Hot Topics in HIV. Barcelona PDF Free Download

Hot Topics in HIV. Barcelona 2018 Paving the way to an AIDS-free World. Mario Stevenson, PhD. Department of Medicine.

Reproductive Cycle of HIV and Sites of Action of Major Classes of Antiretroviral Medications (25 options) Fusion Inhibitors CCR5 Antagonists Reverse Transcriptase Inhibitors (RTI) Nucleoside RTI (NRTIs) Nonnucleoside RTI (NNRTIs) Integrase strand transfer inhibitors (INSTI) Protease inhibitors (PI) Gandhi M, Gandhi RT. N Engl J Med 2014;371:248-259.

Closing the Gap : Life Expectancy With current ART, 20 yo HIV+ adult is expected to live into their early 70s Mid-point life expectancy at age 20 Lower life expectancy in patients who start ART with CD4 count <350 Non-whites and IDUs also have shorter lifeexpectancies Samji H et al, PLoS One, 2013

What is driving the search for a cure? Current therapies are extremely effective - reduced pill burden, fewer side effects. Virus in blood can be reduced to undetectable levels for years. Why not maintain the status quo and go with life-long ART?

Why do people want to be cured?

Aside from the personal perspective, limitations in ART drive a global rationale for cure Courtesy: Steve Deeks

Despite massive global investment, less than 50% of global population is on ART with an undetectable viral load Sustained virus control is even less common A major limitation with current therapeutic strategies is the need to access and adhere to daily intervention for many decades

Global ART, in its current form, is still an elusive target. Long-acting antiretroviral formulations will improve adherence With more effective ART, will there still be a robust rationale for a practical and scaleable cure?

HIV Cure versus Remission No virus No stigma Impossible to prove Virus persists Stigma, inflammation Much easier to achieve Courtesy: Steve Deeks

What are the viable strategies by which a cure or remission might be achieved?

Viable pathways toward a durable remission/cure Gene and cell-based therapy Shock and kill Block and lock Early ART Remission (immunotherapy)

Gene and Cell-based Therapies

Viable pathways toward a durable remission/cure Gene and cell-based therapy Proof of concept: Berlin Patient Allogeneic stem cell transplant: several nearcures Multiple feasible pathways, including direct excision of provirus Will this ever be scalable on a global level and safer than ART? Targeting of infected cells will be challenging

Gene Therapy for HIV- no specific markers on latently infected cells to enable specific vector targeting

Shock and Kill

Viable pathways towards a durable remission/cure: Shock and kill Multiple latency reversing agents (LRAs) tested: effect is modest at best and inconsistent Basic discovery aimed at identifying novel pathways or combinations

Multiple latency reversal agents active in vitro Kim, Anderson and Lewin. Cell Host Microbe 2018 An alternate strategy involves locking down proviral activity

Block and Lock

Viable pathways toward a durable remission/cure Block and lock Most proviruses are difficult to reactivate ex vivo Permanent latency may be inducible by inhibiting tat or several host pathways, including mtor

Early ART

Viable pathways towards a durable remission/cure: Early ART Prevention of latency Preservation of immune function Post-treatment control

Can early ART prevent the establishment of a latent reservoir, leading to a cure?

If no durable and sustained host response is present, a single virus can cause acute infection at any time, posing major risk to the individual and his or her sexual partners

Very early ART reduces the reservoir but is not curative N=8; ART in Fiebig I for >96 weeks; VL<50 c/ml; CD4>400 cells/ul Ananworanich J et al., CROI2017, Seattle, WA

Immunotherapy Encouragement from monkey but not human studies

Curing monkeys has proven to be relatively easy

Some (10% to 25%) of people who start therapy early (but not too early) and remain on therapy for years will exhibit at least partial control after ART is interrupted May occur in chronic infection (rare) No biomarker Mechanism unknown Low reservoir size, low T cell activation Classic CTL responses low, in contrast to elite controllers Non-cytolytic NK cell responses

Studies of elite control, post-treatment control, and postvaccine control all suggest that the immune system can effectively control HIV but mechanisms remain undefined Antibodies Dendritc Cells T cells NK Cells Courtesy: Steve Deeks

Immunotherapy for HIV infection Two decades of largely failed approaches Weak immunogenicity Pre-existing immuno-dominant responses that are dysfunctional CTL escape Inflammation and counter-regulatory immunosuppression High virus burden Immune-privileged tissue sanctuaries

