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IMMUNOBIOLOGY OF HIV INFECTION AND AIDS

IMMUNOBIOLOGY OF HIV INFECTION AND AIDS. IMMUNOBIOLOGY OF HIV INFECTION AND AIDS. HISTORICAL REMARKS:. 40‘s: - origin of HIV - genetically derived from simian retroviruses in Equatorial Africa late 50‘s: - first evidence of HIV infection in human

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IMMUNOBIOLOGY OF HIV INFECTION AND AIDS

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  1. IMMUNOBIOLOGY OF HIV INFECTION AND AIDS

  2. IMMUNOBIOLOGY OF HIV INFECTION AND AIDS HISTORICAL REMARKS: 40‘s: - origin of HIV - genetically derived from simian retroviruses in Equatorial Africa late 50‘s: - first evidence of HIV infection in human spring 1981: - first reports on AIDS 1983: - identification of causative agent HIV-1 1985: - routine screening for anti-HIV antibodies in hospitals late 80‘s: - antiretroviral therapy 90‘s: - new paradigma of HIV/AIDS pathogenesis late 90‘s: - new therapeutical approach (combination therapy) - extensive search for efficient active immunisation 

  3. CHARACTERIZATION OF HIV VIRUS: f. RETROVIRIDAE ssRNA -------------- ds DNA reverse transcriptase sf. ONCOVIRINAE sf. LENTIVIRINAE HIV-1, HIV-2 ------- ------- oncoviruses lentiviruses malignant transformation cell killing

  4. CHARACTERIZATION OF HIV VIRUS: - lentivirus: - integration into genome (provirus) - cytopathic after prolonged period of infection - HIV-1, HIV-2 GENETIC CHARACTERIZATION - 9 structural and regulatory genes - env: - envelope glycoproteins gp160, gp120, gp41 - pol: - reverse transcriptase (RT), integrases, p60 - gag: - coreproteins, p24

  5. STRUCTURE OF HIV-1 VIRUS envelope glycoproteins dřeňové proteiny gp120 gp41 p17 p24 core proteins p9 lipidic bilayer p32 reverse transkriptase (p66) RNA

  6. REPLICATION OF HIV VIRUS: principal permissive cells are: - CD4+ T cells - monocyte-macrophages infection is started by monocytotropic strains of HIV the shift from monocytotropic strains to lymphotropic strains in the course of HIV infection caused by genetic instability of HIV strains principal receptor is CD4 molecule correceptors are molecules of receptors for chemokines: - CCR5: monocytotropic strains - CXCR4: lymphotropic strains

  7. HIV-1 HOST CELL INTERACTION IST initiation IIND adsorption IIIRD penetration gp120 gp41 gp41 binding- site for CD4 molecule viral RNA gp120 V3 V3loop V1 V3loop CCR5 V2 CD4 V3 CD4 CCR-5 V4

  8. MACROPHAGES; CELL RECEPTORS FOR HIV-1 ENTRY • virus entry: • interaction between env gp120 (gp41) and CD4, • and receptor for chemokines HIV-1 CD4 CD4 CCR-5 CCR-532 INFECTED MACROPHAGE NON-INFECTED MACROPHAGE

  9. uncoating of HIV virus viral RNA replication, reverse transcription and integration   RT integrases vRNA --------------- ds DNA ----------------- genome (provirus) activation of infected cells: - replication of HIV - translation of HIV proteins - synthesis of viral polyprotein precursors - cleveage of polyprotein by viral proteases - assembly of viral particule - lysis of infected cell

  10. REPLICATION OF HIV-1 penetration uncoating reverse transcription integ- ration trans- cription translation budding viral proteases mRNA HIV ribosome proviral DNA RT polypeptide HIV ER genomic RNA Golgi.a. viral mRNA cDNA dsDNA glycosylation virio assembly cytoplasm nucleus cytoplasm

  11. EPIDEMIOLOGY OF HIV INFECTION: HIV is transmited horizontally via: - blood and blood products (organs) - sexual intercourse (homo-, heterosexual) - I.V. drug abuse HIV is transmited vertically via: - mother to child patterns of HIV transmission: - western countries pattern - developing countries pattern HIV transmission is highly enhanced in the presence of sexually transmited diseases HIV is not transmited via personal contact at home, in hospital

