Frank Kirchhoff Institute of Molecular Virology University of
Ulm Lack of Innate control of HIV
Slide 2
HIV-1 maintains high viral loads despite a strong (but usually
ineffective) antiviral immune response Host restriction factors and
their viral antagonists
Slide 3
Kirchhoff Cell Host & Microbe (2010) Humans developed a
natural combination therapy long before HAART TRIM5 :
destabilization of the viral capsid APOBEC3G: lethal
hyper-mutations Tetherin: inhibition of virus release
Slide 4
Kirchhoff Cell Host & Microbe (2010) Humans developed a
natural combination therapy long before HAART TRIM5 :
destabilization of the viral capsid APOBEC3G: lethal
hyper-mutations Tetherin: inhibition of virus release
Slide 5
Kirchhoff Cell Host & Microbe (2010) Humans developed a
natural combination therapy long before HAART TRIM5 :
destabilization of the viral capsid APOBEC3G: lethal
hyper-mutations Tetherin: inhibition of virus release
Slide 6
Kirchhoff Cell Host & Microbe (2010) Humans developed a
natural combination therapy long before HAART TRIM5 :
destabilization of the viral capsid APOBEC3G: lethal
hyper-mutations Tetherin: inhibition of virus release
Slide 7
Humans developed a natural combination therapy long before
HAART TRIM5 : 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
Slide 8
HIV and SIV contain several small accessory genes
Slide 9
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)
Slide 10
Bieniasz, Nat. Immunol. 2004 The cytidine deaminase APOBEC3
induces lethal G>A hyper-mutations of the viral genome (Sheehy
et al., Nature 2002)
Target Cell Entry viral RNA, Gag and Pol proteins Envelope
protein Infected Cell Release Assembly Nuclear import integration
Reverse transcription Courtesy Paul Bieniasz TRIM5 TRIM5 : a
capsid-specific restriction factor (Stremlau et al., Nature 2004)
HIV-1 is blocked by simian but not human TRIM5
Slide 13
Adapted from Ho & Bieniasz Cell, 2008 ABOBEC3G & TRIM5
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
Adaptation of SIVcpz to chimpanzees paved the way for the spread of
HIV-1 in humans: SIVcpz is resistant against human ABOBEC3G &
TRIM5
Slide 14
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
Slide 15
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
Slide 16
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
Slide 17
Switches between Nef- and Vpu-mediated tetherin antagonism
preceded the emergence of HIV-1
Slide 18
Tetherin shows species-specific sequence variations Human
tetherin is resistent to Nef Nef Vpu adapted from Sauter et al.
Cell 2010 SIVcpz/gor HIV-1 M, N
Slide 19
Tetherin is a significant but not insurmountable barrier to
zoonotic transmission of SIVs to humans Sauter et al., Cell Host
& Microbe (2009) M N O P Tetherin CD4 + + - - + - + + HIV-1 Vpu
function Only the HIV-1 M Vpu is optimally adapted to humans Sauter
et al., Cell (2010)
Slide 20
As a countermeasure some modern retroviruses, like HIV-1,
evolved specific tools (Vif, Vpu, Vpr, Vpx, Nef) to antagonize them
Humans and other mammals have evolved antiretroviral factors (TRIM5
, APOBEC3G, tetherin) Kirchhoff, Cell Host & Microbe
(2010)
Slide 21
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
Slide 22
Beatrice H. Hahn Hui Li Frederic Bibollet-Ruche Matthis Kraus
(Alabama, USA) Michaela Mller-Trutwin (Paris, France) Martine
Peeters (Montpellier, France) Paul Sharp Elisabeth Bailes
(Nottingham, UK) Guido Silvestri (Philadelphia, USA) Ulrich
Schubert Jrg Votteler (Erlangen, Germany) Paul Bieniasz Theodora
Hatziioannou (New York, USA) Cristian Apetrei Ivona Pandrea
(Tulane, USA) Ulrich Nienhaus Karen Clauss (Ulm, Germany) Donald
Sodora (Seattle, USA) Acknowledgments Cris Apetrei Ivona Pandrea
(Pittsburgh, USA)
Slide 23
Molecular Virology, Ulm Funding: DFG, EU, NIH Daniel SauterAnke
Specht
Slide 24
Thanks for your attention ???
Slide 25
SIVs switched between Vpu- and Nef-mediated tetherin antagonism
to cross the species barrier and to become HIV-1 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) Adapted from Sauter, Specht, Kirchhoff, Cell 2010