Immunotherapy to enhance T cell function

Similarities between HIV persistence and cancer HIV Cancer Increased immune checkpoint markers on antigen-specific cells Epigenetically programmed exhausted T-cells (Tex) Reduce antigen burden Antiretroviral therapy Chemotherapy Radiotherapy Surgery Long lived forms Slow cycling Indefinite proliferative potential HIV latency Cancer stem cells Sharon Lewin

Latent HIV is enriched in CD4+ T-cells that express PD1, TIM3 and TIGIT CD8+ T cell dysfunction reversed in HIV-infected individuals on ART ex vivo with inhibitors of PD-1, CTLA-4 and TIGIT

Tissue sanctuaries Follicular disruption

B cell follicles: a relative sanctuary and may be a site for cryptic replication CD20 antibodies and IL-15 may break down barrier Fukazawa et al., Nature Med 2015; Banga et al., Nature Med 2016; Leong et al., Nature Immunol 2016

Supplemental Figure 1 CD8 and CD20 staining of axillary lymph node (Rh24827) CD20 (white) and CD8 + (red) staining of axillary node B cell follicle: a relative sanctuary for HIV as CD8+ effector T cells are excluded from B cell

Where are we in 2018?

HIV Cure 2018: Elimination and cure Reducing the reservoir size is possible with early ART and transplantation but the effect is incomplete and not scalable Proof-of-concept exists for most steps in the shock and kill strategy but this approach is not expected to be fully curative Block and lock remains promising but has yet to be tested in the clinic

HIV Cure 2018: Immunotherapy and remission Using immunotherapy (particularly in combination) to reduce and control the reservoir may be the most promising approach Post-treatment control provides proof-of-concept that a durable and effective host response can be induced therapeutically Cancer immunotherapy provides further evidence that the immune system can be retrained to effectively target rare diseased cells that exist in hard-to-reach tissues Correlates of control unknown, making treatment interruptions the only interpretable outcome

HIV Cure : Target Product Profile Efficacy: aviremia in absence of therapy > 2 years; early failure is tolerable, late failures must be rare Product: administered for limited period of time (e.g., 6 months); specialized (tertiary) care not required Target Population: effective ART initiated at any stage and in all populations Long-term safety: comparable to ART, transmission risk negligible Cost: < $1400 (RLS)

Health care expenditure in Africa is far below other nations

Is a global HIV cure realistic? The realities of global ART leave millions vulnerable and drive the rationale for curing, rather than treating, infection. Advances in long term formulation may offer a safer, scaleable and more practical solution, particularly in LMICs

HIV Cure Research in Africa Increasing cure research in Africa is urgently needed What do those living with HIV in Africa want from a cure? Will remaining antibody-positive remain a key source of stigma? What will a cure need to cost to be effective? What can be practically given in non-urban health care clinics? Will HIV subtype have an impact on the effectiveness of current cure interventions? Most vaccines are based on subtype B Will host factors unique to to the dominant African population be important? Current studies enrolled older, primarily white men-who-have-sex-with men who have been on long-term ART (decades) Will persistent inflammation be a concern? Will common prevalent co-infection affect or preclude the use immunotherapy?

Delivery of potent neutralizing antibodies using AAV The only protein expressed from AAV vector comes from the transgene put into it Proven ability to achieve long-term expression of the transgene product Outstanding safety record in human gene therapy trials Little or no integration of AAV vector DNA into host genome sequences

Delivery of potent neutralizing antibodies using AAV An SHIV-infected monkey The was only protein injected expressed with from AAV AAV expressing two potent antibodies vector comes from the transgene put into it One year later, the monkey has been cured! This is unexpected given Proven what ability we to think achieve we long-term know expression of the transgene product about how HIV persists in the body Outstanding safety record in human gene therapy trials Little or no integration of AAV vector DNA into host genome sequences

20 adults (and one child) who started therapy early (but not in hyperacute stage), remained on therapy for years, and had no rebound after stopping therapy Virus still remains detectable in blood but under control-even in absence of ARTfunctional cure?

Mississippi baby born to an HIV-positive mother who had not received antiretroviral treatment during pregnancy. Infant was treated from 30 hours after birth but parents stopped therapy after 18 months. Infant remained off drugs for next 27 months yet virus remained undetectable in blood until virus rebounded two months shy of infant s 4 th birthday.

44 million HIV infections; 1 validated cure, Timothy Brown (Berlin Patient) What was different about this case?

44 million HIV infections; 1 validated cure, Timothy Brown (Berlin Patient) Infected 1995. On ARVs until 2006 where he develops acute myeloid leukemia. Fails chemotherapy then receives two bone marrow transplants from a donor who had a mutation in CCR5- a co-receptor for the virus. 8 years later, virus is undetectable in all tissues even though Timothy Brown is not on therapy.

