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 suppressing HIV to undetectable stopping therapy in the blood levels

START STOP HAART

Circulating 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/ 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 – 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 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 – Genetic approaches to other disease entities Thank You!