HIV-Pathogenese

Molekulare Mechanismen der Pathogenese
bei Infektionskrankheiten
HIV-Pathogenese
Hans-Georg Kräusslich
Abteilung Virologie, Hygiene Institut
INF 324, 4.OG
http://www.virology-heidelberg.de
Eine Pandemie der Gegenwart
Entfernter Donner
Morbidity and Mortality Weekly Report, 5.6.1981
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. 15-39%
All 5 patients had
5-15%
laboratory-confirmed previous or current
cytomegalovirus
1-5%
Prävalenz
in
(CMV) infection and
candidal
mucosal0,5-1%
infection. Case reports
der
0,1-0,5%
of these patients follow.......
Bevölkerung
<0,1%
unbekannt
Heute: 5 Millionen Infektionen pro Jahr
3 Millionen Tote pro Jahr
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. 9 000 Nukleotide
Relativ instabil
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 Ogroup HIV-1.
Zentrale Stellung der CD4+ T-Zellen für die erworbene Immunität
HIV infiziert CD4-positive Zellen, die den
Korezeptor CCR5 oder CXCR4 tragen
Primary HIV-infection
Unspezific symptoms
1 to 3 weeks after exposition
similar to infectious mononucleosis
¾ p24-Antigen detectable by 4 weeks p.i.
¾ HIV-genome detectable by 4 weeks p.i.
¾ Seroconversion 3 to 12 weeks p.i.
¾ Strong reduction in virus load
with immune response
Maculopapillary exanthema
in primary HIV-infection
Course of HIV infection
infection seroconversion
minor or no symptoms
disease markes
Set point
Prognosis!!
ARC / AIDS
virus load
CD4+ PBL
immune response
antibodies to HIV env
HIV-specific CTL
antibodies to p24
4-8 weeks
up to 12 years
2-3 years
Die Wahrscheinlichkeit, AIDS innerhalb
von drei Jahren zu entwickeln
%
CD4 -Zellen/µl
>750
501-750
351-500
201-350
<200
100
80
60
40
20
0
>30K
>55K
10K-30K
20K-55K
3K-10K
7K-20K
501-3K
1500-7K
<500 VL bDNA
<1500 VL PCR
AIDS: Opportunistic infections
CMV-Retinitis
Kaposi-Sarkoma
Cytomegalovirus
Interstitial Pneumonia:
Pneumocystis carinii
Human Herpesvirus 8
Oral Leukoplakia
Epstein-Barr-Virus
Oral Candidiasis
Candida albicans
Der Verlauf der HIV-Infektion wird von
Virusreplikation und Immunantwort bestimmt
Rolle von Antikörpern in der HIV-Infektion
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
Spätphase der Infektion
Infektion und Lyse der Vorläuferzellen
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)
Der Eisberg
Plasma
(2% der Viruslast)
Lymphatisches
Gewebe
(98% der Viruslast)
Viruslast
Viral reservoirs and plasma viremia
Activated
T cell
106
Resting Tcell (G1)
Quiescent Tcell (Go)
HAART
Viral RNA (copies/ml)
105
Therapy can dramaticallymacrophage
reduce virusDendritic
load in
cell
almost
all patients under therapy
t1/2: 24h
104
Therapy can be sucessful for several years
103
Drug therapy cannot
the virus from latently
t1/2: eliminate
14d
2
10
infected
cells harbouring integrated genomes
t1/2: 8months
Life-long therapy?
101
t1/2: years
0
6
12
24
T (months)
Currently available therapeutic approaches against
HIV
Receptor
binding
Fusion
Maturation
¾ RT inhibitors
¾ PR inhibitors
Reverse
Transcription
Integration
Transscription
¾ entry/fusion
inhibitors
Assembly
Translation
Budding
Deaths per 100,000 Population
Trends in Annual Death Rates Among Persons
25 - 44 Years Old, USA, 1982 - 2000
40
35
30
25
20
15
10
5
0
82
82
84
84
86
86
88
90
Year
CDC
92
94
96
98
00
Dynamik der HIV-Infektion
Flint et al., Molecular Virology, 2004
HAART restores CD4 counts and
reduces the risk of AIDS
CD4
virus
HAART
AIDS
500
200
0
0.5
8
0
0.5
years
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
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:
¾ allow patients to stop drug use for a given period of time
¾ enhance viral control under HAART to prevent treatment failure
¾ 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
Therapeutic vaccination
Post- HAART?
Plasma virus
HAART
+ vaccine
Restore
immunity
to HIV
anti-HIV CTLs + antibodies
CD4 T cells
anti-HIV CD4 T cells