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Genetic Restriction of HIV-1 Infection and Progression to AIDS by a Deletion Allele of the CKR5 Structural Gene. Presented by: Poincyane Assis.

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Introduction

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  1. Genetic Restriction of HIV-1 Infection and Progression to AIDS by a Deletion Allele of the CKR5 Structural Gene.Presented by: Poincyane Assis Dean, M., M. Carrington, C. Winkler, G.A. Huttley, M.W. Smith, R. Allikmets, J.J. Goedert, S.P. Buchbinder, E. Vittinghoff, E. Gomperts, S. Donfield, D. Vlahov, R. Kaslow, A. Saah, C. Rinaldo, and R. Detels.

  2. Introduction • Transmission of the HIV-1 virus • Medicinal advancement • HIV-1 research findings of possible HIV-resistance gene implicates the need for genetic studies • Association of specific alleles of HLA(Human lymphocyte antigen with progression of infection to AIDS diagnosis

  3. Genotypic markers and HIV-1 Infection

  4. CKR5 and Delta 32 • CKR5 is a chemokine (chemical factor released by immune cell, acts as natural suppresson • CKR5 and receptor are proteins • If Delta 32 base pair deleted then a frame shift of amino acid occurs • 32 magic number; 33 has no frame shift • Addition or deletion not divisible by three will cause a frame shift. • Codons are triplet code which consists of three nucleotides

  5. What is CKR5 32 role in HIV infection? • Long-term study on six cohorts who fall into high-risk groups for HIV-1 infection • Significant difference in genotype distribution not allele frequency of CKR5 • 17 homozygotes for CKR5 32 found • CKR5 32 associated with resistance to HIV-1 infection and antibody production • Significant number of heterozygotes infected patients to examine rates of HIV-1 progression to AIDS.

  6. Recessive versus Dominant • Recessive restriction is expressed with 2 copies • Dominate phenotype with only 1 allele • Allele is and alternative form of a gene • Homozygous (same alleles) • Heterozygous (different alleles)

  7. CKR5 32 genotypes analysis in relation to AIDS progression • Frequency of CKR5 32 heterozygotes in HIV- infected patients

  8. CKR5 32 genotypes analysis in relation to AIDS progression • Dependence of disease progression on CKR5 genotype from MHCS, SFCC, DCG.

  9. CKR5 32 genotypes analysis in relation to AIDS progression • Dependence of disease progression to AIDS on the CKR5 genotype among 148 HIV-1-seropositive members of the SFCC

  10. Survival Analysis • Comparison of CKR5 genotypes: homozygous/heterozygous using 1992 AIDS definition • Results show heterozygous have delayed progression to AIDS compared to homozygous. • Trend observed in all cohorts except DCG(43 patients) • Effects of CKR5 32 may be dominant and gene interaction is necessary to prolong development of AIDS

  11. Table 2. CKR5 genotype distribution among HIV-1-seropositive and HIV-1-seronegative individuals in the same risk group

  12. Deletion Allele – CKR5 • Deletion allele absent in HIV-1-infected individuals • Results prove that CKR5 heterozygotes progression to AIDS is slower than CKR5 homozygotes for normal gene. • Hence, it is proposed that the CKR5 allele may act as a recessive restriction gene. • CKR5 – An alternative antiviral therapy????

  13. Conclusion A Genetic restriction experiment including HIV-1-infected individuals vs. HIV-1-antibody-negative individuals were performed The study includes the chemokine receptor 5 (CKR5) protein. CKR5 (structural Gene) is a deletion allele found at a frequency of ~0.1 in Caucasian Americans. Cohort study show 17 deletion homozygotes occurring exclusively in HIV-1-antibody-negative individuals.

  14. Reference • Dean, M. et al. 1996. Genetic Restriction of HIV-1 Infection and Progression to AIDS by a Deletion Allele of the CKR5 Structural Gene. Science 273:1858-1862

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