How was the Berlin Patient (Tim Brown) Cured? Total body irradiation, anti-thymocyte globulin, graft vs. host disease may have eliminated virus producing cells Donor cells may have been protected from HIV because of lack of CCR5 (coreceptor) CCR5 -/- TBI GvH ATG Slide courtesy R Gandhi Chronically producing cell How do we apply the lessons from this cure without incurring risks of stem cell transplant?

Lesson: not being able to detect HIV doesn t mean it s not there! We need more sensitive and accurate measures.

While there has been one hit and some near misses, these examples have galvanized the field to develop a cure for HIV-1 infection!

Strategies for eliminating HIV-1 infection!

What do I need to do to be cured of HIV? Current Cure Strategies Induce HIV expression to make cells vulnerable to clearance Enhance elimination of HIV expressing cells Stimulation & recruitment of CD8+ CTLs, Monocytes, NKs Y Y Effector antibodies targeted to cells expressing HIV envelope Modify host CD4 cells to make them impervious to HIV Courtesy of John Mellors

Fold HIV induction Combination Latency Reversing Agents (LRA): More Effective Induction of HIV expression Single LRA Combo LRA HDAC inhibitor + protein kinase C (PKC) agonist more effective at inducing HIV expression than either is alone However, concerns regarding toxicity of PKC agonists. Laird G et al JCI, 2015

TLR-7 Agonist Toll-like receptor-7 (TLR-7) Expressed by plasmacytoid dendritic cells and B cells TLR-7 agonist: Enhances NK, T and B cell activation Induces HIV expression Promising results in SIV+ ART-treated macaques Now in human trials Whitney Nature Med 2018 V1 V2 24 48 72 168 0 24 48 72 168 0 3. When ART stopped, 2 of 9 animals did not have SIV rebound 1. Induces SIV viremia (LRA) Vehicle No stimulation Pre-TLR7 Post 10th Post 19th Post 19th 24 48 72 168 0 No stimulation 24 48 72 168 0 Pre-TLR7 Post 10th Post 19th 24 48 72 168 0 Post 19th 24 48 72 168 0 No stimulation 24 48 72 168 0 Pre-TLR7 Post 10th Post 19th Post 19th 24 48 72 168 2. Reduces SIV reservoir 10 5 10 4 10 3 10 2 10 1 0 No stimulation 24 48 72 168 0 Pre-TLR7 Post 10th Post 10th 24 48 72 168 Placebo GS-986 (0.1mg/kg) GS-9620 (0.05mg/kg) GS-9620 (0.15mg/kg) 7 PBMC LN PBMC LN PBMC LN PBMC LN 10 162-09 344-10 293-09 177-10 10 6 305-10 280-10 288-10 295-10 304-10 341-10 412-10 ConA ConA ConA ConA 0 Post 10th

Modify CD4 cells to make them impervious to HIV (Gene Therapy) Infusion of autologous CD4 cells in which CCR5 gene (encodes HIV coreceptor) excised by zinc-finger nuclease Modified CD4 cells: half-life 48 wks Modified cells decline less during ART interruption than unmodified cells ( 1.8 vs. 7.25 cells/day) During ATI, HIV RNA undetectable in 1 participant (heterozygous for CCR5 delta 32) Modifying CD34+ hematopoietic Stem/Progenitor Cells with anti-hiv Gene Transfer Construct and fusion inhibitor CRISPR/Cas9: host cell modification or proviral editing We need to understand how to more efficiently and feasibly modify host cells to resist infection

Broadly neutralizing antibodies (bnabs) Potent neutralization of broad variety of HIV isolates Can be engineered to prolong halflife or improve immune function Bispecific antibodies, dual affinity retargeting antibodies; vectored delivery In human studies: Reduce HIV RNA levels Delay HIV rebound when ART stopped Being tested for HIV prevention, treatment and reservoir reduction gp41 MPER: 2F5, 4E10 10e8 Trimer (gp120/41) 8ANC195 PGT151 35022 Cell Membrane V1V2 Glycan: PG6, PG16, CH01-04 PGT141-45, PGDM1400 CAP256- VRC26 CD4 Binding Site: VRC01, PG04, CH31 3BNC117, 12A12 CH103, VRC07-523 N332 Glycan Supersite: PGT121, PGT128 10-1074 Caskey M et al, Nature 2015; Lynch R et al, Sci Transl Med 2015; Mascola JR, CROI 2016, plenary. Bar K et al, NEJM, 2016 Scheid JF et al, Nature, 2016 Caskey M et al, Nat Med, 2017

Immune Therapy with bnabs Time to HIV RNA 200 after ART withdrawal VRC01 only slightly delays viral rebound when ART is stopped; viral resistance emerges (ACTG A5340) Bar et al, NEJM, 2016 VRC01 in patients on ART does not clear infected cells or reduce low-level residual viremia (ACTG A5342). Riddler S et al, CROI 2017, abstract 330LB Combining different bnabs is under evaluation May need to combine antibodies or other interventions that mediate killing of infected cells with latency reversing agents that induce HIV expression

Although bnabs hold tremendous promise, stable delivery is likely to be a challenge. AAV for sustained bnab delivery!

