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Moving Toward a CureWhere are We Now?

Steven Deeks, MDProfessor of MedicineUniversi ty of Cal i fornia, San Francisco

Disclosures

• Research support–Merck–ViiV–Gilead

HIV Cure: DefinitionsCure versus remission

• Cure: complete eradication of all HIV•HIV antibody negative (no stigma)• Likely achieved with the Berlin Patient• Impossible to prove

HIV Cure: DefinitionsCure versus remission

• Remission: HIV persists but does not cause disease–HIV antibody infected (stigma)–HIV-associated morbidity (inflammation)

will likely persist

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HIV “Cure”: Target Product Profile

Efficacy: aviremia in absence of therapy > 2 years; early failure is tolerable, late failures must be rareProduct: oral/parental; administered for limited period of time (e.g., 6 months); specialized (tertiary) care not requiredTarget Population: effective ART initiated at any stage and in all populations (gender, subtype), CD4+ T cell count > 350 cells/mm3

Long-term safety: comparable to ART, transmission risk negligibleCost: < $1400 (RLS)

HIV Cure: DefinitionsReservoir

• Population of replication-competent HIV that persists during ART and ignites new rounds of replication when ART is stopped

• Rare, tissue-based, may be impossible to directly measure

• VRC01: 2018• HIV-specific

tracers (Merck): 2019

Viable pathways toward a cure

Gene and cell therapyEarly ARTShock and killImmunotherapy

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Viable pathways towards a durable remission/cure: Gene therapy

• Gene and cell therapy–Development of an HIV-resistant

immune system–Excision of replication-competent HIV

(CRISPR)• Approach supported by success of the

Berlin Patient and the near-success of the Boston Patients

Viable pathways towards a durable remission/cure: Early ART

• Prevention of latency – PEP– Mississippi baby

AtaboutthetimeHIVRNAbecomesdetectable,thereservoirsizebeginstoincreasedramatically,withanapparent100-foldincreaseoverthenexttwoweeks

Reservoirlargelyestablishedbyweek4ofinfection

Viable pathways towards a durable remission/cure: Shock and kill

• Shock and kill– Reservoir reduction leading to complete or

near-complete eradication of the replication-competent virus production

• Approach supported by recent success in reversing latency in vivo and perhaps reducing reservoir size (at least in NHPs)

Unless all virus is eradicated (which might not be possible) some durable host mechanism of control will be needed to

prevent late failures

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• A single cell containing latent HIV can reignite viral replication at any time

• The impact on the health of the “cured” person and his or her sexual partner can be profound

Viable pathways towards a durable remission/cure: Immunotherapy

• Durable host-mediated control of HIV (“remission”)

• Zero tolerance for persistent viremia at a level that might be associated with transmission

• May not fully restore immune health

• Approach inspired by observations made in elite controllers and advances in cancer immunotherapy

Correlate Author

↓ HIV replication in autologous CD4 cells (mediated by CD8 cells)

Saez-Cirion, PNAS 07; Quigley NM 10

↑ CD8+ T cell proliferation Migueles, Nat Imm 02, Betts Blood 06, Horton, JI 2006

↑ CD4+ T cell proliferation and CD4 “help” Lichterfeld, JEM 04; Emu JV 05; Tilton JV 07; Ferre JV 10; Chevalier JV 11; Soghoian STM 12; Ranasinghe NM 13

↑ CD8 TCR diversity and clonal turnover Almeidia, JEM 07↑ IL2 production (HIV-specific CD4 and CD8) Zimerali PNAS 05; Emu JV 05; Ferre Blood

09↓ CD38 (HIV-specific CD8) Saez-Cirion PNAS 07↓ CTLA-4 (HIV-specific CD4 cells) Kaufmann Nat Imm 07↓ Immune blockade (PD-1) Zhang Blood 07; Quigley NM 10↑ Perforin/granzyme killing Migueles Immunity 08; Hersperger PLoS

Path 10 & Blood 11↑ Gag-specific degranulation, cytokines Betts, Blood 06; Zimmerli, PNAS 05;

Almeida, JEM 07↑ HIV-specific central memory van Grevenynghe NM 08; Ndhlovu JV 15↓ T reg number/function Nilsson Blood 06, Favre STM 10, Shaw JV 11,

Elahl NM 11, Hunt PLoS ONE 11

HIV Remission: Lesson from studies of “elite” control

• 20 adults (and one child) who started therapy early, remained on therapy for years, and had only transient rebound after stopping therapy

• Correlates: Low reservoir size, low T cell activation and as of yet a poorly defined immune mechanism of control

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All models of durable SIV/HIV remission suggest that durable control of established infection will require (1) low disease burden, (2) low inflammation and (3) sustained T cell responses that are primed, reside in tissues, and target susceptible epitopes

