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

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Presentation on theme: "Frank Kirchhoff Institute of Molecular Virology University of Ulm Lack of Innate control of HIV."— Presentation transcript:

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

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

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

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

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

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

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

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

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

12 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 

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 

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

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 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

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 CD HIV-1 Vpu function Only the HIV-1 M Vpu is “optimally” adapted to humans Sauter et al., Cell (2010)

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)

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

22 Beatrice H. Hahn Hui Li Frederic Bibollet-Ruche Matthis Kraus (Alabama, USA) Michaela Müller-Trutwin (Paris, France) Martine Peeters (Montpellier, France) Paul Sharp Elisabeth Bailes (Nottingham, UK) Guido Silvestri (Philadelphia, USA) Ulrich Schubert Jörg 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)

23 Molecular Virology, Ulm Funding: DFG, EU, NIH Daniel SauterAnke Specht

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 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


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