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HLA-A*7401 is Associated with Protection
from HIV-1 Acquisition and Disease
Progression in Mbeya, Tanzania
Rebecca N. Koehler, PhD.
Department of Molecular Virology and Pathogenesis
U.S. Military HIV Research Program
The views expressed are those of the authors and should not be construed to represent the
positions of the U.S. Department of Defense or the National Institutes of Health
Pathogen-Driven Selection as a Molder of
Global Immunogenetic Complexity
Irish
Yupik Korean
Chinese
Croatian (Han)
Pima
Kenyan
Luo
Guarani-Kaiowa Zulu
Complexity of HLA-A allele variants
Class I HLA: a bridge between
innate and adaptive immunity
TCR
HLA
HIV-infected cell
CTL
KIR
HLA
NK Cell
Objective: Characterize HLA genetic influence on HIV acquisition and
disease progression in highly complex genetic setting: East Africa
Population under study
•! 3096 consented adults enrolled
months
•! HIV sero-prevalence (16.4%)
•! HIV sero-incidence (1.36 per 100
person years)
•! HIV subtype distribution:
•! Subtypes C> A= A/C> A/C/D> A/D, C/D, D
(Arroyo, AIDS 2005)
Mbeya
•!Patients were ARV-naïve at evaluation
•!Available specimens (PBMCs):
•!508 HIV sero-prevalent
•!99 HIV sero-incident
•!174 HIV sero-negative Age distribution
High-resolution and high-throughput class I
HLA genotyping
HLA immunogenetic HLA-A HLA-B HLA-C
complexity in East Africa 14 alleles 23 alleles 12 alleles
105 genotypes 276 genotypes 78 genotypes
HLA-A
HLA-B
HLA-C
Koehler et al (submitted)
Class I HLA play role in HIV Acquisition
Odds Ratio for HIV Acquisition
OR=0.13 (95% CI: 0.01-0.71)
p= 0.01
HLA-A*0205
HLA-A
OR=0.36 (95% CI: 0.15-0.80)
p= 0.01
HLA-A*7401
carrier non-carrier
HLA-B
OR=0.5 (95% CI: 0.28-0.87)
p= 0.01
HLA-Cw*0401
HLA-C
OR=2.84(95% CI: 1.16-7.25)
p= 0.02
HLA-Cw*0702
Class I HLA alleles association with
markers of disease progression
FEMALE n=329 MALE n=179
Odds Ratio of CD4 count<200/uL Odds Ratio of CD4 count<200/uL
HLA-A
HLA-A
OR=0.31 (95% CI: 0.07-0.91)
p= 0.03
OR=0.15 (95% CI: 0.008-0.78)
p= 0.01
HLA-B
HLA-B
•!Sero-prevalent (n=506)
•!Cross sectional analysis
HLA-C
of CD4 cell counts
HLA-C
•!based on first available
samples
•!Age adjusted
Summary of Results
•! HLA-A*7401 had a protective effect (independent of LD with
HLA-B and -C, age and recruitment site):
!! HIV acquisition: OR=0.36 (95% CI: 0.15-0.79, p=0.01)
!! disease progression:
-! females: OR=0.31 (95% CI: 0.07-0.91, p= 0.03 )
-! males; OR=0.15 (95% CI: 0.008-0.78,p= 0.01)
•! Other alleles also showed a protective effect for HIV acquisition
(A*0205, Cw*0401) or disease progression (A*3002, B*5703,
Cw*1801).
•! Other alleles were associated with
increased risk of HIV acquisition protective detrimental
(Cw*0702) or disease progression
(A*0205, B*5801, B*5802, Cw*0704)
Discussion: Potential mechanisms for HLA-
A*7401-mediated protection
•! HLA-A*7401 is in strong LD •! HLA- A*7401 serves as ligand
with unknown protective factor of receptor in innate immunity
effector cell
HLA
•! HLA- A*7401 is genetically
related to A*3201, which is a
putative ligand for KIR3DL1
Malaria prevalence http://www.uams.edu/
Conclusions
•! In this initial and exploratory analysis, HLA-
A*7401 was associated with protection from
HIV acquisition and disease progression
•! These results will need to be validated in
additional cohorts
•! The mechanism by which HLA-A*7401
exerts its influence will need to be further
elucidated
Acknowledgements
MHRP Mbeya Medical Research
Section of Host Genetics Programme (Mbeya, Tanzania)
Gustavo Kijak
Leonard Maboko
Anne Walsh
Nasheed Moqueet Ludwig-Maximilians University
(Munich, Germany)
Francine McCutchan
Michael Hoelscher
Eric Sanders-Buell
Sodsai Tovanabutra Elmar Saathoff
Jeffery Currier
Silvia Ratto-Kim The study participants
Merlin Robb
Jerome Kim Funding:
Nelson Michael Henry M. Jackson Foundation for the Advancement
of Military Medicine, Inc.,
U.S. Department of Defense
NIAID/NIH
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