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DNA methylation as an epigenetic marker in HIV-2 disease in West Africa? Alberta Davis MRC Laboratories , Gambia 18 th

DNA methylation as an epigenetic marker in HIV-2 disease in West Africa? Alberta Davis MRC Laboratories , Gambia 18 th January 2013. HIV pathogenicity and clinical outcomes. AIDS: causal agents; retroviruses HIV-1 HIV-2

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DNA methylation as an epigenetic marker in HIV-2 disease in West Africa? Alberta Davis MRC Laboratories , Gambia 18 th

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  1. DNA methylation as an epigenetic marker in HIV-2 disease in West Africa? Alberta Davis MRC Laboratories, Gambia 18th January 2013

  2. HIV pathogenicity and clinical outcomes • AIDS: causal agents; retroviruses • HIV-1 • HIV-2 • HIV-1 “elite” controllers, long term non progressors (LTNPs), exposed uninfected. (Saksenaet al 2007) • HIV-2 infection is less progressive (low VL, low transmission, slow decline of CD4 T cells, prolonged survival). • 20% of HIV-2 infected individuals exhibit high VL and a clinical presentation indistinguishable from AIDS in HIV-1.(Esbjörnssonet al, 2012)

  3. Determinants of progression to AIDS

  4. Host determinants • CCR5 receptor: • Viral entry into CD4 T cells. • mutation confers resistance to infection with HIV. • Variable CCR5 expression in HIV-1 is associated with matrices of infection and pathogenesis. • Low and protective levels of CCR5 on CD4+ T cells is exhibited in HIV-2 infections (Shea et al 2004). • IL-2 –CCR5 are coregulated genes and CCR5 can influence signaling events during T cell activation (Camargo et al 2009).

  5. Epigenetics and its regulation of genes • Epigenetic mechanisms: • Heritable but reversible without change in DNA sequence • DNA methylation in CpG dinucleotide = gene repression

  6. hypothesis “ The DNA methylation status of regulatory regions of CCR5 and IL-2 serve as a determinant of differential HIV-2 pathogenicity” • Objective • To determine the methylation status at CCR5 cis-regulatory CpG sites and IL-2 gene loci in progressive and non progressive infections • Evaluate the frequencies of CCR5 genetic variants

  7. Methods • HIV-2 rich cohorts – Guinea Bissau and Gambia. • Interrogated patient database based on previous studies of HIV-2 non progression (Berry et al 2002, Schim van der Loeffet al 2010). • Categorised samples into various groups based on CD4 and Viral load • Progressor: CD4 <200 cells/uland VL > 10,000 copies/ml • Non progressor: CD4 >500 cells/ul and VL < 100 copies/ml

  8. Overview of patient profiles

  9. Specific CpG in CCR5 cis regulatory sites Bisulphite modification and pyrosequencing(CCR5 and IL-2)

  10. Association between DNA methylation and CD4 CD4 > 500 (n = 21) CD4 > 200 (n = 15)

  11. Correlation CD4 and methylation of CCR5 and IL-2

  12. Progressor (L/H) and non progressor (H/L) phenotypes show different methylation patterns L/H (n = 12) H/L (n = 12)

  13. Conclusion • The CD4 count and VL load could be influenced by methylation levels. • Viral control in non progressors is being achieved by low CCR5 expression and maintenance of CD4+ T cells which produce IL-2. • Progressors are less methylated at CCR5 regulatory regions but more methylated at the IL-2 locus than non progressors. • No significant difference was found at CCR5 promoter 2 possibly because Pr2 is active only upon T cell activation

  14. Recruitment of patient and blood sampling in Guinea Bissau Duration in the cohort (1989, 1997, 2003, 2006) • HIV-2 non progressor,HIV-2 progressor,HIV-1 asymptomatics, Healthy controls. • CCR5 and IL-2 DNA methylation • CCR5and IL-2 mRNA expression levels • CCR5 allelic discrimination • Immunophenotyping by flow cytometry • Multiplex cytokine analysis by Bioplex-cytokine analysis

  15. Acknowledgements UTHSCSA Prof Sunil K. Ahuja Dr He Weijing KomathyJayasekar Una Aluyen ShivaliChag MRC Unit Dr Assan Jaye Pa SaidouChaw, MD Dr Alfred Ngwa Ramou-Sarge Njie Gilleh Thomas James Jafali

  16. THANK YOU!

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