The HIV/AIDS Pandemic: Advances Made and Challenges Ahead
David D. Ho, M.D.
Aaron Diamond AIDS Research Center,
The Rockefeller University
Los Angeles, 1981: tip of the iceberg – acquired immunodeficiency syndrome (AIDS)
Common characteristics: gay men with marked depletion of CD4 T cells
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
1983: detection of the causative agent – human immunodeficiency virus (HIV)
F. Barre-Sinoussi & L. Montagnier
The Global HIV Pandemic: 25 million dead and 35 million living
The epidemic rages on with 2.5 million new infections per year
Leading causes of death in Africa, 2000
22.6
10.19.1
6.75.5
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 Perinatalconditions
TB Cerebro-vascular disease
Diarrheal disease
Lowerrespiratory infections
Measles Ischemic heart
disease
Maternalconditions
% ofTotal
HIV prevalence among pregnant women in South Africa, 1990 to 2001
0
5
10
15
20
25
30
‘90 ‘00‘91 ‘92 ‘93 ‘94 ‘95 ‘96 ‘97 ‘98 ‘99 ‘01
HIV
pre
va
len
ce
(%)
Orphans in Sub-Saharan Africa: >12 million
HIV-1: the causative agent of AIDS
HIV-1 genomic organization
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?
HIV-1 life cycle and antiretroviral drugs
RT inhibitors
protease inhibitors
entry inhibitors
Integrase inhibitors
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
Sustained reduction of viral load by combination antiviral therapy
Decline in AIDS mortality in the U.S. with the useof combination antiretroviral therapy since 1995
1986 1988 1990 1992 1994 1996 1998 2000 2002
Year
0
50,000
150,000
200,000
300,000
350,000
100,000
250,000
450,000
5,000
150,000
750,000
650,000
550,000
350,000
450,000
250,000
850,000
0
New AIDS cases
DeathPeople livingWith AIDS
No
. o
f ca
ses
and
no
. o
f d
eath
s
No
. o
f p
erso
ns
livi
ng
wit
h A
IDS
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
Where are we in HIV vaccine development?
• No protective vaccine available
• No protective vaccine in the foreseeable future
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
Chen et al. Nature, 433: 834, 2005.
Variable loops
Glycosylation
Entropic forces
Features of gp120 that preclude the efficient neutralization of HIV by antibodies
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
-Infrequently administered
-No side effects
-No overlap with current therapies
Ideal PrEP agent
Ibalizumab: HIV-neutralizing mAb directed to domain 2 of human CD4
(5A8, TNX-355)
Freeman et al, Structure, in press
Structure of ibalizumab Fab bound to 2-domain CD4 (2.2Å)
Contact sites between ibalizumab and CD4
Superimposition of known structures of ibalizumab Fab, CD4, and gp120 core
20 40 60 80 1000
20
40
60
80
100
0.01
0.1
1
10
Viruses
Ma
xim
um
pe
rce
nt
inh
ibit
ion
(M
PI)
IC5
0 ( g
/mL
)
Breadth and potency of ibalizumab (MPI and IC50)against a panel of 118 HIV clones
Ibalizumab is active and safe in vivo in humans
Phase 1a 1b 2a 2b
N 30 22 82 113
Dose10 mg/kg single-
dose, monotherapy10 mg/kg weekly, 9 WK monotherapy
10 mg/kg, bi-weekly + OBR
800 mg Q2W vs. 2000 mg Q4W,
+OBR
Route IV IV IV IV
SubjectsHIV-positive adults on stable therapy
HIV-positive adults on failing regimens
HIV-positive adults w/multi-drug resistant HIV
HIV-positive adults w/multi-drug resistant HIV
CD4 (cells/uL)
+131 +112 +48 +49
VL log) -1.33 -0.95 -1.00 -1.96
Serious Events
No drug-related SAEs
No drug-related SAEs
No drug-related SAEs
No drug-related SAEs to date
Gates Foundation support to explore its use for PrEP
Superimposition of known structures of ibalizumab Fab, CD4, MHC II-TCR,
31
Moving toward proof of principle with the current form:Phase 1 study in healthy volunteersPassive protection against SIV challenge in macaques
Making a better ibalizumab:Improve routeImprove stabilityImprove affinityImprove PKImprove breadth
Ultimate goal:Decrease dose to <10 mgDecrease frequency to 2 monthsDecrease cost
Ibalizumab as PrEP
32
Ibalizumab PK in monkeys: SC versus IV
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 selectedfrom CDR1H mutants
Improving ibalizumab breadth by attacking a second site
m36
PG9, VRC01
A fusion construct attacking CD4 and gp120 simultaneously
iMab-m36
m36
39
Figure 2. iMabm36 is active against ibalizumab-sensitive and resistant viruses
iMab-S viruses iMab-R viruses
Fusion with m36 broadens the breadth of ibalizumab
iMab-m36 is active against ibalizumab-resistant viruses
iMAb gel con
10 - 4 10 - 3 10 - 2 10 - 1 101
-50
50
100
G02
G07
G08
G09
G10
G11
G12
G18
G20
G21
G22
G25
m366
10 - 4 10 - 3 10 - 2 10 - 1 101
-50
-25
25
50
75
100
G02
G07
G08
G09
G10
G11
G12
G18
G20
G21
G22
G25
iMab [1.6g/ml] iMab-m36 [1.6g/ml] Viruses
Other fusion constructs attacking both CD4 and gp120
PG9-scFv
PG9-iMab
or VRC01-scFv
or VRC01-iMab
iMAb gel con
0.0001 0.001 0.01 0.1 1 10
-40
-20
0
20
40
60
80
100
G02
G08
G09
G11
G12
G18
G20
G21
G22
G25
Ne
utr
ali
zati
on
(%
)
concentration (ug/mL)
iMab-VRC01
0.0001 0.001 0.01 0.1 1 10
-40
-20
0
20
40
60
80
100
G02
G08
G09
G11
G12
G18
G20
G21
G22
G25
Ne
utr
ali
zati
on
(%
)
concentration (ug/mL)
VRC01 fusion also increases the breadth of ibalizumab
IIIiMab
To create improved variants of ibalizumab and otherHIV-neutralizing monoclonal antibodies that are potent, broad, and could be given in low doses SConce every 2 months.
It has not escaped us that such improved biologicscould also be used, especially in combination, to change the paradigm of HIV therapy from daily to monthly regimens.
Our ultimate goal
