Deletion of the CKR5 Gene

1. Deletion of the CKR5 Gene Can it Stop AIDS?

2. 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 that’s used with CD4+ when HIV infects a cell

3. Important definitions CKR5 Δ32 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

4. 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.

5. CKR5 Δ32 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

6. 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

7. 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)

8. Without CKR5, M-Tropic infection is not possible, thus T-Tropic infection and AIDS is not possible Without CKR5, HIV’s 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

9. Other Possibilities MIP-1ά: macrophage inflammatory protein (tracks CD8+ cells) RANTES: regulated activaation, normal T expressed and secreted MIP-1β: macrophage inflammatory protein (tracks CD4+ cells) SDF1: stromal derived factor These are nonreceptor chemokines

10. Other Possibilities Other nonreceptor chemokines have been found to block HIV infection by preventing the virus from binding to the coreceptors CD4+ and CKR5

11. 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 doesn’t create a correct copy of CKR5

12. In Conclusion: • This mutant creates an ineffectual CKR5 gene because of Δ32 deletion • Without infection into macrophages in early stages if infection, HIV’s 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

13. 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-1ά, MIP-1β, and SDF1.