HIV Eradication: A Fantasy or an Achievable Scientific Goal? Robert T. Schooley, M.D. Professor of Medicine University of California, San Diego HIV Eradication • Why? • How? • Who? • When? Why Should Eradication be a Goal? • Treatment – Works but it is lifelong, expensive and has side effects – Health care systems are not infinitely expandable • Prevention – Only incompletely effective in some populations – AIDS vaccine research is at best a speculative effort – Treatment as prevention works • If it is taken How? Cure has been a Goal for Nearly Two Decades 1996: Hit Hard and Hit Early Palmer, et. al., J Intern Med 2011 Creation of the Latent State CD4 Precursor Cell Uninfected SusceptibleCD4 Cell Activated Lytically Latently Infected CD4 Cell Infected CD4 Cell HIV Eradication - What We Need To Learn 1 in 106 CD4 cells HIV Reservoir Persists during ART HIV infection is characterized by Antiretroviral drugs are capable of HIV rebounds after high levels of circulating viruses suppressing HIV to undetectable stopping therapy in the blood levels START STOP HAART Circulating virus Limit of detection Time Types of Cure • Sterilizing vs. Functional cure – Functional: the host’s immune system is able to control HIV infection without help from ART. – Sterilizing: HIV is cleared everywhere. HIV Eradication – Functional Immunity Immune Enhancement 1 in 106 CD4 cells Interruption of long-term treatment started during primary infection may lead to control of viremia. Sáez-Cirión A, Bacchus C, Hocqueloux L, Avettand-Fenoel V, et al. (2013) Post-Treatment HIV-1 Controllers with a Long-Term Virological Remission after the Interruption of Early Initiated Antiretroviral Therapy ANRS VISCONTI Study. PLoS Pathog 9(3): e1003211. Enhance HIV specific immune response Therapeutic Vaccines • Concept: Induce control of HIV replication in someone who is already infected. • ALVAC-HIV-recombinant canarypox: made things worse. • Rh-CMV/SIV vector • PD-1 axis Autran et al. AIDS 2008 ACTG 5197: Design Study Week 0 4 26 38 54 250 Vaccination Phase Analytical Treatment Long-term Interruption Observation Schooley, et., al., J Infect Dis Schooley, et., al., J Infect Dis HIV Eradication – Sterilizing Immunity 1 in 106 CD4 cells Stopping Lytic Viral Replication and Activating CD4 Cells CD4 Precursor Cell Uninfected SusceptibleCD4 Cell Activated Lytically Latently Infected CD4 Cell Infected CD4 Cell HIV-1 RNA <5c/mL For > 26 weeks AZT, 3TC, Abacavir, OKT3 Nevirapine, IL-2 r/Indinavir Lymph Node Biopsies Prins, et. al. , AIDS, 1999 Dose Limiting Side Effects • Fever • Hypotension • Headache • Seizures • Nausea • Hypothyroidism • Vomiting • Acute Renal Failure • Diarrhea requiring Dialysis Prins, et. al. , AIDS, 1999 CD4 T cells dropped from 300 – 600/mm3 to <10/mm3 within an hour of OKT3 therapy In 2 of 3 patients, no CD4 cells could be found in peripheral blood during treatment; in these no HIV-1 DNA in peripheral blood. After therapy, cellular HIV-1 DNA levels returned to pre-therapy levels No detectable change in culturable HIV-1 from resting CD4 cells after therapy Prins, et. al. , AIDS, 1999 Activating T-Cells to Activate HIV-1 Playing the piano with mittens on….. Stopping Lytic Viral Infection and Activating Latent Virus CD4 Precursor Cell Uninfected SusceptibleCD4 Cell Latently Infected CD4 Cell Vorinostat (HDACi) upregulates HIV RNA expression. NM Archin et al. Nature 487, 482-485 (2012) doi:10.1038/nature11286 3B3-PE38 kills vRNA producing cells leads to a more rapid reduction in vRNA levels versus ART only Denton PW, Long JM, Wietgrefe SW, Sykes C, et al. (2014) Targeted Cytotoxic Therapy Kills Persisting HIV Infected Cells During ART. PLoS Pathog 10(1): e1003872. doi:10.1371/journal.ppat.1003872 Induction of Cellular Resistance • Stem cell approaches to replace CD4 cells and other susceptible cells with those that will not support the growth of virus – Bone marrow or stem cell transplantation – Cellular receptor modifications – δ32 CCR5 mutation – Expression of “hostile” nucleic acids • Ribozymes • mRna • siRNA HIV-1 and Secondary Receptor Tropism CXCR4 CCR5-Modified CD4 T Cells during Treatment Interruption did not decrease, unlike unmodified CD4 T cells Tebas P et al. N Engl J Med 2014;370:901-910. Who? HIV-1 Cure: The Two Successes • The Berlin Patient • The Mississippi Baby The Berlin Patient SCT x 2 Chemo and Rad CCR5 ∆∆32 GVHD CCR5 WT AML HIV CCR5 ∆∆32 No AML No HIV Hütter G et al. N Engl J Med 2009;360:692-698. The Mississippi Baby Persaud, et. al., NEJM 2013 Absence of Detectable Viremia in an HIV-1 Infected Infant Treated Early Persaud D et al. N Engl J Med 2013;369:1828-1835. When? When? • Conceptual validation has already occurred • Likely to occur earlier in selected populations – Infants – Acutely infected individuals • Chronic infection – A slower step-by-step process • Multiple compartments Moving Forward…. • Why? We might actually succeed – Many would argue that a pathway to cure is more straightforward than a pathway to a vaccine • If we fail, there are a tremendous number of things we might learn – HIV immunobiology – HIV regulation – Stem cell biology – Genetic approaches to other disease entities Thank You! .