Download HIV: Science, Sex and Society. Lecture 2

HIV: Science, Sex and Society.
Lecture 2.
Strategies for the cure of HIV-1.
Mario Stevenson, Ph.D
Department of Medicine.
Main topics:
• Review of the obstacles to viral eradication
• Treatment as prevention
• Berlin Patient; Visconti Patients; Mississippi
Baby; Boston Patients
• Gene therapy approaches
• Shock and kill
• Immune-based strategies
Question: What was likely the most important
component of Timothy Brown’s treatment that
led to him being cured of HIV infection?
A: He also had leukemia
B: He received an experimental vaccine
C: His treatment was started early after he first
became infected
D: He received a bone marrow transplant from an
individual with a CCR5 mutation
E: All of the above
MechanismsofofHIV
HIV persistence
Mechanisms
persistence
Latent reservoir
T cell survival
Homeostatic
proliferation
Active reservoir
Ongoing
viral replication
Courtesy N. Chomont
Finzi et al. Science 1997 ; Wong et al. Science 1997 ; Chun et al. PNAS 1997 ;
Palmer et al. PNAS 2008 ; Chomont et al. Nat Med 2009
Treatment as prevention:
The power of PreP!
virus particles in plasma (log10)
Antiviral treatment: impact on transmission
107
106
105
104
103
102
101
0
0
Years
Time on antiviral cocktails (ART)
virus particles in plasma (log10)
Antiviral treatment: impact on transmission
When an infected individual
has low viral load on therapy,
that individual does not
transmit the virus!
107
106
105
104
103
102
101
0
0
1
2
3
months on antiviral cocktails (ART)
PARTNER Cohort –
Follow-up of Serodiscordant Couples when
HIV+ Partner Has Suppressed Viral Load
Behavior - HIV Neg # Condomless Sex
Partner
Acts
Observed Linked
Transmissions
95% CI
(transmissions/100
CYFU)
HT - Receptive
Vaginal Intercourse
13,728
0
1.25
HT - Insertive
Vaginal Intercourse
14,295
0
1.32
MSM - Receptive
Anal Intercourse
7,738
0
1.97
MSM - Insertive
Anal Intercourse
11,749
0
1.37
Rodger A, et al. 21st CROI Meeting, Boston, MA; March 3-6, 2014. Abst.
153LB.
Using Antiretroviral Medications for HIV-1 Prevention
PrEP
Prior to exposure
PEP
Time of
transmission
ART
After infection
PreP trial HPTN 052: 1763 discordant couples
(1 partner infected, the other uninfected) in nine
countries. Infection and clinical status was
monitored. Both partners started on ARVs
immediately or after delayed interval.
HPTN 052: HIV-1 Transmissions
96% Decrease
Cohen MS, Chen YQ, McCauley M, et al. N Engl J Med 2011; 365(6):493.
The Global iPrEx Study
•Use antivirals in high-risk
individuals to prevent infection- a
drug-based vaccine
Limitations
•Success depends on how well
enrollees took the drugs and
stayed on the drugs.
•New formulations of drugs last for
months after single dose.
A cure is needed!
34 MILLION PEOPLE LIVE WITH HIV/AIDS WORLDWIDE
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?
Immune inflammation reduces
lifespan!
Immune inflammation, as measured by Tcell activation, is lower in treated than
untreated adults, but consistently higher
than “normal”
P < 0.001
80
% CD38+HLADR+
CD8+ T Cells
P < 0.001
60
40
20
0
HIV
HIV+
Negative
Untreated
(n=82)
(n = 82)
NonHIV+
Controller
ART
(n=65)
(n
= 65)
HAART
HIV(n=132)
(n = 132)
Hunt et al JID 2003, PLoS ONE 2011 and unpublished
Immune inflammation, as measured by T-cell
activation, is lower in treated than untreated adults, but
consistently higher than “normal”
P < 0.001
80
% CD38+HLADR+
CD8+ T Cells
Individuals onPART
< 0.001develop “aging”
diseases earlier in life.
