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Correlations between transmitted HI V drug resistance mutations and - - PowerPoint PPT Presentation

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Correlations between transmitted HI V drug resistance mutations and HLA of therapy-naive HI V-patients 20.04.2007 | Martin Dumer, Institut fr Virologie, Universitt zu Kln / Labor Thiele, Kaiserslautern Host Genetic Factors OBrien SJ

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20.04.2007 | Martin Däumer, Institut für Virologie, Universität zu Köln / Labor Thiele, Kaiserslautern

Correlations between transmitted HI V drug resistance mutations and HLA of therapy-naive HI V-patients

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20.04.2007 | Martin Däumer Seite 2

Institut f Institut fü ür Immunologie und Genetik r Immunologie und Genetik Medizinisches Labor Kaiserslautern Medizinisches Labor Kaiserslautern

Host Genetic Factors

O’Brien SJ and Nelson GW. Human genes that limit AI DS. Nat Gen 2004

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20.04.2007 | Martin Däumer Seite 3

Institut f Institut fü ür Immunologie und Genetik r Immunologie und Genetik Medizinisches Labor Kaiserslautern Medizinisches Labor Kaiserslautern

I ntrahost Evolution

■Evading host immune response ■Developing drug resistance

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20.04.2007 | Martin Däumer Seite 4

Institut f Institut fü ür Immunologie und Genetik r Immunologie und Genetik Medizinisches Labor Kaiserslautern Medizinisches Labor Kaiserslautern

Escape from Humoral Immunity

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20.04.2007 | Martin Däumer Seite 5

Institut f Institut fü ür Immunologie und Genetik r Immunologie und Genetik Medizinisches Labor Kaiserslautern Medizinisches Labor Kaiserslautern

Escape from Cell Mediated Immunity

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20.04.2007 | Martin Däumer Seite 6

Institut f Institut fü ür Immunologie und Genetik r Immunologie und Genetik Medizinisches Labor Kaiserslautern Medizinisches Labor Kaiserslautern

Human Leukocyte Antigen (HLA)

Human leukocyte antigen

displays peptides on cell surfaces in order to

present antigens in the course of an adaptive immune response located on short arm of chromosome 6

most polymorphic region of entire human genome

HLA class I

associated with (viral) infections interacts with cytotoxic T-cells (CTL)

HLA class II

stimulates the helper T-cell activity

HLA class III

encodes other components of the immune system

e.g. complement components and cytokines

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20.04.2007 | Martin Däumer Seite 7

Institut f Institut fü ür Immunologie und Genetik r Immunologie und Genetik Medizinisches Labor Kaiserslautern Medizinisches Labor Kaiserslautern

Basic genetics to HLA

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20.04.2007 | Martin Däumer Seite 8

Institut f Institut fü ür Immunologie und Genetik r Immunologie und Genetik Medizinisches Labor Kaiserslautern Medizinisches Labor Kaiserslautern

Peptide processing and presentation

Degradation of viral proteins inside cell into small peptides in cytosol

  • Peptides are loaded onto HLA molecule and

transported to cell surface

  • Impaired presentation or processing of the

peptides is due to mutations in CTL epitopes

cells are not destroyed by CTL

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20.04.2007 | Martin Däumer Seite 9

Institut f Institut fü ür Immunologie und Genetik r Immunologie und Genetik Medizinisches Labor Kaiserslautern Medizinisches Labor Kaiserslautern

Problem definition

Do transmitted resistance mutations correlate with certain HLA types indicating escape from the immune system?

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20.04.2007 | Martin Däumer Seite 10

Institut f Institut fü ür Immunologie und Genetik r Immunologie und Genetik Medizinisches Labor Kaiserslautern Medizinisches Labor Kaiserslautern

Patients and Methods

103 therapy-naive patients (RESINA) with documented drug resistance mutations in protease or / and reverse transcriptase Determination of HLA-A and –B type by sequencing (n=75) Frequencies of HLA-types were correlated with mutations in protease and reverse transcriptase Significance of correlation determined using Fisher‘s exact probability test

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20.04.2007 | Martin Däumer Seite 11

Institut f Institut fü ür Immunologie und Genetik r Immunologie und Genetik Medizinisches Labor Kaiserslautern Medizinisches Labor Kaiserslautern

Ethnic analysis of the study cohort

Or igin of P a t ie nt s Caucasians 80% Africans 8% Asiens 4%

  • rigin unknown

8%

The HLA-type is origin dependent.

