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XVIII International AIDS Conference, Vienna, 2010

Track A Report Guido Poli Vita-Salute San Raffaele University & Scientific Institute, Milano, Italy. XVIII International AIDS Conference, Vienna, 2010 . Track A - Rapporteur talk. HIV life cycle: road map for anti-HIV drug discovery

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XVIII International AIDS Conference, Vienna, 2010

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  1. Track A ReportGuido PoliVita-Salute San Raffaele University & Scientific Institute, Milano, Italy XVIII International AIDS Conference, Vienna, 2010

  2. Track A - Rapporteur talk • HIV life cycle: road map for anti-HIV drug discovery • New findings in LTNP & Elite Controllers: keys for vaccine development • The hardest target: HIV persistence in latently infected cells and reservoirs • Concluding remarks

  3. Track A - Rapporteur talk • HIV life cycle: road map for anti-HIV drug discovery • New findings in LTNP & Elite Controllers: keys for vaccine development • The hardest target: HIV persistence in latently infected cells and reservoirs • Concluding remarks

  4. The HIV Life Cycle... Courtesy of Anthony S. Fauci, Bethesda, USA

  5. …Road Map for Anti-HIV Drug Discovery Courtesy of Anthony S. Fauci, Bethesda, USA

  6. …Road Map for Anti-HIV Drug Discovery TBR-652 (D.E. Martin) LEDGINs (F. Christ)

  7. Track A - Rapporteur talk • HIV life cycle: road map for anti-HIV drug discovery • New findings in LTNP & Elite Controllers: keys for vaccine development • The hardest target: HIV persistence in latently infected cells and reservoirs • Concluding remarks

  8. Natural Control of HIV Infection • Long-Term Non Progressors (LTNP) • >7-10 years of infection • No therapy • No symptoms • Stable CD4+ T-cell counts > 500/mm3 • 1-5 % of all infected individuals • Elite & Viremic Controllers* • plasma viremia < 50 copies/ml for >1 year • No therapy • *As above, but with viremia <2,000 copies/ml • <1% of all infected individuals Adapted from Sara Rowland-Jones, Oxford, U.K.

  9. TCM Protective HLA-B Alleles Limit HIV Infection of CD4+ (central) Memory Cells TTM TEM TN % infected CD4 T cells subsets Benjamin Descours, Paris, France

  10. p=0.0159 p=0.0079 p21 b-actin HIV neg EC progressors 2 4 2 4 1 1 3 3 5 5 2 4 1 3 n=5 n=5 n=4 HIV neg EC progressors CD4+ T cells from Elite Controllers Resist HIV-1 Infection by Upregulation of p21 • Inhibitor of Cyclin-dependent kinases • Contributes to resistance of monocyte/macrophages and hematopoietic stem cells to HIV-1 infection • Interferes with HIV-1 both pre- and post-proviral DNA integration Mathias Lichterfeld, Boston, USA

  11. MicroRNA Expression Pattern May Discriminate HIV Exposure from Infection • miRNAs are short RNA molecules that bind to complementary sequences in the 3' UTR of target mRNAs, usually resulting in gene silencing • The human genome may encode over 1,000 miRNAs,targeting about 60% of mammalian genes • Aberrant expression of miRNAs has been implicated in numerous diseases; miRNA-based therapies are under investigation.

  12. MicroRNA Expression Pattern May Discriminate HIV Exposure from Infection • MEU (multiply Exposed Uninfected) show a prevalent downregulation of miRNAs • LTNP show a prevalent upregulation of miRNAs Claudio Casoli, Milano, Italy MEU Naïve LTNP

  13. Track A - Rapporteur talk • HIV life cycle: road map for anti-HIV drug discovery • New findings in LTNP & Elite Controllers: keys for vaccine development • The hardest target: HIV persistence in latently infected cells and reservoirs • Concluding remarks

  14. HAART Gene therapy Inhibit HIV replication shRNA (tat/rev, TAR) Reduce CCR5 Potential Approaches Towards “The Cure” (i.e., HIV Eradication) Activated CD4+ T-cell Resting CD4+ T-cell Sharon R. Lewin, Melbourne, Australia

  15. Transactivator CDK9 CycT1 Deciphering the Transcriptional Complex Recruited by HIV-1 Tat… Drugs:TSA, Prostratin,… P-TEFb PS-2 CTD Tar-RNA CTD PS-5 PS-5 Pol-II Pol-II NTEFs NTEFs Latent provirus / stalled LTR Activated provirus MonsefBenkirane, Montpellier, France

  16. …An Important Lead to New HIV Drug Discovery PAF1 CDC73 Processive elongation Activating signals CDK9 CDK9 CycT1 CycT1 Latency Core P-TEFb Virus Production Active/elongating P-TEFb Structure of the Tat associated P-TEFbcomplex may provide opportunities to design inhibitory peptides or reactivate latent HIV-1 and purging the reservoirs AFF1 AFF4 EAF1 ELL ENL AF9 MonsefBenkirane, Montpellier, France)

  17. Track A - Rapporteur talk • HIV life cycle: road map for anti-HIV drug discovery • New findings in LTNP & Elite Controllers: keys for vaccine development • The hardest target: HIV persistence in latently infected cells and reservoirs • Concluding remarks

  18. The Track A Rapporteur’s Team! RienkJeeninga (The Netherlands) TakafiraMduluza (Botszwana) LavinaGaru (India) Patricia Monteiro (Canada)

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