CKR532 Deletion: Restriction Gene Against HIV1 Infection and Delayed Progression to AIDS

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CKR5?32 Deletion Restriction Gene Against HIV-1
Infection and Delayed Progression to AIDS

• Angeliz Rivera
• BIO 475
• March 1, 2006

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HIV-1 Infection

• Invades CD4 and macrophages
• Initiates infection in macrophages (M-tropic)
• Later become T-tropic (invades T cell CD4)
• Cell have to display a second receptor
• Within 10 to 15 years it destroys key cells

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AIDS

• T-tropic viruses kill the cell they infect
• Overall drop of CD4
• Onset of opportunistic infections and cancer
• Todays define by presence of AIDS-defining
  illness or by a drop in CD4 T cells to fewer than
  200 per cubic mm.

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CKR5

• Chemokine receptor protein
• Serve as second receptor for M tropic strains of
  HIV
• Alteration to gene for gp120 change CKR5
• Genetic change causes M tropic to shift to T
  tropic

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CKR5?32 Deletion

• Located in human chromosome 3p21
• Causes a frameshift at aminoacid 185
• Is nonfunctional both as chemokine receptor and
  an HIV-1 co-receptor
• Protective against HIV-1

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Dean, M., M. Carrington, C. Winkler, G.A.
Huttley, M.W. Smith, R. Allikmets, J.J. Goedert,
S.P. Buchbinder, E. Vittinghoff, E. Gomperts, S.
Donfield, D. Vlahov, R. Kaslow, A. Saah, C.
Rinaldo, R.Detels, Hemophilia Growth and
Developmental Study, Multicenter AIDS Cohort
Study, Multicenter Hemophilia Cohort Study, San
Francisco City Cohort, ALIVE Study, and S.J.
OBrien. 1996. Genetic restriction of HIV-1
infection and progression to AIDS by a deletion
allele of the CKR5 structural gene. Science
2731856-1862.
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Objective

• Examine association of CKR5 genotype and rates
  of progression

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Frequency of CKR5?32/ heterozygotes in patients
that progress to AIDS vs. non progressors
Note Progression to AIDS vs. non progressors are
defined differently by the different cohorts.
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Results

• Homosexual cohorts, but not the hemophiliac
  cohorts, showed greater than twice the of
  heterozygotes among non progressor compared with
  progressor to AIDS.
• Differential response due to different route of
  transmission, exposure level, and viral load.

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Dependence of disease progression on CKR5
genotype among seroconverters
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Dependence of disease progression on CKR5
genotype among seroconverters
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Results

• /?32 heterozygotes have a delayed progression to
  AIDS compared with / homozygotes

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Conclusion

• The CKR5?32 deletion may act as a recessive
  restriction gene against HIV-1 infection and may
  exert a dominant phenotype of delaying
  progression to AIDS among infected individuals.

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