60
Immune inflammation leads to comorbidities
including cardiovascular issues
40
and diabetes that can reduce an HIVinfected
20 individuals lifespan by 5-6 yearseven though the individual is on ARVs and
virus
is undetectable in blood!
0
HIV
HIV+
Negative
Untreated
(n=82)
(n = 82)
NonHIV+
Controller
ART
(n=65)
(n
= 65)
HAART
HIV(n=132)
(n = 132)
Hunt et al JID 2003, PLoS ONE 2011 and unpublished
The changing face of ART
15 years ago!
Today!
Tomorrow?
Is HIV curable?
Lessons from early ART
initiation!
Sterilizing cure- all virus has been
eliminated from the body
Functional cure- virus remains but
doesn’t rebound after antiviral
cocktails are removed
Early phases of HIV-1 infection
• 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 4th 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.
What was different about this case?
CCR5 alleles
ATI: Patient B
27
ATI: Patient B
Suggests presence of CCR5 null
stem cells is necessary for the
cure in the setting of BMT
28
Genetic approaches to
eliminating HIV infection!
Why can’t we use CCR5 null BMT to cure
HIV infection?
• Identification of immunologically matched donors
with CCR5 mutation is challenging
• BMT carries a 25% mortality rate.
• Costs are significant ~300K
• BMT to cure HIV is unethical when ARVs sustain
survival. Physician can not increase risk for patient.
• Scientists are developing approaches to create the
CCR5 mutation in an infected individuals stem cells
Gene therapy for cure of HIV-1
Gene therapy for cure of HIV-1
Challenges behind genetic therapies to
cure HIV-1 infection!
• Cost- $100K!
• Most of the 40 million infections worldwide are in
resource-limited regions where average per capita
healthcare expenditure is several hundred dollars
• Long-term concerns with modifying an individuals
DNA.
Eliminating the latent
reservoir using kick and kill
approaches!
Comparison of latent and active HIV infection
Latent Cell Frequency
Slow decay of latently infected CD4+ T cells
Time to eradication
> 73.4 years
-
0
15
30
45
Time on HAART (years)
Courtesy Bob Siliciano
Shock and kill approach for cure of HIV!
“Kick and Kill” Pilot study of vorinostat (SAHA) in long-term
treated adults
800
Baseline ART
VOR 400 mg
Relative HIV-1 gag RNA copies
600
400
200
100
60
40
20
0
Pt. 1
Pt. 2
Pt. 3
Pt. 4
Pt. 5
Pt. 6
Pt. 7
2012!
Pt. 8
“Kick and Kill” Pilot study of vorinostat (SAHA) in long-term
treated adults
•Changes in viral RNA levels were very
modest
•Unclear whether viral protein- the essential
target of “shock and kill” strategy, was
produced
•Unclear whether latency is the same in all
cells
800
Baseline ART
VOR 400 mg
Relative HIV-1 gag RNA copies
600
400
200
100
60
40
20
0
Pt. 1
Pt. 2
Pt. 3
Pt. 4
Pt. 5
Pt. 6
Pt. 7
2012!
Pt. 8
If there are different
faucets or
reservoirs, water in
each sink empties
at different rates
Immune-based approaches
to eliminate the viral
reservoirs!
•
CMV engineered as a live HIV/SIV vaccine causes high
levels of tissue-based “killer” CD8+ T cells that target novel
parts of the virus
•
Vector stimulates “unconventional” MHC II/HLA E restricted
CD8+ T cell responses that are potent, effector memory
differentiated, widely distributed and indefinitely persistent
•
These cells clear latency during early infection, resulting in
first clear documentation of a “cure” in this model
Getting CD8 T-cells to the right place!
Baseline reservoir size and timing of viral rebound
Jonathan Li
Baseline reservoir size and timing of viral rebound
Implications of active reservoir:
Infected cells may be recognizeable
to immune system- “shock and kill”
may not be required. Therefore,
boosting antiviral immunity may help
clear the viral reservoirs
Jonathan Li