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20.04.2007 | Martin Däumer Seite 12

Institut f Institut fü ür Immunologie und Genetik r Immunologie und Genetik Medizinisches Labor Kaiserslautern Medizinisches Labor Kaiserslautern

Mutations in RT

Frequency of HLA-B*44 41,7% 9,3% 5,8% 0,0% 5,0% 10,0% 15,0% 20,0% 25,0% 30,0% 35,0% 40,0% 45,0% Subgroup (K 103 R) Whole Group Literature Value Occurrence [%]

Frequency of HLA-B*07 20,6% 10,7% 12,2% 0,0% 5,0% 10,0% 15,0% 20,0% 25,0% Subgroup (V 118 I) Whole Group Literature Value Occurrence [%] Frequency of HLA-B*07 + HLA-B*40 17,6% 5,3% 0,8% 0,0% 2,0% 4,0% 6,0% 8,0% 10,0% 12,0% 14,0% 16,0% 18,0% 20,0% Subgroup (V 118 I) Whole Group Literature Value Occurrence [%]

n = 17; P = 0.0344

Frequencies of HLA-types in subgroups compared to the whole group as well as literature values

n = 6; P = 0.0018 n = 17; P = 0.0531

Frequency of HLA-B*40 11,8% 8,0% 6,7% 0,0% 2,0% 4,0% 6,0% 8,0% 10,0% 12,0% 14,0% Subgroup (V 118 I) Whole Group Literature Value Occurrence [%]

n = 17; P = 0.4700

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20.04.2007 | Martin Däumer Seite 13

Institut f Institut fü ür Immunologie und Genetik r Immunologie und Genetik Medizinisches Labor Kaiserslautern Medizinisches Labor Kaiserslautern

Frequency of HLA-B*44 40,0% 9,3% 5,8% 0,0% 5,0% 10,0% 15,0% 20,0% 25,0% 30,0% 35,0% 40,0% 45,0% Subgroup (L 210 F) Whole Group Literature Value Occurrence [%]

Frequency of HLA-A*11 50,0% 8,0% 6,2% 0,0% 10,0% 20,0% 30,0% 40,0% 50,0% 60,0% Subgroup (V 75 I) Whole Group Literature Value Occurrence [%]

n = 2; P = 0.0323 n = 5; P = 0.0074

Mutations in RT

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20.04.2007 | Martin Däumer Seite 14

Institut f Institut fü ür Immunologie und Genetik r Immunologie und Genetik Medizinisches Labor Kaiserslautern Medizinisches Labor Kaiserslautern

Mutations in PR

Frequency of HLA-A*01 37,5% 12,7% 15,2% 5,7% 0,0% 5,0% 10,0% 15,0% 20,0% 25,0% 30,0% 35,0% 40,0% Subgroup (L 33 F) Whole Group Literature Value for Caucasian Population Literature Value for African Population Occurrence [%] Frequency of HLA-B*35 25,0% 14,7% 9,7% 8,5% 0,0% 5,0% 10,0% 15,0% 20,0% 25,0% 30,0% Subgroup (L 33 F) Whole Group Literature Value for Caucasian Population Literature Value for African Population Occurrence [%]

Frequency of HLA-A*01 + HLA-B*35 50,0% 5,3% 1,5% 0,5% 0,0% 10,0% 20,0% 30,0% 40,0% 50,0% 60,0% Subgroup (L 33 F) Whole Group Literature Value for Caucasian Population Literature Value for African Population Occurrence [%]

n = 4; P = 0.0643 n = 4; P = 0.6044 n = 4; P = 0.0125

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20.04.2007 | Martin Däumer Seite 15

Institut f Institut fü ür Immunologie und Genetik r Immunologie und Genetik Medizinisches Labor Kaiserslautern Medizinisches Labor Kaiserslautern

Frequency of HLA-A*03 40,0% 14,0% 13,4% 0,0% 5,0% 10,0% 15,0% 20,0% 25,0% 30,0% 35,0% 40,0% 45,0% Subgroup (M 46 I / L) Whole Group Literature Value Occurrence [%] Frequency of HLA-B*35 40,0% 14,7% 9,7% 0,0% 5,0% 10,0% 15,0% 20,0% 25,0% 30,0% 35,0% 40,0% 45,0% Subgroup (M 46 I / L) Whole Group Literature Value Occurrence [%]

Frequency of HLA-A*03 + HLA-B*35 60,0% 12,0% 1,3% 0,0% 10,0% 20,0% 30,0% 40,0% 50,0% 60,0% 70,0% Subgroup (M 46 I / L) Whole Group Literature Value Occurrence [%]

n = 5; P = 0.0109 n = 5; P = 0.0344 n = 5; P = 0.0406

Mutations in PR

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20.04.2007 | Martin Däumer Seite 16

Institut f Institut fü ür Immunologie und Genetik r Immunologie und Genetik Medizinisches Labor Kaiserslautern Medizinisches Labor Kaiserslautern

Correlation of resistance mutations and HLA types

Frequency in genotype Mutation HLA-A / -B Subgroup Whole group

K103R B* 44 41.7 % 9.3 % 5.8 % 0.0018 V118I B* 07 + B* 40 17.6 % 5.3 % 0.8 % 0.0344 L210F B* 44 40 % 9.3 % 5.8 % 0.0074 V75I A* 11 50 % 8 % 6.2 % 0.0323 L33F A* 01 + B* 35 50% 5.3 % 1.5 % Caucasians 0.5 % Africans 0.0125 M46I/L A* 03 40 % 14 % 13.4 % 0.0344 M46I/L B* 35 40 % 14.7 % 9.7 % 0.0406 M46I/L A* 03 + B* 35 60% 12 % 1.3 % 0.0109

  • Lit. Value

P value Phenotypic HLA frequency: presence of the HLA molecule on the cell surface, independent of the gene dose Genotypic HLA frequency: presence of the HLA molecule multiplied by the gene dose

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20.04.2007 | Martin Däumer Seite 17

Institut f Institut fü ür Immunologie und Genetik r Immunologie und Genetik Medizinisches Labor Kaiserslautern Medizinisches Labor Kaiserslautern

Control

I s this cohort representative?

