Cell- and Tissue-based Measures of Viral Persistence Are Associated with Immune Activation and...
-
Upload
cecilia-victoria-turner -
Category
Documents
-
view
219 -
download
0
Transcript of Cell- and Tissue-based Measures of Viral Persistence Are Associated with Immune Activation and...
Cell- and Tissue-based Measures of Viral Persistence Are Associated with
Immune Activation and PD-1-Expressing CD4+ T cells
H Hatano1, V Jain1, PW Hunt1, JN Martin1, TH Lee2, E Sinclair1, JM McCune1, F Hecht1, MP Busch1,2, SG Deeks1
1University of California, San Francisco, CA, USA2Blood Systems Research Institute, San Francisco, CA, USA
What are the determinants of HIV persistence?
• Determinants of HIV persistence during long-term HAART remain unknown, but may include:– Ongoing viral replication (Buzon, Nat Med 2010)
– Potency of HIV-specific responses• Mucosal HIV-specific T cell responses (Hatano, JID 2011)
Higher Levels of GALT HIV-specific CD8+ T Cells Are Associated with Lower Levels of Proviral DNA
rho = - 0.50, p = 0.03
CD4CD8
rho = - 0.42, p = 0.07
0 1 2
0
1
2
3
4
5
log10 Proviral DNA(per mil PBMC)
% G
ag-s
pec
ific
CD
4+ T
cel
ls (
GA
LT
)0 1 2
0.0
0.5
1.0
1.5
log10 Proviral DNA(per mil PBMC)
% G
ag-s
pec
ific
CD
8+ T
cel
ls (
GA
LT
)
Hatano et al, JID 2011
What are the determinants of HIV persistence?
• Determinants of HIV persistence during long-term HAART remain unknown, but may include:– Persistent immune activation
• Immune activation levels remain elevated despite effective HAART-mediated viral suppression
– Negative regulators that reverse activated state (PD-1) (Chomont, Nat Med 2009)
• PD-1high CD4+ T cells have high levels of proviral DNA• Triggering of PD-1 inhibits HIV transcription, and inhibiting the
PD-1/PD-L1 interaction increases HIV production• PD-1 expressing CD4+ T cells → Preferential reservoir for HIV
• Understanding the causes of persistent inflammation are important for preventing non-AIDS morbidity and for strategies towards cure
Study Objectives• To assess the relationship between measurements
of viral persistence and immune activation– Plasma RNA– Cell-associated RNA and proviral DNA– Tissue-associated RNA and proviral DNA
• To determine the relationship between treatment response and – T cell activation/dysfunction – Viral persistence
• To identify potential interventions to decrease HIV persistence
Methods
• 190 HAART-suppressed subjects identified from UCSF SCOPE/OPTIONS cohorts
• Ultrasensitive plasma HIV RNA– Modified Roche CAP/CTM v2.0 (LOD <5 copies/mL)
• Cell-associated RNA• Proviral DNA• Immune activation (% CD4+ and CD8+ T cells)
– CD38+HLA-DR+, PD-1
• Gut-associated lymphoid tissue (GALT) samples were obtained from 14 subjects
Baseline Characteristics
(n=190)
CD4 count (cells/mm3) 523
Age (years) 51
Gender (% male) 92%
Duration VL suppression (months) 31
Nadir CD4 count (cells/mm3) 113
No Association Between Low-Level Plasma RNA Levels and T Cell Activation
All p-values > 0.20
Modest Association Between Cell-Based Measures of Viral Persistence and T Cell Activation
rho = 0.23, p = 0.014 rho = 0.16, p = 0.057
rho = 0.22, p = 0.008 rho = 0.14, p = 0.088
Highly Significant Association between Proviral DNA Levels and Frequency of PD-1
Expressing CD4+ T Cells
rho = 0.28, p = 0.0005
These observations are consistent with
PD-1 being a marker of latently infected CD4+ T
cells (Chomont et al, Nature Med
2009)
Strong Association Between Viral Persistence in GALT and T Cell Activation
What is the relationship between treatment response and…
-Viral Persistence? -T Cell Activation/Dysfunction?
