paradise madlala, phd hiv pathogenesis programme (hpp) university of university of kwazulu-natal
DESCRIPTION
Association Polymorphisms in the Regulatory Region of Cyclophilin A gene ( PPIA ) with Gene Expression Levels and HIV/AIDS Disease Progression. Paradise Madlala, PhD HIV Pathogenesis Programme (HPP) University of University of KwaZulu-Natal. Background. - PowerPoint PPT PresentationTRANSCRIPT
Washington D.C., USA, 22-27 July 2012www.aids2012.org
Association Polymorphisms in the Regulatory Region of Cyclophilin A gene (PPIA) with Gene Expression
Levels and HIV/AIDS Disease Progression
Paradise Madlala, PhD
HIV Pathogenesis Programme (HPP)University of University of KwaZulu-Natal
Washington D.C., USA, 22-27 July 2012www.aids2012.org
Background• We investigated the association of two SNPs (C1604G and
A1650G) with HIV-1 clinical out comes in the CAPRISA AI 002 and Sinikithemba cohorts. PRC-RFLP was used to genotype the SNPs.
• Real time RT-PCR was used to quantify CypA mRNA expression levels in PBMCs genotyped for A1650G.
• HIV-1 replication capacity was performed in PBMCs genotyped for A1650G
Washington D.C., USA, 22-27 July 2012www.aids2012.org
AA AG/GG2
4
6
8
p < 0.01
A_Early Chronic Phase
L o
g V
i r
a l L
o a
d
(c o
p i e
s / m
l)
AA AG/GG
10
20
30
40p < 0.01
B_Early Chronic Phase
S q
r t
C
D 4
+
T
C e
l l s
(
c e
l l s
/ l)
0 300 600 900 1200 1500 180060
70
80
90
100
AA (n = 23)AG/GG (n = 24)
N = 47RH = 3.18
p=0.05
C _CAPRISA AI 002 cohort
Time since seroconversion (Days)
S q
r t
C
D 4
+
T
C e
l l s
(
c e
l l s
/l)
0 6 12 18 24 30 36 42 48 54 60 66 72-5
-4
-3
-2
-1
0
AA (n = 146)AG/GG (178)
N = 324p = 0.02
D_Sinikithemba Cohort
Duration of follow up, months
S
qrtC
D 4
/ m
on
ths
Association of 1650G with faster rate of CD4+ T Cell Decline in Sinikithemba Cohort
Washington D.C., USA, 22-27 July 2012www.aids2012.org
CypA expression levels and HIV-1 replication and in genotyped PBMCs
AA
AG
/GG
AA
AG
/GG
AA
AG
/GG
AA
AG
/GG
1
10
Day 0 Day 2 Day 7 Day 10
Post HIVInfectionPre HIVInfection
p=0.05p=0.04
C
Cy
pA
/GA
PD
H
AA
AG
/GG
AA
AG
/GG
AA
AG
/GG
0.2
0.3
0.4
0.5
0.6
Day 2 Day 7 Day 10Post HIVInfection
D
p24 (
ng
/mL
)
AA AG/GG0.0001
0.001
0.01
0.1
1
10
100
1000A
Seronegative participants
Cy
pA
/GA
PD
H
AA AG/GG0.0001
0.001
0.01
0.1
1
10
100
1000 P < 0.01
B
HIV-1 positive participants
Cy
pA
/GA
PD
H
Washington D.C., USA, 22-27 July 2012www.aids2012.org
• The minor allele (G) of SNP A1650G (1650G) was associated with lower CD4+ T cell counts and higher viral loads during primary HIV-1 infection and rapid CD4+ T cell decline during chronic infection in black South Africans.
• Following HIV-1 infection, 1650G was associated with higher CypA mRNA expression levels in vivo. However, no differences were observed in HIV-1 negative participants.
• IL2/PHA stimulated PBMCs genotyped for SNP A1650G also showed no differences in CypA mRNA expression prior to HIV-1 infection in vitro.
• HIV-1 infection results in differential CypA mRNA expression between AA versus AG/GG individuals.
Discussion and Conclusion
Washington D.C., USA, 22-27 July 2012www.aids2012.org
Acknowledgements
UKZN • Prof. Salim Karim• Prof. Bruce Walker• Prof. Philip Goulder• Prof. Thumbi Ndung’u
Ravesh Singh
NCI • Dr. Cheryl Winkler
KU Leuven• Prof. Zeger Debyser
Funding• EU FP7- THINC Consortium• DST/NRF• NIH• UKZN
Dr. An Ping