Investigation of the already reported correlation D121x & HLA-B* 35 (P = 0.0001) (Moore et al., 2002)

Our study revealed a P value of: 0.000005 proves that this study cohort acts like a normal population

  • f HIV positive patients and the previous selection of

patients did not cause a shift (bias) in the normal distribution

  • f variation
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20.04.2007 | Martin Däumer Seite 18

Institut f Institut fü ür Immunologie und Genetik r Immunologie und Genetik Medizinisches Labor Kaiserslautern Medizinisches Labor Kaiserslautern

Summary I

Ethnic analysis

  • 80.5 % of Caucasian origin
  • 7.8 % of African origin
  • 3.9 % of Asian origin
  • 7.8 % origin unknown

75/ 103 ART naive patients who harbor HIV drug resistance mutations were typed

for both HLA-A & -B for 8 resistance associated positions not yet reported significant correlations between drug resistance mutations and HLA-type were found: K103R & HLA-B* 44; V118I & HLA-B* 07 + HLA-B* 40; L210F & HLA-B* 44; V75I & HLA-A* 11; L33F & HLA-A* 01 + HLA-B* 35; M46I/L & HLA-A* 03; M46I/L & HLA-B* 35; M46I/L & HLA-A* 03 + HLA-B* 35

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20.04.2007 | Martin Däumer Seite 19

Institut f Institut fü ür Immunologie und Genetik r Immunologie und Genetik Medizinisches Labor Kaiserslautern Medizinisches Labor Kaiserslautern

Summary I I / Discussion

Control: already reported correlation D121x & HLA-B* 35 (Moore et al., 2002) was also found in our cohort Our results support the finding that 2/3 (67%) of the CTL epitopes on HIV are HLA- B restricted (Kiepiela et al., 2004)

  • 4 of the 6 possible escape variants are HLA-B restricted, only 2 are HLA-A

restricted According to a study with heavily antiretroviral-treated patients (Mason et al., 2004) L210W in combination with HLA-B* 44 is less frequently recognized than the wild- type

  • ur study revealed L210F in combination with HLA-B* 44 as a possible

escape mutation (Phe is homologous to Trp)

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20.04.2007 | Martin Däumer Seite 20

Institut f Institut fü ür Immunologie und Genetik r Immunologie und Genetik Medizinisches Labor Kaiserslautern Medizinisches Labor Kaiserslautern

Conclusions

■the results of this study contribute to the understanding of the relationship

between HIV infection and immune response

■the knowledge about HLA restricted HIV drug resistance mutations might be

helpful in designing new therapy strategies

■the results of this study indicate that the prevalence of transmitted drug

resistance could effectively be higher than determined by several nationwide survey programs

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20.04.2007 | Martin Däumer Seite 21

Institut f Institut fü ür Immunologie und Genetik r Immunologie und Genetik Medizinisches Labor Kaiserslautern Medizinisches Labor Kaiserslautern

Future Aspects

Next step: ELISPOT

This assay will clarify whether these resistance mutations

concomitantly represent CTL escape mutations in the respective HLA background

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20.04.2007 | Martin Däumer Seite 22

Institut f Institut fü ür Immunologie und Genetik r Immunologie und Genetik Medizinisches Labor Kaiserslautern Medizinisches Labor Kaiserslautern

Rolf Kaiser Institute of Virology, University of Cologne

Finja Schweitzer

Melanie Balduin Saleta Sierra-Aragon Dörte Hammerschmidt Achim Buech MPI for Informatics, Saarbrücken Andre Altmann

Kirsten Roomp

Thomas Lengauer

Bernhard Thiele

Institute of Immunology and Genetics, Medical Laboratory, Kaiserslautern

Rolf Klein

Daniel Hoffmann FH Bingen; caesar, Bonn Joachim Selbig MPl of Molecular Plant Physiology, Golm Eugen Schülter caesar, Bonn Hauke Walter Institute of Clinical and Molecular Virology, Klaus Korn German National Reference Center for Retroviruses, University of Erlangen-Nürnberg

Marc Oette

  • Dept. of Gastroenterology, University of Düsseldorf

Gerd Fätkenheuer

  • Dept. of Internal Medicine I, University of Cologne

Jürgen Rockstroh

  • Dept. of Internal Medicine I, University of Bonn

Thomas Berg Medical Laboratory, Berlin Patrick Braun PZB Aachen

Acknowledgements