These same attributes apply to cancer immunotherapy

Immunotherapy for HIV infectionTwo decades of largely failed approaches

• Weak immunogenicity– Pre-existing immuno-dominant responses– CTL escape

• Inflammation and counter-regulatory immunosuppression

• High virus burden• Immune-privileged tissues sanctuaries

Immunotherapy and HIV remission

Enhanced T cell immunityInhibition of harmful inflammatory responsesLow disease burden (reservoir)Disruption of sanctuariers

CTL escape emerges during early HIV infection and gets deposited in “reservoir”

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T cell vaccines generally expand those pre-existing immunodominantclonotypes that failed to control the initial infection High levels of tissue-based CD8+ T-effector cells that recognize unusual

and diverse epitopes, including those restricted by class II MHC molecules

Borducci/Barouch, Nature 2016

Ad26/MVA prime-boost vaccine with TLR7 agonist reduces reservoir during ART and controls SIV post-ART, with 3/10 animals exhibited durable “remission”

Immunotherapy and HIV remission

Enhanced T cell immunityInhibition of harmful inflammatory responsesLow disease burden (reservoir)Disruption of sanctuariers

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HuntetalJID2003,PLoS ONE2011andunpublished

T-cell “activation” is lower in treated than untreated adults, but consistently higher than “normal”

Similar trends consistently observed with multiple measures of inflammation, including IL-6, sCD14, sCD163 and PD-1 expression of T cells

Oncology model: The inflammatory response in cancer tissue stimulates a potent and durable anti-inflammatory response

Pauken andWherry,Cell,2015.Zarour HM,ClinicalCancerResearch,2016.

McKinneyetal.,Nature,2015.

Chronic antigen exposure (infection, cancer, autoimmunity) leads to T cell dysfunction

• CITN 12: Phase I Study of pembrolizumab (anti-PD-1) in patients with HIV and relapsed/refractory or disseminated malignant neoplasm

• AMC 095: Phase I study of ipilimumab (anti-PD-1) and nivolumab (anti-CTLA-4) in advanced HIV-associated tumors (including anal CA and KS)

Careful assessment of safety and efficacy of immunotherapies in HIV/cancer will provide pathway for developing curative interventions

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Sirolimus (rapamycin)—which reduces T cell activation and T cell proliferation and enhances generation of memory—is associated with low “reservoir” size post-renal transplant

Immunotherapy and HIV remission

Enhanced T cell immunityInhibition of harmful inflammatory responsesLow disease burdenDisruption of sanctuaries

Reservoir prevention/reductionAny curative intervention will almost certainly work better in a low reservoir state

• Early ART• Shock and kill

Estimated Months since HIV Infection

Plas

ma

HIV

-1 R

NA

(cop

ies/

mL)

0 2 4 6 8 10 1210

100

1000 PrEP Baseline VisitDay 10 of HIV infectionWT Subtype B virusTDF/FTC started

Day 18 of HIV infectionDRV/r/RGV/TDF/FTCstarted

*

HIV RNA: 4.7 copies/mil CD4HIV DNA: ND

Rectum/LeukapheresisHIV RNA/DNA: ND

Viral outgrowth assay, TILDA: ND

Estimated Day of HIV Infection:Days 10, 17, 27, 32, 46, 67: WB indet (p55 only)Day 130: WB non-reactive

LLOD(<40copies/mL)

HIV DNA(ddPCR) x2: ND

Ultrasensitive plasma HIV RNA(<0.06 copies/mL): NDTotal Inducible Virus Recovery: NDHIV DNA: ND

LN, ileum/rectum: ND

CSF,BM: ND

Lack of Detectable HIV DNA in a PrEP Study Participant Treated During “Hyperacute” Infection

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HIV“shock”therapyhasworkedintheclinicbuthasfailedtoreducereservoir

Immunotherapy and HIV remission

Enhanced T cell immunityInhibition of harmful inflammatory responsesLow disease burden (reservoir)Disruption of sanctuariers

SIV RNAscope staining of Lymph Node

Transient disruption of the B cell follicle with anti-CD20 antibodies enables CTL-mediated elimination of SIV (and perhaps HIV)

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Experimental medicine

Large immunotherapy program now emerging for HIV cure

Probe studies: safety feasibility, biologic activity

α4β7integrinexpressionenablesmigrationofTcellstogutmucosa(siteofmassiveHIVreplication)

Anti-α4β7integrinantibodyadministrationduringARTincreasedmucosalCD4+TcelllevelsandreducedmucosalSIVDNA

TreatedanimalscontrolledSIVpost-ART

Combination strategies will likely be needed to achieve a durable remissionA number of viable combinations should be available for testing in a few years

HIV Remission

Enhanced CTLVaccine

Adjuvants (TLR)

Reverse immune suppression

Immune-modifiersICBs

Low ReservoirShock and Kill

Early ART

SanctuariesB cell follicle

distuption

Acknowledgements