Molekulare Mechanismen der Pathogenese bei Infektionskrankheiten. HIV-Pathogenese. Hans-Georg Kräusslich

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1 Molekulare Mechanismen der Pathogenese bei Infektionskrankheiten HIV-Pathogenese Hans-Georg Kräusslich Abteilung Virologie, Hygiene Institut INF 324, 4.OG

2 Eine Pandemie der Gegenwart Entfernter Donner Morbidity and Mortality Weekly Report, Pneumocystis Pneumonia --- Los Angeles In the period October 1980-May 1981, 5 young men, all active homosexuals, were treated for biopsy-confirmed Pneumocystis carinii pneumonia at 3 different hospitals in Los Angeles, California. Two of the patients died. All 5 patients had 15-39% laboratory-confirmed previous or current 5-15% cytomegalovirus (CMV) infection and Prävalenz candidal in 1-5% mucosal infection. Case reports der Bevölkerung of these patients follow... 0,5-1% 0,1-0,5% <0,1% unbekannt Heute: 5 Millionen Infektionen pro Jahr 3 Millionen Tote pro Jahr

3 Humanes Immundefizienzvirus Umhüllte RNA-Viren HIV-1 2 Typen (HIV-1, HIV-2) mit zahlreichen Subtypen Reverse Transkriptase im Virus RNA=>DNA Integration ins Wirtsgenom ss + Strang, ca Nukleotide Relativ instabil

4 HIV is a monkey-derived virus HIV-1 and HIV-2 are caused by independent transmissions from chimpanzee and sooty mangabey, respectively. HIV-1 type O is derived from a related gorilla virus. Three independent monkey to human transmissions (from chimpanzees) caused epidemics with M-, N-, and O- group HIV-1.

5 Zentrale Stellung der CD4 + T-Zellen für die erworbene Immunität

6 HIV infiziert CD4-positive Zellen, die den Korezeptor CCR5 oder CXCR4 tragen

7 Primary HIV-infection Unspezific symptoms 1 to 3 weeks after exposition similar to infectious mononucleosis p24-antigen detectable by 4 weeks p.i. HIV-genome detectable by 4 weeks p.i. Seroconversion 3 to 12 weeks p.i. Strong reduction in virus load with immune response Maculopapillary exanthema in primary HIV-infection

8 Course of HIV infection infection seroconversion minor or no symptoms ARC / AIDS disease markes Set point Prognosis!! CD4+ PBL virus load immune response HIV-specific CTL antibodies to p24 antibodies to HIV env 4-8 weeks up to 12 years 2-3 years

9 Die Wahrscheinlichkeit, AIDS innerhalb von drei Jahren zu entwickeln % CD4 -Zellen/µl > < >30K >55K 10K-30K 20K-55K 3K-10K 7K-20K 501-3K K <500 <1500 VL bdna VL PCR

10 AIDS: Opportunistic infections Kaposi-Sarkoma Human Herpesvirus 8 CMV-Retinitis Cytomegalovirus Interstitial Pneumonia: Pneumocystis carinii Oral Leukoplakia Epstein-Barr-Virus Oral Candidiasis Candida albicans

11 Der Verlauf der HIV-Infektion wird von Virusreplikation und Immunantwort bestimmt

12 Rolle von Antikörpern in der HIV-Infektion

13 Störungen der zellulären Immunantwort bei HIV-Infektion CD4 + -Zellen: Zytolyse (virus- und CTL-induziert) Störung der Proliferation (IL-2; IL-2 Rezeptor) Verminderte Antigen-spezifische Antwort CD4-Oberflächenexpression lösliches HIV-env bindet an CD4 und blockiert sterisch CTLs: Reduktion der Zellzahl Fehlende CD4 + Helferzellen Infektion und Lyse der Vorläuferzellen Spätphase der Infektion Monozyten/MO: Nur zum kleinen Teil infiziert Gestörte Chemotaxis, Fc-Rezeptorfunktion, Komplement-vermittelte Elimination vermutlich durch lösliches, virales Antigen B-Zellen: Polyklonale Aktivierung (lösl. virales Antigen) Autoantikörper NK-Zellen: Geringe Zytotoxizität (fehlende Helferzellen; Zytotoxizität ist IL-2 abhängig)

14 Der Eisberg Plasma (2% der Viruslast) Lymphatisches Gewebe (98% der Viruslast) Viruslast

15 Viral reservoirs and plasma viremia Viral RNA (copies/ml) HAART t1/2: 24h Activated T cell 10 Therapy 5 can dramaticallymacrophage reduce virusdendritic load in cell Drug therapy cannot t1/2: eliminate 14d the virus from latently 10 2 t1/2: 8months Resting T- cell (G1) almost all patients under therapy Therapy can be sucessful for several years infected cells harbouring integrated genomes Life-long therapy? t1/2: years Quiescent T- cell (Go) T (months)

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17 Currently available therapeutic approaches against HIV Receptor binding Reverse Transcription Fusion Maturation RT inhibitors PR inhibitors Integration Assembly entry/fusion inhibitors Transscription Translation Budding

18 Trends in Annual Death Rates Among Persons Years Old, USA, Deaths per 100,000 Population CDC Year

19 Dynamik der HIV-Infektion Flint et al., Molecular Virology, 2004

20 HAART restores CD4 counts and reduces the risk of AIDS CD4 virus AIDS HAART years

21 IMMUNE RESTORATION WITH HAART (or HAART plus IL-2) Increased number of CD4 + lymphocytes Increased number of naive T cells Immune response to recall antigens Increased proportion of cells specific for certain pathogens Increased proportion of IL-2 producing CD4 T cells to anti CD3 mab Increased thymic outcome of T cells HIV-specific immunity not restored

22 Therapeutic vaccination Principle: boost the specific antiviral immune response of patients in order to allow temporal or long-lasting control of virus replication in the absence of therapy Aims: allow patients to stop drug use for a given period of time enhance viral control under HAART to prevent treatment failure allow the delay of HAART onset, in particular if drugs are not available Optimistic aim: turn patients into long-term non-progressors Very optimistic aim: eradicate virus

23 Therapeutic vaccination Plasma virus HAART + vaccine Post- HAART? Restore immunity to HIV anti-hiv CTLs + antibodies anti-hiv CD4 T cells CD4 T cells