Deletion of the CKR5 Gene

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Deletion of the CKR5 Gene

• Can it Stop AIDS?

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Important definitions
Homozygous Mutants Two similar genes on two
different chromosomes that are mutants due to
deletion leading to a frame shift
CD4 (cluster differentiation) A glycoprotein
coreceptor that the HIV virus uses to infiltrate
a macrophage
CKR5 (chemokine receptor 5) A glycoprotien
coreceptor thats used with CD4 when HIV infects
a cell
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Important definitions
CKR5 ?32 Deletion deletion of 32 nucleotides.
When the number of nucleotides deletion are not
divisible by 3, a frame shift occurs since an
amino acid is determined by 3 nucleotides
M Tropic In the early stages of HIV infection,
the virus is attracted to macrophage cells. This
is the Non-syncytium-inducing (NSI) phase
T Tropic In the later stages of HIV infection,
the virus is attracted to T-lymphocyte cell. This
is the Syncytium-inducing (SI) phase
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How can CKR5 deletion prevent AIDS?
Because CKR5 is a coreceptor neededfor the HIV
virus to infect a cell, if it is absent, the
virus cannot infect the cell.
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CKR5 ?32 deletion
When two homozygous recessive genes are present
in a cell, CKR5 undergoes a frame shift, and the
result is a defective CKR5 coreceptor protein.
The result is an inability of HIV infection
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Evidence of CKR5 Mutations inhibiting HIV
infection
People with two recessive copies of a mutant CKR5
gene will not get infected by HIV and will never
have AIDS
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Position of CKR5 Gene
CKR5 is located on the 3rd chromosome, 21st gene
of the petite (short) end of the chromosme (3p21)
These chromosomes were mapped using Radiation
Hybrid panels (RH panels)
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Without CKR5, M-Tropic infection is not possible,
thus T-Tropic infection and AIDS is not possible
Without CKR5, HIVs GP120 protein cannot bind to
the macrophages in M-tropic stage, and cannot
mutate in order to bind to CKR4 (fusin)
coreceptor in T-cells
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Other Possibilities
MIP-1? macrophage inflammatory protein (tracks
CD8 cells)
RANTES regulated activaation, normal T expressed
and secreted
MIP-1ß macrophage inflammatory protein (tracks
CD4 cells)
SDF1 stromal derived factor
These are nonreceptor chemokines
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Other Possibilities
Other nonreceptor chemokines have been found to
block HIV infection by preventing the virus from
binding to the coreceptors CD4 and CKR5
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In Conclusion

• The HIV virus requires coreceptors to infiltrate
  cells
• Those coreceptors are primarily CD4 and CKR5
• It has been found that in some HIV resistant
  individuals, the CKR5 receptor is absent
• Upon further examination, it is seen that the
  gene that expresses CKR5 is a mutant that doesnt
  create a correct copy of CKR5

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In Conclusion

• This mutant creates an ineffectual CKR5 gene
  because of ?32 deletion
• Without infection into macrophages in early
  stages if infection, HIVs GP32 protein cannot
  mutate and infect T cells
• Other chemokines outside the cell are able to
  block HIV infection by binding to the CD4 and
  CKR5 coreceptors of the cells

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In Other Words

• We may be able to prevent HIV infection by
  mutating 3p21 genes and CKR5.
• Or
• We may be able to prevent HIV infection by having
  more chemokines like RANTES, MIP-1?, MIP-1ß, and
  SDF1.