HIV病毒ppt課件

1、HIV：Human Immunodeficiency VirusGengfu Xiaoxiaogengfu163 Epidemiologyn1980-1981: New York and California; CDCn1983-1984: Montagnier and colleagues at the Pasteur Institute; Gallo and coworkers at the NIHnSince the initial detection of the epidemic in the United States and Europe, it has grown to inv

2、olve an estimated 60 million persons worldwide, with 5 million new infections per year, with epidemics expanding in south Asia and China China also has a severe problem with up to 1.5 million HIV-infected people in 2019 (prevalence rate: 0.1%). It is predicted that if nothing is done to prevent the

3、increasing infection rate, China will have 10 million cases by 2019. Origin of HIV nThe global HIV epidemic is the result of a cross-species infection of humans by a chimpanzee lentivirus, simian immunodeficiency virus (SIVcpz), which occurred in west central Africa nSIVcpz is an asymptomatic infect

4、ion in chimpanzeesnDate of introduction of the M group into the human population is estimated to be around 1931, based on analysis of large numbers of sequenced HIV isolates, assuming a constant rate of evolutionnThis approach has been validated by successfully timing the earliest historic isolate,

5、which was sequenced from a stored plasma sample obtained in 1959 from a person who died in Manchester, England HIV-1 GenotypesnM (main); O (outlier); and N (non-M, non-O) nThe M group of HIV-1, which includes more than 95% of the global virus isolates, consists of at least nine discrete clades or su

6、bgroups (A, B, C, D, F, G, H, J, and K) and 15 circulating recombinant forms (CRF) nHIV-1 group O isolates have been recovered from individuals living in Cameroon, Gabon, and Equatorial Guinea; their genomes share approximately 65% identity with group M virusesnEarly in the epidemic, group O strains

7、 may have been responsible for more than 20% of HIV-1 infections in Cameroon but currently are associated with approximately only 1% HIV-1 GenotypesnClade A viruses, the most common HIV-1 subtype in Africa early in the epidemic, currently account for more than a quarter of the infections globally, a

8、nd are present predominantly in eastern and central African countries nClade B viruses, the most intensively studied HIV-1 subtype, remain the most prevalent isolates in Europe and North America nClade C viruses have become the dominant subtype and now account for nearly half of HIV-1 infections wor

9、ldwide nCRF01, a clade A/clade E recombinant originally isolated in Thailand HIV-1 GenotypesType B found in western countries, may be transmitted more effectively by homosexual intercourse and via blood (as in intra-venous drug use) whereas types C and E may be transmitted more via a heterosexual ro

10、uteTypes C and E replicate better in Langerhans cells found in the mucosa of the cervix, vagina and penis while type B replicates better in the rectal mucosa. It also appears that type E is more readily transmitted between sexual partners than type BSubtype D seems to be more virulent than subtype A

11、, that is infected persons progress to overt disease more rapidly Subtypes D and C seem to be transmitted more effectively from mother to child than subtype AHIV-1 GenotypesMechanisms of Transmission nIn South Africa for example, 4% of 16-year-old girls are HIV seropositive, whereas by age 21 this n

12、umber increases to 31%nmicrobicides /sexually transmitted diseases STD Mechanisms of Transmission Mechanisms of Transmission Cysts of Pneumocystis carinii in AIDS. Methenamine silver stain. Histopathology of lung shows characteristic cysts with cup forms and dot-like cyst wall thickeningsKaposis sar

13、coma (skin)In 1994, a Kaposis sarcoma-associated herpes virus (KSHV, now known as human herpes virus-8 (HHV-8) was identified The cytomegalovirus (CMV) is related to the herpes virus and is present in almost everyone. CMV is the most common type of virus that infects those who are HIV positiveCMV re

14、tinitisOpportunistic TumoursnThe most frequent opportunistic tumour, Kaposis sarcoma, is observed in 20% of patients with AIDSnKS is observed mostly in homosexuals and its relative incidence is declining. It is now associated with a human herpes virus 8 (HHV-8)nMalignant lymphomas are also frequentl

15、y seen in AIDS patientsOpportunistic InfectionsProtozoalpneumocystis carinii (now thought to be a fungi), toxoplasmosis, crytosporidosisFungalcandidiasis, crytococcosishistoplasmosis, coccidiodomycosisBacterial Mycobacterium avium complex, MTBatypical mycobacterial diseasesalmonella septicaemiamulti

16、ple or recurrent pyogenic bacterial infectionViralCMV, HBV/HCV, HGV Human Immunodeficiency VirusHIVHIVGenomeTAT: Trans-Activator of TranscriptionREV: Regulator of Virion protein expressionNEF: Negative Regulatory Factor VIF: Virion Infectivity FactorVPU: Viral Protein U VPR: Viral Protein RReplicati

17、onViral Envelope Protein & Cellular ReceptorCD4 normally functions to stabilize the interaction between the T-cell receptor on the surface of T lymphocytes and class II major histocompatibility complex (MHC-II) molecules on antigen-presenting cells. CD4+ T leukemia cell lines such as CEM, Jurkat