Can we cure HIV? Thus far, HIV has been cured only under extraordinary circumstances HIV cure remains an aspirational goal. Studies underway to test new ways of reversing latency and clearing infected cells. Combination approaches likely to be needed. Increased knowledge of mechanisms of HIV persistence, how to measure the reservoir, and how to reduce the reservoir are needed if we are to cure HIV. Given safety of antiretroviral therapy and uncertainties regarding risks of new interventions, cure studies must adhere to the highest scientific and ethical standards.

World AIDS Day, 2013:... the United States should be at the forefront of new discoveries into how to put HIV into long-term remission without requiring lifelong therapies -- or, better yet, to eliminate it completely. Patient: One day I d love to say, I used to have HIV.

Potential Barriers to Cure; Anatomic Sanctuaries Pharmacologic sanctuaries Anatomic sanctuaries Central nervous system Infected cells may persist in lymph node germinal centers 1-2, which exclude cytotoxic T cells Paiardini and Lichterfeld, Nature Med, 2016 1. Fukazawa Y et al, Nat Med 2015. 2. Banga R et al, Nat Med, 2016;

Antibody approaches to cure Antibody-based strategies are made possible by an incredible array of antibodies with potent neutralizing activity against a broad range of HIV-1 isolates that have been isolated and characterized over the last several years

Strategy # 2: Improve Elimination of HIV Infected Cells ( Kill ) Antibodies to enhance elimination of infected cells Antibody-dependent cytotoxicity? Enhance HIV specific immunity using therapeutic vaccination Ad26/MVA; CMV vector; ChAd/MVA Reverse immune exhaustion of HIV-specific T Cells Anti PD1, Anti PD-L1 Improve function of HIV specific CD8 cells Ex vivo education : HIV Antigen Expanded T cell therapy (HXTC) Genetic modification (chimeric antigen receptor or CAR T cells) Challenge: HIV escape mutations in latently infected cells 1 1 Deng K et al, Nature, 2015

Summary! Reservoir of long-lived, latently infected CD4+ T cells as well as macrophages (CNS?). Residual viral replication and potential replenishment of viral reservoirs. Reservoir may be dynamic. Cure strategies that target active and dormant viral reservoirs may be required to achieve complete viral elimination.

Colleagues/Collaborators/Contributors: University of Miami Natasha Sharova Mark Sharkey Dunja Babic Francesc Cunyat Moira Vignoles David Watkins IRSI Caixa, Barcelona Ventura Clotet Javier Picado Julia Blanco Roger Paredes University of Minnesota Tim Schacker Ashley Haase UCSF Steve Deeks Mike McCune DARE Collaboratory University of Nebraska Courtney Fletcher NIAID NIMH

Cautionary Tale - 1 Mississippi child: Born to HIV-infected mother; started on ART within 30 hrs of birth; treated for 18 months, then lost to follow-up When re-engaged in care, undetectable plasma HIV RNA 27 months later: Persaud D et al, NEJM, 2013; Luzuriaga K et al, NEJM 2015.

In some surveys, stigma is the major driving motivation for a cure

Universal ART, widespread testing and expanded PrEP has reduced new infection by 50%

Immunotherapy: Curing monkeys with SIV has proven surprisingly easy if you design the study correcting SIV is not HIV, monkeys are not people CMV/HIV vaccine: 50% of vaccinated monkeys who become infected are eventually cured Vaccine + vaccine adjuvant (TLR7 agonists) Broadly neutralizing antibodies during acute infection Broadly neutralizing antibodies + TLR7 agonists

The changing face of ART 15 years ago! Today! Tomorrow?

Anti PDL1 in HIV infection Double-blind placebo*-controlled study of single dose infusions of BMS-936559 with 4 sequential dose-escalating cohorts Cohort 1: 8 participants (6 active / 2 placebo) No effect on HIV RNA in cells or plasma Hypophysitis in one individual at week 36 Study ceased due to preclinical retinal toxicity in macaques Eron et al., J Infect Dis 2016