Can we cure HIV/AIDS?: A 2014 progress report

Zeena Nackerdien

What constitutes a cure?(1)

Eradication cure: no HIV, effective immune response, no HAART needed

Functional cure: control of HIV without ART or deleterious immune effects

Hybrid cure: Reduce functional virus reservoirs & improve immune response without ART

HAART, highly active anti-retroviral therapy1. Mellors J. HIV Cure Research. 2014 Conference on Retroviruses and Opportunistic Infections; San Francisco, CA, 2014.

ART: prevention/initial treatment of HIV+-adults & adolescents (2-3)

*CD4 counts should be done every 3 to 6 months to assess the urgency of ART initiation and the need for opportunistic infection prophylaxis. CD4 count done at baseline & repeated per tailored management regimen; HCP, healthcare provider; mo., months; pt, patient; aPrEP candidates: when exposed to HIV e.g., through drugs /sex.2. US Centers for Disease Control. Preexposure prophylaxis for the prevention of HIV in the United States 2014 [cited 2014 May]. : http://www.cdc.gov/hiv/pdf/guidelines/PrEPguidelines2014.pdf3. AIDSInfo. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents: Initiating Antiretroviral Therapy in Treatment-Naive Patients: National Institute of Health; 2014 [cited 2014 May]. http://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/10/initiating-art-in-treatment-na%C3%AFve-patients..

PrEP candidatesa

• Truvada® used as PrEP

• Individuals must commit to taking drug daily & seeing an HCP every 3 mo. for HIV testing & other follow-up

• Viral load &CD4-cell count* should guide start & continuation of ART in HIV+-pts to reduce risk of disease progression

• ART is recommended in HIV+-pts. to prevent transmission

• Pt. education: Benefit/risk profiles & importance of adherence• Tailored onset/deferral of

ART may be done on a case-by-case basis

PrEP c

an ↓ HIV

risk

by >90%

Treatment-naïve pts

Strict adherence for

full & durable viral

suppression

Pivotal cases inspiring renewed search for a cure

(A) The ‘Berlin’ patient (4)

• Male with AML & HIV, allogeneic CCR5 32/32 stem cell recipient• No viral rebound 20 months after transplantation & ending ART

(B) Two Boston cases (5)

• Patients with Hodgkin’s lymphoma & HIV received bone marrow from WT CCR5-donor • Initial aviremia, but rebound 4 & 8 months, respectively, after ART cessation

Differences

• Aggressive myeloablation in (A) versus (B)• Donor in (B) was WTCCR5 versus (A)

Studies of ECs such as the Berlin patient aid development of an effective vaccine (6) Likely to also show how best to

maintain memory CD4+- & CD8+-T cells

Caveat:~10% progress to AIDS; GALT-damage in ECs associated with various types of end-organ damage

Boston failures show importance of HIV- resistance phenotypes Different groups are modulating

host cell response by CCR5-editing in lymphocytes or HSCsAML, acute myeloid leukemia; ART, anti-retroviral therapy; CCR5, C-C chemokine receptor type 5; ECs, elite controllers i.e., undetectable viral loads without treatment; GALT, gut-

associated lymphoid tissue; HSCs, hematopoietic stem cells; WT, wild type4. Hutter G, Nowak D, Mossner M, Ganepola S, Mussig A, Allers K, et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. NEJM, 2009;360(7):692-8.5. Seclen E. Bone Marrow Transplant to Fight Cancer and HIV Infection. AIDS reviews. 2014;16(1):53-4.6. Shasha D, Walker BD. Lessons to be Learned from Natural Control of HIV - Future Directions, Therapeutic, and Preventive Implications. Frontiers in immunology. 2013;4:162.

Non-ART strategies: Gene editing

Chimeric nuclease* deleting 32 bp segment of

CCR5 (32/32)

*Gene-editing chimeric nucleases e.g., ZFN, Zinc-finger nucleases, TALENS, transcription activator-like effector nucleases & CRISPR (clustered regularly interspaced short palindromic repeats)/Cas-based endonucleases ;bp, base pairs7.Tebas P, Stein D, Tang WW, Frank I, Wang SQ, Lee G, et al. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. NEJM. 2014;370(10):901-10.

