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HLA-A7401 is Associated with Protection from HIV-1 Acquisition by fwo93561

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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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