intro

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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.
• 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.

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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 CD4T cells that have
  been relatively resistant to infection.

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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).

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Representation of Chemokine Receptor clusters in
the Human Genome
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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.

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

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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.

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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 (G35.0, p2.510-8).
• 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.

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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.

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Analysis of CKR5 Heterozygote frequency
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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, p0.0045).
• Probability is gt0.01 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.

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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.

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Conclu

• A Genetic restriction experiment including
  HIV-1-infected individuals vs. HIV-1-antibody-nega
  tive 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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