Attachment of HIV to a CD4+ T-helper cell

ZFN-modified autologous CD4 T cell infusions were safe in 12 pts. with chronic aviremic HIV infection

[NCT00842634](7)

Non-ART strategies: HIV vaccines (8)

HIV efficacy trials• VAX004, no efficacy• VAX003, no efficacy• Phambili, no efficacy• HVTN505, no efficacy• STEP, Increased HIV infectionVirus-like particles, inactivated-,live attenuated vaccine developmentpromoted new discoveries

New discoveries• Adjuvants• Booster regimens (homing for

lymph nodes to control HIV replication & to

↓refractory memory CD8+-T cells• Therapeutic vaccines,

peptides + dendritic cells, to ↑HIV immunity, even after ART cessation

RV144 trial:31,2% efficacy (canarypox vector)

8. Lema D, Garcia A, De Sanctis JB. Hiv vaccines: a brief overview. Scandinavian journal of immunology. 2014 (e-pub).

Minimum needs for a successful vaccine (8)

Env, envelope protein8. Lema D, Garcia A, De Sanctis JB. Hiv vaccines: a brief overview. Scandinavian journal of immunology. 2014 (e-pub).

Suggested criteria for an effective

vaccine

Enhance a strongmucosal immunity, reduce infective viral entry to a minimum

Induce broad & potent antibody responses against Env, generating efficient effector memory T-cell responses

Generate efficient CTL to eliminate infected cells

Target viral proteome & viral replication

Decrease virus spreading

Immunization strategies(8)

8. Lema D, Garcia A, De Sanctis JB. HIv vaccines: a brief overview. Scandinavian Journal of Immunology. 2014 (e-pub).

Lipoidal biocarriers

DNA vaccines

Viral-like

particles

Live recombinant

vaccines Mucosal immunizatio

n

Live attenuated & inactivated vaccines

Protein subunit vaccines

Challenges (1)

ART, antiretroviral therapy; ID seq., identical sequences*HIVs can persist in a latent state in the form of integrated & transcriptionally silent proviruses1. Mellors J. HIV Cure Research. 2014 Conference on Retroviruses and Opportunistic Infections; San Francisco, CA2014.

Persistent viremia

Rebound viremia

Latent virus*

reservoir

Clonal expansion implied by ↑ID seq.

HIV diversity

Human diversity

ART risks: need to be

safe & effective

Future directions(9)

ImmunotherapiesTherapeutic HIV vaccines

Target viral reservoirs

Effective genome editing

Early treatment interventions

Anti-inflammatory therapies

HIV CURE

9. Saez-Cirion A, Jacquelin B, Barre-Sinoussi F, Muller-Trutwin M. Immune responses during spontaneous control of HIV and AIDS: what is the hope for a cure? Philosophical transactions of the Royal Society of London Series B, Biological sciences. 2014;369(1645):20130436.

Scientific strategy for HIV cure (10)

ART, anti-retroviral therapy; SIV, simian immunodeficiency virus

10. Deeks SG, Autran B, Berkhout B, Benkirane M, Cairns S, Chomont N, et al. Towards an HIV cure: a global scientific strategy. Nature reviews Immunology. 2012;12(8):607-14.

The International AIDS Society Scientific

Working Group on HIV Cure

Determine tissue & cellular sources of persistent SIV/HIV in animal models & people

on long-term ART

Determine origins of inflammation & immune activation in the presence of ART &

consequences for HIV/SIV persistence

Determine host mechanisms that control HIV replication in the absence of therapy

Develop and test strategies to enhance the capacity of the host immune response to

controlactive viral replication

Develop therapies to safely test & eliminate latent infection in animal

models & people on ART

Study, compare and validate assays to measure persistent HIV infection and to

detect latentlyinfected cells

Determine mech. for HIV persistence during prolonged ART & in natural

controllers