Will treated subjects with a low CD4+ T cell count require unique curative strategies?
Pla
sma
HIV
RN
A(c
op
ies/
mL
)
Low CD4 High CD40
50
100
150
Plasma RNA Levels Similar in Low and High CD4+ Groups
p = NS
Cell-Associated RNA and Proviral DNA Levels Are Higher in Low CD4+ Group
p = 0.008 p = 0.001
CD4+ T Cell Activation and PD-1 Expression are Higher in Low CD4+ Group
%C
D38
+H
LA
-DR
+C
D4+
T c
ells
Low CD4 High CD40
5
10
15
20
25
p < 0.0001
%P
D1+
C
D4+
T c
ells
Low CD4 High CD40
20
40
60 p < 0.0001
%C
D38
+H
LA
-DR
+P
D1+
CD
4+ T
cel
ls
Low CD4 High CD40
5
10
15
p < 0.0001%
CD
38+
HL
A-D
R+
CC
R5+
PD
1+C
D4+
T c
ells
Low CD4 High CD4
0
2
4 p < 0.0001
Higher Frequencies of PD-1 Expressing TCM CD4+ T Cells in Low CD4+ Group
% C
D45
RA
-CC
R7+
PD
1+C
D4+
T c
ells
Low CD4 High CD40
5
10
15
20
p < 0.0001
% C
D45
RA
-CC
R7+
CD
38+
HL
A-D
R+
PD
1+C
D4+
T c
ells
Low CD4 High CD40
2
4
6
p < 0.0001%
CD
45R
A-C
CR
7+C
D38
+H
LA
-DR
+C
CR
5+P
D1+
CD
4+ T
cel
ls
Low CD4 High CD40.0
0.5
1.0
1.5
p < 0.0001
Conclusions I.• No associations between ultrasensitive
plasma HIV RNA levels and immune activation
• Cell-based measurements of viral persistence were modestly but consistently associated with markers of immune activation/dysfunction and frequency of PD-1 expressing CD4+ T cells
• Stronger positive correlation between tissue-based measurements of viral persistence and immune activation
• Highly significant association between proviral DNA levels and frequency of PD-1 expressing CD4+ T Cells
• Phase I study of an anti-PD-1 monoclonal antibody aimed at clearing the latent reservoir is in development (ACTG 5301)
Potential Eradication Strategies
ACTG 5301 Study Schema
• Study Design: Single arm, dose-finding study• Population:
– HIV-infected female and male subjects ≥ 18 years of age. Females of reproductive potential are excluded from the study.
– Screening CD4+ T cell count > 350 cells/mm3
– Plasma HV RNA < 75 copies/mL while taking HAART for previous 36 months
• Sample size: 40 (10 subjects in each dose cohort)• Study duration: 16 weeks• Intervention: Single IV dose of open-label MK3475
at dose of 0.1, 1, 3, or 10 mg/kg
• Treated patients with a low CD4+ T cell count had:– Higher cell-based measures of viral
persistence– Expansion of CD4+ T cells expressing PD-1
• Most consistently observed in the central memory compartment
• Treated individuals with low CD4+ T cell counts may be more difficult to cure and/or will require unique interventions
Conclusions II.
Implications
• Understanding the causes of viral persistence and inflammation in the setting of HAART are necessary to develop new strategies towards cure
• Future studies of viral persistence should focus on cell- and tissue-based measurements of viral persistence, not on plasma RNA (Chun, JID 2008; Yukl, JID 2010;
Hatano, JID 2011)
Acknowledgements
UCSF/SFGH/PHP UCSF/SFGH/DEM FundingVivek Jain Elizabeth Sinclair NIAID K23AI075985Peter Hunt Joseph M. McCune Ma SomsoukJeffrey Martin VGTI Florida Frederick Hecht Nicolas ChomontSteven Deeks Rafick Sekaly
UCSF/SFVAMC Roche, Inc.Steven Yukl Tri DoJoseph Wong
UCSF/BSRITzong-Hae Lee Michael Busch