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intro. Persons in a population respond to diseases differently due to the phenotypic variations of resistance. It is proposed that inheritance factors play a major role in mortality rates.

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  • Persons in a population respond to diseases differently due to the phenotypic variations of resistance.
  • It is proposed that inheritance factors play a major role in mortality rates.
  • HIV-1 epidemic has evoked the study of genetic variation and susceptibility to infections in different hosts.
  • Research has shown a specific allele of the HLA locus to be associated with different rates of progression from infection to AIDS.
chemokine receptors
Chemokine Receptors
  • Chemokine receptors are G-protein-linked serpentine receptors
  • Also used as co-receptors for the binding of immunodeficiency viruses (eg HIV) to leucocytes.
  • Chemokines RANTES, MIP-1 , and MIP-1 role as natural HIV-1 suppressors are being studied.
  • The chemokine co-receptor and receptors associated with the above mentioned are 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.
the genetic mapping of ckr5 and fusin
The Genetic mapping of CKR5 and Fusin
  • The locus encoding fusin and the CKR5 are genetically mapped using the polymerase chain reaction (PCR).
  • PCR screens a panel of 90 radiation hybrid (RH) DNA samples of the human genome.
  • The allocation of RH results indicates that fusin is positioned on chromosome 2q21 and CKR5 on chromosome 3p21.
  • These loci are mapped in small clusters along different locations in the human genome (represented in the subsequent graph).
determination of genotype frequency among hiv 1 infected versus non infected individuals
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.
analysis of graph
Analysis of Graph
  • According to the data displayed in the 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.
further examination of ckr5 allele
Further Examination of CKR5 Allele
  • Distribution of alleles and genotypes with genomic DNA were determined in 1955 patients in order to find important variables in HIV-1 infection and its progression
  • 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.
hiv 1 infected vs non infected
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).
  • Therefore, the CKR5 32 gene seem to have a recessive phenotype associated with HIV-1 infection resistance and antibody production.
  • Homozygous CKR5 32 allele was non existent in HIV-1 infected patients but the Heterozygote gene was found.
  • In homosexual HIV-1 infected long term non progressors heterozygotes were twice the percentage compared to rapid progressors.
  • In Hemophilia individuals the heterozygote frequency differences between rapid progressors and non progressors were insignificant.
hemophiliacs vs homosexuals
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.
homozygotes vs heterozygotes for ckr5 32 gene
Homozygotes vs Heterozygotes for CKR5 32 gene
  • Multiple tests in 1987 and 1992 for AIDS definition show that 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.
  • Hence single-gene CKR5 32 may be dominant and due to interaction with other genes/environment it may prolong AIDS in infected persons.
results of investigation
Results of Investigation
  • Persons homozygous (recessive) for CKR5 have greater reduced risk of HIV-1 infection due to absence of functional CKR5 co-receptor.
  • Heterozygotes can be infected but due to CKR5 HIV-1 co –receptor limiting viral spreading in infected persons ultimately delaying AIDS.
  • Large differences in frequencies of CKR5 were found amongst Caucasians (0.11) compared to African Americans (0.017) which may be because CKR5 is a recent recessive mutation.
  • A Genetic restriction experiment including HIV-1-infected individuals vs. HIV-1-antibody-negative individuals were performed on 1955 patients.
  • 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.
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  • Eight CKR5 variant alleles were found. These include the 32 deletion; a variant that occurred as a heterozygote in 15 individuals of 600 screened by SSCP; four variants found as heterozygous in single individuals that were HIV-1 infected, but had not progressed to AIDS after 7 to 10 years; and two variants in HIV-1-infected individuals that had not been followed for long term as yet. Preliminary sequence analysis revealed missense alterations in codons for conserved amino acids in three of the variants.
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