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Genetic Restriction of HIV-1 Infection and Progression to AIDS by a Deletion Allele of the CKR5 Structural Gene

Genetic Restriction of HIV-1 Infection and Progression to AIDS by a Deletion Allele of the CKR5 Structural Gene. 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 By Jacinta Gaitor.

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Genetic Restriction of HIV-1 Infection and Progression to AIDS by a Deletion Allele of the CKR5 Structural Gene

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  1. Genetic Restriction of HIV-1 Infection and Progression to AIDS by a Deletion Allele of the CKR5 Structural Gene 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 By Jacinta Gaitor

  2. Introduction • Phenotypic variations of resistance in a population. • HIV-1 epidemic has evoked the study of genetic variation and susceptibility to infections in different hosts. • HLA locus associated with different rates of progression from infection to AIDS.

  3. Chemokine Receptors • Chemokine receptors are G-protein-linked serpentine receptors • Co-receptors for the binding of immunodeficiency viruses (eg HIV) to leucocytes. • Chemokines RANTES, MIP-1 , and MIP-1 role as natural HIV-1 • Fusin, CD4, CKR2B, CKR3 and CKR5 (principal cellular receptor). • Individuals at high risk for the HIV-1 infection have been observed to have CD4+T cells that have been relatively resistant to infection.

  4. The Genetic mapping of CKR5 and Fusin • Fusin and the CKR5 are genetically mapped using the polymerase chain reaction (PCR). • RH results indicates that fusin is positioned on chromosome 2q21 and CKR5 on chromosome 3p21.

  5. Representation of Chemokine Receptor clusters in the Human Genome

  6. Determination of Genotype Frequency among HIV-1 Infected versus Non-infected Individuals • Genomic DNA was screened by using 170 mapped polymorphic loci. • Distortion of allele and geneotype frequency among HIV-1 positive vs high risked HIV-1 negative persons were determined.

  7. A Graph Showing Genotypic markers and HIV-1 infection [G test ]

  8. Analysis of Graph • CKR5 show a significant distortion of genotype frequencies among the infected vs uninfected. • The other loci (CD4, chemokine SCYAL, HLADQAL, TCRA,TCRB) on the other hand did not show such a significance.

  9. Further Examination of CKR5 Allele • Distribution of alleles and genotypes with genomic DNA were determined in 1955 patients • Subjects used for the experiment were high risk HIV-1 type ndividuals. • The experiment also included HIV-1-exposed seronegative individuals, HIV-1-infected AIDS patients, and HIV-1-infected individuals who have not yet progressed to AIDS. • CKR5 frequency was found to be greatest in high risk HIV-1 individuals and less in those cosidered to be of low risk. • CKR5 frequency was found least in African Americans.

  10. HIV-1 infected vs non infected • CKR5 frequencies were found to be relatively the same in HIV-! Infected and non infected individuals. • A significant difference of CKR5 was found in the genotypic distribution between infected and non infected individuals. • High risk HIV-I antibody negative individuals were found to have 17 homozygous CKR5 32 genes which is highly significant (G=35.0, p=2.5*10-8). • Homozygous CKR5 32 allele was non existent in HIV-1 infected patients but the Heterozygote gene was found.

  11. Hemophiliacs vs Homosexuals • There is a difference in response in hemophiliacs vs homosexuals due to : • 1) transmission • 2)exposure level • 3)viral load • Hemophiliacs consist of large doses of HIV-1 contaminating clotting factors. • Homosexuals sexual transmission involve HIV-1 mucosal epithelium infection.

  12. Analysis of CKR5 Heterozygote frequency

  13. Homozygotes vs Heterozygotes for CKR5 32 gene • Heterozygotes for CKR5 show a delayed progression to AIDS ic comparison with homozygotes (x2 =8.1, p=0.0045). • Probability is >0.01 therefore difference is significant. • CKR5 32 may be dominant and due to interaction with other genes/environment it may prolong AIDS in infected persons.

  14. Results of Investigation • Persons homozygous (recessive) for CKR5 have greater reduced risk of HIV-1 infection • Heterozygotes can be infected but due to CKR5 HIV-1 co –receptor limiting viral spreading in infected persons ultimately delaying AIDS.

  15. 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.

  16. 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????

  17. References • 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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