Track A Report Guido Poli Vita-Salute San Raffaele University & Scientific Institute, Milano, Italy XVIII International AIDS Conference, Vienna, 2010

Track A - Rapporteur talk 1.HIV life cycle: road map for anti-HIV drug discovery 2.New findings in LTNP & Elite Controllers: keys for vaccine development 3.The hardest target: HIV persistence in latently infected cells and reservoirs 4.Concluding remarks

Track A - Rapporteur talk 1.HIV life cycle: road map for anti-HIV drug discovery 2.New findings in LTNP & Elite Controllers: keys for vaccine development 3.The hardest target: HIV persistence in latently infected cells and reservoirs 4.Concluding remarks

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

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

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

Track A - Rapporteur talk 1.HIV life cycle: road map for anti-HIV drug discovery 2.New findings in LTNP & Elite Controllers: keys for vaccine development 3.The hardest target: HIV persistence in latently infected cells and reservoirs 4.Concluding remarks

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 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.

Protective HLA-B Alleles Limit HIV Infection of CD4+ (central) Memory Cells TNTN T CM T TM T EM % infected CD4 T cells subsets Benjamin Descours, Paris, France

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

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.

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 LTNP Naïve

Track A - Rapporteur talk 1.HIV life cycle: road map for anti-HIV drug discovery 2.New findings in LTNP & Elite Controllers: keys for vaccine development 3.The hardest target: HIV persistence in latently infected cells and reservoirs 4.Concluding remarks

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

Deciphering the Transcriptional Complex Recruited by HIV-1 Tat… Pol- II Tar-RNACT D PS-5 NTEF s Latent provirus / stalled LTR Pol- II CT D PS-5 Transactivato r CDK9 CycT1 PS-2 P-TEFb NTEF s Drugs:TSA, Prostratin,… Activated provirus Monsef Benkirane, Montpellier, France

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

Track A - Rapporteur talk 1.HIV life cycle: road map for anti-HIV drug discovery 2.New findings in LTNP & Elite Controllers: keys for vaccine development 3.The hardest target: HIV persistence in latently infected cells and reservoirs 4.Concluding remarks

The Track A Rapporteur’s Team! Rienk Jeeninga (The Netherlands) Rienk Jeeninga (The Netherlands) Lavina Garu (India) (India) Patricia Monteiro (Canada) (Canada) Takafira Mduluza (Botszwana) (Botszwana)