Frank Kirchhoff Institute of Molecular Virology University of Ulm

1. Lack of Innate control of HIV Frank Kirchhoff Institute of Molecular Virology University of Ulm

2. HIV-1 maintains high viral loads despite a strong (but usually ineffective) antiviral immune response Host restriction factors and their viral antagonists

3. Humans developed a „natural combination therapy“ long before HAART TRIM5a:destabilization of the viral capsid APOBEC3G:lethal hyper-mutations Tetherin:inhibition of virusrelease Kirchhoff Cell Host & Microbe (2010)

4. Humans developed a „natural combination therapy“ long before HAART TRIM5a:destabilization of the viral capsid APOBEC3G:lethal hyper-mutations Tetherin:inhibition of virusrelease Kirchhoff Cell Host & Microbe (2010)

5. Humans developed a „natural combination therapy“ long before HAART TRIM5a:destabilization of the viral capsid APOBEC3G:lethal hyper-mutations Tetherin:inhibition of virusrelease Kirchhoff Cell Host & Microbe (2010)

6. Humans developed a „natural combination therapy“ long before HAART TRIM5a:destabilization of the viral capsid APOBEC3G:lethal hyper-mutations Tetherin:inhibition of virusrelease Kirchhoff Cell Host & Microbe (2010)

7. Humans developed a „natural combination therapy“ long before HAART TRIM5a:destabilization of the viral capsid APOBEC3G:lethal hyper-mutations Tetherin:inhibition of virusrelease Usually pretty effective: ~8% of our genome are of retroviral origin But HIV has developed effective countermeasures

8. HIV and SIV contain several small „accessory“ genes

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)

10. The cytidine deaminase APOBEC3 induces lethal G–>A hyper-mutations of the viral genome (Sheehy et al., Nature 2002) Bieniasz, Nat. Immunol. 2004

11. Vif: degrades APOBEC3 (Sheehy et al., Nature 2002) Bieniasz, Nat. Immunol. 2004

12. 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

13. 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

14. Courtesy Paul Spearman Tetherin: blocks virus releaseNeil et al., Nature 2008; Van Damme et al., Cell Host & Microbe 2008 Perez-Caballero et al., Cell 2009

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

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

17. Switches between Nef- and Vpu-mediated tetherin antagonism preceded the emergence of HIV-1

18. Vpu Nef Tetherin shows species-specific sequence variations Human tetherin is resistent to Nef adapted from Sauter et al. Cell 2010 SIVcpz/gor HIV-1 M, N

19. Only the HIV-1 M Vpu is “optimally” adapted to humans 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)

20. 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)

21. HIV-1 seems to have a countermeasure for all host defenses Strengthening the hostdefensesorinhibiting the viral antagonistsmayallowtoregaincontrol

22. Acknowledgments Beatrice H. Hahn Hui Li Frederic Bibollet-Ruche Matthis Kraus (Alabama, USA) Ulrich Schubert Jörg Votteler (Erlangen, Germany) Paul Bieniasz Theodora Hatziioannou (New York, USA) Guido Silvestri (Philadelphia, USA) Cristian Apetrei Ivona Pandrea (Tulane, USA) Paul Sharp Elisabeth Bailes (Nottingham, UK) Donald Sodora (Seattle, USA) Michaela Müller-Trutwin (Paris, France) Ulrich Nienhaus Karen Clauss (Ulm, Germany) Martine Peeters (Montpellier, France) Cris Apetrei Ivona Pandrea (Pittsburgh, USA)

23. Molecular Virology, Ulm Daniel Sauter Anke Specht Funding: DFG, EU, NIH

24. Thanks for your attention ???

25. 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)