式更加隐蔽，男性同性性行为人群疫情上升明显，配偶间传播增加，未开展预防母婴传播项目地区的母婴传播率处于较高水平；抗艾滋病病毒治疗耐药增多加大了治疗的压力和难度。同时，一些地区和部门对艾滋病防治工作重视不够，政策落实不到位，防治措施覆盖面不足；现有的防治技术、手段和能力尚不能满足工作需求，防控工作的针对性和有效性有待进一步提高，基层基础工作有待加强。防治工作出现的新问题与原有问题以及难点问题交织并存，情况更加复杂，防治任务十分艰巨。 。防控措施“中国遏制与防治艾滋病“十二五”行动计划（一）扩大宣传教育覆盖面，营造良好社会氛围。 （二）扩大综合干预覆盖面，提高干预工作质量。 （三）加强血液安全管理，预防医源性传播。 （四）扩大监测检测覆盖面，最大限度发现感染者。 （五）扩大治疗覆盖面，提高治疗水平和可及性。 （六）加强对感染者和病人的服务和管理，全面落实关怀措施。 （七）实施分类指导，全面推进艾滋病防治工作。防控措施切断传播途径任何与单一固定的HIV阴性伴侣以外的性行为都应该使用安全套保护；不共用未经灭菌处理的