Lack of Innate control of HIV
Frank Kirchhoff
Institute of Molecular Virology
University of Ulm
HIV-1 maintains high viral loads despite a strong
(but usually ineffective) antiviral immune response
Host restriction factors and their viral antagonists
Humans developed a „natural combination therapy“
long before HAART
TRIM5a: destabilization
of the viral capsid
APOBEC3G: lethal
hyper-mutations
Tetherin: inhibition of
virus release
Kirchhoff
Cell Host & Microbe
(2010)
Humans developed a „natural combination therapy“
long before HAART
TRIM5a: destabilization
of the viral capsid
APOBEC3G: lethal
hyper-mutations
Tetherin: inhibition of
virus release
Kirchhoff
Cell Host & Microbe
(2010)
Humans developed a „natural combination therapy“
long before HAART
TRIM5a: destabilization
of the viral capsid
APOBEC3G: lethal
hyper-mutations
Tetherin: inhibition of
virus release
Kirchhoff
Cell Host & Microbe
(2010)
Humans developed a „natural combination therapy“
long before HAART
TRIM5a: destabilization
of the viral capsid
APOBEC3G: lethal
hyper-mutations
Tetherin: inhibition of
virus release
Kirchhoff
Cell Host & Microbe
(2010)
Humans developed a „natural combination therapy“
long before HAART
TRIM5a: destabilization
of the viral capsid
APOBEC3G: lethal
hyper-mutations
Tetherin: inhibition of
virus release
Usually pretty effective: ~8% of our genome are of retroviral origin
But HIV has developed effective countermeasures
HIV and SIV contain several small „accessory“ genes
Accessory genes of HIV and SIV
Rabbit ~10 million years
RELIK: Tat, Rev
Lemur: ~7 million years
pSIVgml: Tat, Rev, Vif
Monkeys, Apes, Humans: today
HIV & SIV: Tat, Rev, Vif, Vpr, Nef,
Vpu, Vpx
Kirchhoff, Cell Host & Microbe (2010)
The cytidine deaminase APOBEC3 induces lethal G–>A hyper-mutations
of the viral genome (Sheehy et al., Nature 2002)
Bieniasz, Nat. Immunol. 2004
Vif: degrades APOBEC3 (Sheehy et al., Nature 2002)
Bieniasz, Nat. Immunol. 2004
TRIM5a: a capsid-specific restriction factor (Stremlau et al., Nature 2004)
Infected Cell
Target Cell
Release
Entry
TRIM5a
Reverse
transcription
Envelope
protein
Nuclear import
integration
Assembly
HIV-1 is blocked by simian
but not human TRIM5a
viral RNA,
Gag and Pol
proteins
Courtesy Paul Bieniasz
ABOBEC3G & TRIM5a are important for the host tropismus of HIV & SIV
Restriction factors usually
have broad antiviral activity
HIV & SIV are resistant against the
antiviral factors of their own hosts
Adapted from
Ho & Bieniasz
Cell, 2008
Adaptation of SIVcpz to chimpanzees paved the way for the spread of HIV-1 in
humans: SIVcpz is resistant against human ABOBEC3G & TRIM5a
Courtesy Paul Spearman
Tetherin: blocks virus release
Neil et al., Nature 2008; Van Damme et al., Cell Host & Microbe 2008
Perez-Caballero et al., Cell 2009
Courtesy Paul Spearman
HIV-1 M Vpu: antagonizes “tetherin” and degrades CD4
Neil et al., Nature 2008; Van Damme et al., Cell Host & Microbe 2008
Kirchhoff, Nat. Rev. Microbiology 2009
Courtesy Paul Spearman
HIV-1 M Vpu: antagonizes “tetherin” and degrades CD4
Neil et al., Nature 2008; Van Damme et al., Cell Host & Microbe 2008
Kirchhoff, Nat. Rev. Microbiology 2009
Switches between Nef- and Vpu-mediated tetherin antagonism
preceded the emergence of HIV-1
Tetherin shows species-specific sequence variations
Human tetherin is resistent to Nef
SIVcpz/gor
HIV-1 M, N
adapted from Sauter et al. Cell 2010
Nef
Vpu
Tetherin is a significant – but not insurmountable – barrier
to zoonotic transmission of SIVs to humans
Sauter et al., Cell Host & Microbe (2009)
HIV-1 Vpu function
M
N
O
P
Tetherin +
+
-
-
+
-
+
+
CD4
Sauter et al.,
Cell (2010)
Only the HIV-1 M Vpu is “optimally” adapted to humans
Humans and other mammals have evolved antiretroviral factors
(TRIM5a, APOBEC3G, tetherin)
As a countermeasure some „modern“ retroviruses, like HIV-1,
evolved specific tools (Vif, Vpu, Vpr, Vpx, Nef) to antagonize them
Kirchhoff,
Cell Host & Microbe (2010)
HIV-1 seems to have a countermeasure for all host defenses
Strengthening the host defenses or inhibiting
the viral antagonists may allow to regain control
Acknowledgments
Beatrice H. Hahn
Hui Li
Frederic Bibollet-Ruche
Matthis Kraus
(Alabama, USA)
Guido Silvestri
Ulrich Schubert
Jörg Votteler
(Erlangen, Germany)
Paul Bieniasz
Theodora Hatziioannou
(New York, USA)
(Philadelphia, USA)
Paul Sharp
Elisabeth Bailes
(Nottingham, UK)
Michaela Müller-Trutwin
(Paris, France)
Martine Peeters
(Montpellier, France)
Cris Apetrei
Ivona Pandrea
(Pittsburgh, USA)
Cristian Apetrei
Ivona Pandrea
(Tulane, USA)
Donald Sodora
(Seattle, USA)
Ulrich Nienhaus
Karen Clauss
(Ulm, Germany)
Molecular Virology, Ulm
Anke Specht
Daniel Sauter
Funding: DFG, EU, NIH
Thanks for your attention
???
SIVs switched between Vpu- and Nef-mediated tetherin
antagonism to cross the species barrier and to become HIV-1
Adapted from
Sauter, Specht,
Kirchhoff, Cell 2010
Human tetherin is resistant to Nef because of a deletion in its cytoplasmic region
(Jia et al., 2009; Lim et al., 2010; Sauter et al., 2009, Zhang et al., 2009)