18、, Hut 78 (including H9) M-tropic, CCR5-using virus(R5) is the predominant HIV-1 phenotype detected in recently infected individuals and remains the dominant virus throughout the asymptomatic phase of HIV-1 infection. In approximately 50% of infected persons, CXCR4-using virus( X4) strains emerge dur

19、ing the later symptomatic stage of infection CNSnHIV-1 replication in monocyte or macrophage lineage microglia within the CNS may persist in patients receiving highly active antiretroviral therapy (HAART) because of inefficient transfer of drugs across the bloodbrain barrier. This viral reservoir co

20、uld contribute to the rebound of plasma viremia invariably observed after cessation of drug administration. CCR5nCCR5/32, contains a 32-bp deletion and encodes a truncated protein that is not efficiently expressed at the cell surface and cannot function as an HIV-1 coreceptor Paxton WA, Martin SR, T

21、se D, et al. Relative resistance to HIV-1 infection of CD4 lymphocytes from persons who remain uninfected despite multiple high-risk sexual exposures. Nat Med 2019; 2:412417 Reverse Transcription The mature HIV-1 RT holoenzyme is a heterodimer of 66- and 51-kd subunits. P51：proteolytic removal of th

22、e C-terminal 15-kd fragment of p66 by PRP61：The active site, located in the palm, contains three critical Asp residues (Asp-110, Asp-185, and Asp-186) in close proximity, and two coordinated Mg2+ ionsTwo major classes of drugs block RTnnucleoside RT inhibitors (NRTIs) and NNRTIsnExamples of NRTIs in

23、clude AZT (zidovudine), 2-deoxy-3-thiacytidine (3TC or lamivudine), 2,3 dideoxyinosine (ddI or didanosine), and 2,3 dideoxycytidine (ddC or zalcitabine)nNNRTIs include nevirapine, efavirenz, and delavirdinenNRTIs are nucleotide mimics that lack the 3-OH and thus act as chain terminators on incorpora

24、tion into DNA, whereas the NNRTIs inhibit DNA polymerization by binding a small hydrophobic pocket near the RT active site and inducing a change in the structure of RT that blocks DNA synthesisnResistance to RT inhibitors, however, often develops in patients as viral variants arise encoding mutant f

25、orms of RT that are no longer blocked by the inhibitors Integration Retroviral IN proteinslow solubility and propensity to aggregate an N-terminal, zinc-binding domain1-55： NMR； four helices with a zinc coordinated by amino acids His-12, His-16, Cys-40, and Cys-43；helix-turn-helix motif; contributes

26、 to dimer formation a catalytic core domain (50-212)： crystallography/a mutation; a five-stranded -sheet flanked by helices;a striking resemblance to RNaseH;Three highly conserved residues : Asp-64, Asp-116, and Glu-152 . Mutations at these positions block HIV-1 IN function both in vivo and in vitro

27、 a relatively nonconserved C-terminal domain：NMR;a five-stranded -barrel folding topology reminiscent of a Src homology 3 (SH3) domainIntegration of DNA provirus into the host genomeTAT: Trans-Activator of TranscriptionHIV-1 Tat is a nuclear protein containing 101aaTAR: transactivation response regi

28、onRecruit GTFs and the RNA pol II holoenzyme to the transcription initiation complexThe TAR RNA binding domain of Tat has been mapped to a Lys/Arg-rich region between residues 48 and 57 TAT / TARThe binding of Tat to TAR RNA is markedly enhanced in the presence of cyclin T1 Rev (regulator of express

29、ion of viral proteins)Rev could promote the nuclear export of intron-containing viral RNA Virus Assembly and Release: Gag Proteins nucleic acid chaperone activity of NC Mild oxidizing agents, such as AT-2 (2,2-dithiopyridine) cause zinc to be ejected from the zinc fingers; Alkylating agents, such as

30、 N-ethylmaleimide (NEM), react with zinc-bound thiols in NC and inactivate virus infectivity Virus Release and Vpr/Vpx Incorporation p6Virus Maturation: Protease The development of PR inhibitors represents a classic example of structure-based drug design More than seven PR inhibitors are in clinical

31、 useVirus loads decline precipitously, but drug-resistant variants soon emergeSaquinavir沙奎那維 escape mutants frequently contain changes at PR residue 48 or 90Ritonavir利托那韋 resistance is often associated with mutations at PR residue 82Vif: virus infectivity factor Counter the antiviral activity of APO

32、BEC3G (Host DNA cytosine deaminase) HIV PathogenesisPossible mechanism for the loss of T4 cells after HIV infection HIV half-livesnThe time required to complete a single HIV life-cycle is approximately 1.5 daysnResting cells that become infected produce virus only after immune stimulation; these cel

33、ls have a half-life of at least 5-6 monthsnSuch long-lived cell populations present a major challenge for anti-retroviral therapy Laboratory DiagnosisScreening assays - EIAs are the most frequently used screening assays. The sensitivity and specificity of the presently available commercial systems n

34、ow approaches 100% but false positive and negative reactions occur. Some assays have problems in detecting HIV-1 subtype OConfirmatory assays - Western blot is regarded as the gold standard for serological diagnosis. However, its sensitivity is lower than screening EIAs. Line immunoassays incorporate various HIV ant