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The HIV/AIDS Pandemic: Advances Made and Challenges Ahead David D. Ho, M.D. Aaron Diamond AIDS Research Center, The Rockefeller University.

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Presentation on theme: "The HIV/AIDS Pandemic: Advances Made and Challenges Ahead David D. Ho, M.D. Aaron Diamond AIDS Research Center, The Rockefeller University."— Presentation transcript:

1 The HIV/AIDS Pandemic: Advances Made and Challenges Ahead David D. Ho, M.D. Aaron Diamond AIDS Research Center, The Rockefeller University

2 Los Angeles, 1981: tip of the iceberg – acquired immunodeficiency syndrome (AIDS) Common characteristics: gay men with marked depletion of CD4 T cells

3 CDC: Groups at risk for AIDS Homosexual men Female sex partners Injection drug users Blood transfusion recipients Hemophiliacs treated with factor VIII Children born to infected women Sex Blood Mother to child

4 1983: detection of the causative agent – human immunodeficiency virus (HIV) F. Barre-Sinoussi & L. Montagnier

5 The Global HIV Pandemic: 25 million dead and 35 million living The epidemic rages on with 2.5 million new infections per year

6 Leading causes of death in Africa, HIV/AIDSMalariaPerinatal conditions TBCerebro- vascular disease Diarrheal disease Lower respiratory infections Measles Ischemic heart disease Maternal conditions % of Total

7 HIV prevalence among pregnant women in South Africa, 1990 to ‘90 ‘00 ‘91‘92‘93‘94‘95‘96‘97‘98‘99‘01 HIV prevalence (%)

8 Orphans in Sub-Saharan Africa: >12 million

9 HIV-1: the causative agent of AIDS

10 HIV-1 genomic organization

11 HIV-1 life cycle and cellular factors that facilitate or restrict virus replication TRIM5α Tetherin APOBEC3G CD4, CCR5, CXCR4 LEDGF P-TEFb Tsg101, ALIX, ESCRT (Vif) (Vpu) Why?

12 HIV-1 life cycle and antiretroviral drugs RT inhibitors protease inhibitors entry inhibitors Integrase inhibitors

13 HIV-1 replication dynamics Duration: 1 d Cell t 1/2 : 0.7 d Virus t 1/2 : 30 min Virus production: to Darwinian evolution fast forward: >10 7 mutants per day: treat hard Heightened (4-6-fold) turnover of CD4 T-cells: treat early

14 Sustained reduction of viral load by combination antiviral therapy

15 Decline in AIDS mortality in the U.S. with the use of combination antiretroviral therapy since Year 0 50, , , , , , , ,000 5, , , , , , , , ,000 0 New AIDS cases Death People living With AIDS No. of cases and no. of deaths No. of persons living with AIDS

16 Social injustice: U.S. vs. Africa 1. The delivery of drugs and services to the developing world 2. The importance of prevention: education and vaccine

17 Where are we in HIV vaccine development? No protective vaccine available No protective vaccine in the foreseeable future

18 Difficulties in developing an HIV vaccine During the natural course of HIV infection, the virus is seldom (<1%) well controlled by the immune system Superinfection has been well documented HIV is extremely plastic and rapidly escapes from immune recognition HIV is relatively resistant to antibody neutralization

19 Chen et al. Nature, 433: 834, Variable loops Glycosylation Entropic forces Features of gp120 that preclude the efficient neutralization of HIV by antibodies

20 Notable HIV-neutralizing monoclonal antibodies b12: CD4-binding site on gp120 2G12: carbohydrate on gp120 2F5, 4E10: membrane-proximal region of gp41 PG9: conformational epitope on gp120 (Science, 2009) VRC01: CD4-binding site on gp120 (Science, 2010) PRO140: anti-CCR5 (anti-co-receptor) Ibalizumab: anti-CD4 (anti-receptor)

21 21 Pre-exposure prophylaxis (PrEP) with HIV-neutralizing monoclonal antibodies If we are unable to induce neutralizing antibodies in vivo, why not produce them ex vivo for passive administration? And turn a heretofore intractable basic discovery problem into a more tangible engineering challenge.

22 22 PrEP with tenofovir +/- emtricitabine has gained traction

23 23 Concerns about daily oral PrEP -Adherence difficulty of a daily drug regimen in a healthy person -Potential long-term side effects of the drug(s) -Tenofovir +/- emtricitabine form the cornerstone of frontline ARV therapy -Infrequently administered -No side effects -No overlap with current therapies Ideal PrEP agent

24 Ibalizumab: HIV-neutralizing mAb directed to domain 2 of human CD4 (5A8, TNX-355)

25 Freeman et al, Structure, in press Structure of ibalizumab Fab bound to 2-domain CD4 (2.2Å)

26 Contact sites between ibalizumab and CD4

27 Superimposition of known structures of ibalizumab Fab, CD4, and gp120 core

28 Breadth and potency of ibalizumab (MPI and IC50) against a panel of 118 HIV clones

29 Ibalizumab is active and safe in vivo in humans Phase1a1b2a2b N Dose 10 mg/kg single- dose, monotherapy 10 mg/kg weekly, 9 WK monotherapy 10 mg/kg, bi-weekly + OBR 800 mg Q2W vs mg Q4W, +OBR Route IV Subjects HIV-positive adults on stable therapy HIV-positive adults on failing regimens HIV-positive adults w/multi-drug resistant HIV CD4  (cells/uL) VL  log) Serious Events No drug-related SAEs No drug-related SAEs to date Gates Foundation support to explore its use for PrEP

30 Superimposition of known structures of ibalizumab Fab, CD4, MHC II-TCR,

31 31 Moving toward proof of principle with the current form: Phase 1 study in healthy volunteers Passive protection against SIV challenge in macaques Making a better ibalizumab: Improve route Improve stability Improve affinity Improve PK Improve breadth Ultimate goal: Decrease dose to <10 mg Decrease frequency to 2 months Decrease cost Ibalizumab as PrEP

32 32 Ibalizumab PK in monkeys: SC versus IV

33 Making a better ibalizumab “Affinity maturation” Change IgG4 to IgG1-LALA Modify Fc to bind FcRn better Sustained release formulation

34 34 Improving the stability of ibalizumab

35 35 “In vitro affinity maturation” to select higher affinity variants

36 36 Higher affinity variants of ibalizumab selected from CDR1H mutants

37 Improving ibalizumab breadth by attacking a second site m36 PG9, VRC01

38 A fusion construct attacking CD4 and gp120 simultaneously iMab-m36 m36

39 39 iMab-S viruses iMab-R viruses Fusion with m36 broadens the breadth of ibalizumab

40 iMab-m36 is active against ibalizumab-resistant viruses iMab [1.6  g/ml] iMab-m36 [1.6  g/ml] Viruses

41 Other fusion constructs attacking both CD4 and gp120 or VRC01-scFv or VRC01-iMab

42 VRC01 fusion also increases the breadth of ibalizumab III iMab

43 To create improved variants of ibalizumab and other HIV-neutralizing monoclonal antibodies that are potent, broad, and could be given in low doses SC once every 2 months. It has not escaped us that such improved biologics could also be used, especially in combination, to change the paradigm of HIV therapy from daily to monthly regimens. Our ultimate goal

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