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The HIV/AIDS Pandemic: Advances Made and Challenges Ahead

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Presentation on theme: "The HIV/AIDS Pandemic: Advances Made and Challenges Ahead"— 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, 2000
22.6 10.1 9.1 6.7 5.5 4.3 3.6 3.1 2.9 2.3 0.0 5.0 10.0 15.0 20.0 25.0 HIV/AIDS Malaria Perinatal conditions TB Cerebro- vascular disease Diarrheal Lower respiratory infections Measles Ischemic heart Maternal % of Total

7 HIV prevalence among pregnant women in South Africa, 1990 to 2001
5 10 15 20 25 30 ‘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
Tetherin (Vpu) CD4, CCR5, CXCR4 Tsg101, ALIX, ESCRT TRIM5α Why? APOBEC3G (Vif) P-TEFb LEDGF 11

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

13 HIV-1 replication dynamics
Duration: 1 d Cell t1/2: 0.7 d Virus t1/2: 30 min Virus production: 1010 to 1012 Darwinian evolution fast forward: >107 mutants per day: treat hard Heightened (4-6-fold) turnover of CD4 T-cells: treat early 13

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 1995 850,000 New AIDS cases 450,000 Death 750,000 350,000 People living With AIDS 650,000 300,000 550,000 250,000 No. of cases and no. of deaths 450,000 No. of persons living with AIDS 200,000 350,000 150,000 250,000 100,000 150,000 50,000 5,000 Year 15

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 16

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 Features of gp120 that preclude the efficient
neutralization of HIV by antibodies Variable loops Glycosylation Entropic forces Chen et al. Nature, 433: 834, 2005.

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 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 PrEP with tenofovir +/- emtricitabine has gained traction

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 Ideal PrEP agent -Infrequently administered -No side effects -No overlap with current therapies

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

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

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
Gates Foundation support to explore its use for PrEP Phase 1a 1b 2a 2b N 30 22 82 113 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 D (cells/uL) +131 +112 +48 +49 VL D (log) -1.33 -0.95 -1.00 -1.96 Serious Events No drug-related SAEs No drug-related SAEs to date

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

31 Ibalizumab as PrEP 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

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 Improving the stability of ibalizumab

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

36 Higher affinity variants of ibalizumab selected
from CDR1H mutants

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

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

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

40 iMab-m36 is active against ibalizumab-resistant viruses
iMab [1.6g/ml] iMab-m [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 Our ultimate goal 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.

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