  12. DETECTION OF HIV INFECTION: direct: - cultivation (time-consuming, expensive) indirect: - detection of specific antibodies in IgG class against gp120 - confirmation of positivity by western blot - presence of specific antibodies is long-lasting molecular: - RT-PCR detection of HIV RNA - very sensitive, quantitative approach - essential to follow of treatment efficiency

  13. NATURAL COURSE OF HIV INFECTION: VIRUS ENTRY viral entry through the mucosa of genital or anal tract first line of defence is mucosal immunity (impaired in a case of STD) multiplication of HIV in regional lymph nodes ACUTE INFECTION viremia (several weeks after virus entry) associated with the signs of accute illness (flu-like) inverted CD4+/CD8+ T cells resultion of clinical symptoms normalisation of laboratory tests asymptomatic carriage of HIV virus

  14. ASYMPTOMATIC PHASE OF HIV INFECTION: - important for further outcome of HIV victim - active replication of HIV in lymphoid tissues - low viral load in peripheral blood - effective immune response against HIV which is TH1 driven - CD8+ T cell mediated cytotoxicity against HIV-infected cells - immune control of HIV replication - continual depletion of CD4+ T cells - TH1 to TH2 response shift - depression of specific T cell mediated immunity (protective) - upregulation of TH2 driven specific humoral immunity (no-protection) - hypergammaglobulinemia - infected people are the source of infection

  15. SYMPTOMATIC PHASE OF HIV INFECTION: • absolute number of CD4+ T cells falls below 0.2x109/l • CLINICAL PRESENTATION: • - lymphadenopathy (ARC) • - full-blowing AIDS • - warning sign: persistent oral candidiasis • - opportunistic infections (Pneumocystis carinii, • mycobacteria, viral infections) • - malignancy (Kaposi sarcoma) • - involvement of CNS (AIDS dementia) • - any organ could be affected

  16. NATURAL COURSE OF HIV-1 INFECTION; changes in specific humoral and cell-mediated anti-HIV response, depletion of CD4+ T-cells abs. CD4+ ly seroconversion death asymptomatic period ARC/AIDS 1109/ l CD4+ T-cells 0,5109/ l 0,2109/ l 0 4-8 weeks up to 15 years 2-3 years viremia anti-gp120 antibodies HIV - specific CTL anti- p24 antibodies 4-8 weeks up to 15 years 2-3 years

  17. HIV-1 INFECTION; CHANGES IN THE PRODUCTION OF CYTOKINES relative amounts of cytokines IL-10 IL-4 INF- IL-2 time ARC acute phase asymptomatic period HIV-1 infection AIDS seroconversion

  18. TREATMENT OF HIV INFECTION AND AIDS: - administration of drugs blocking RT of HIV (azidothymidin, others) - single drug is ineffective (viral resistance development) - combination therapy: - HEART therapy = combination of anti-RT drugs + inhibitors of viral proteases - replication of HIV is suppressed - slower decline of CD4 T cell count - slower progression of AIDS - HIV is not eliminated - enormously expensive approach - profylactic administration of antibiotics

  19. REPLICATION OF HIV-1 TARGETS OF ANTIVIRAL DRUGS rCD4 penetration RT inhibitors tat antagonist uncoating reverse transcription integ- ration protease inhibitors immunomodulation trans- cription translation budding viral proteases mRNA HIV ribosome proviral DNA RT polypeptide HIV ER genomic RNA Golgi.a. viral mRNA cDNA dsDNA glycosylation virio assembly cytoplasm nucleus cytoplasm

  20. ACTIVE IMMUNISATION: • - no efficient vaccine is available today • development of: • - mucosal vaccination • - systemic vaccination • - vaccine stimulated TH1 reactivity is an ultimate goal • - clinical trials are in progress • - no efficient treatment of HIV infection and AIDS is available • - no efficient vaccine is available • - the only way is to avoid HIV infection: - no promiscuity • - safe sex CONCLUDING REMARKS:

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