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Rapid progression to AIDS in HIV+ individuals with a structural variant of chemokine receptor CX3CR1

Rapid progression to AIDS in HIV+ individuals with a structural variant of chemokine receptor CX3CR1.

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Rapid progression to AIDS in HIV+ individuals with a structural variant of chemokine receptor CX3CR1

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  1. Rapid progression to AIDS in HIV+ individuals with a structural variant of chemokine receptor CX3CR1 Sophie Faure, Laurence Meyer, Dominique Costagliola, Celine Vaneensberghe, Emmanuelle Genin, Brigitte Autran, French ALT, and IMMUNOCO study group, David H. McDermott, Philip M. Murphy, Patrice Debre, Ioannis Theodorou, Christophe Combadiere By Kendra Sipres

  2. Human Immunodeficiency Virus (HIV) • HIV enters cells in vitro by CD4 T-Lymphocytes and a coreceptor • The structure of a CD4 cell makes it an easy target for HIV – so it attacks the cell • HIV uses the cells as a breeding ground for new virus particles • Eventually CD4 cells are killed off and chances of getting a severe disease or opportunistic illness is increased greatly

  3. HIV Coreceptors • A coreceptor is required for HIV to enter cells • Coreceptors such as CXCR4 enables certain strains of HIV to fuse with and enter immune cells called T cells • CCR5 are necessary for the entry of HIV into immune cells called macrophages • CCR5 is a binding site for chemokines that play a role in suppressing HIV infection • chemokines suppress HIV replication by binding to the same receptors needed by certain strains of HIV to enter immune cells

  4. CX3CR1 • CX3CR1 is another coreceptor of HIV • This coreceptor is observed in caucasions • It is a leukocyte chemotactic/adhesion receptor for the chemokine fractalkine

  5. CX3CR1-1249 M280 • This is a variant haplotype affecting two amino acids • Isoleucine-249 & methionine-280 are affected • HIV infected patients who are homozygous for this haplotype progress to AIDS more rapidly • Those with other haplotypes progress slower to AIDS

  6. CX3CR1-1249 M280 • CX3CR1 analysis indicated that fractalkine binding is reduced among those homozygous for this certain haplotype • CX3CR1-1249 M280 is a recessive genetic risk factor in HIV and AIDS

  7. Variability in HIV contraction and progression • Factors responsible for variability are not fully known • Mutations in HIV coreceptors were shown to affect transmission & progression • Strongest form of resistance for HIV and AIDS progression is CCR5 32

  8. CCR5 32 • It is a mutant allele that encodes an inactive form of the chemokine receptor CCR5 • Heterozygosity of this allele leads to slower disease progression • Homozygosity of this allele has high resistance to initial infection of HIV

  9. CCR5 • Another CCr5 variant has been found

  10. The known variants account for only a small percentage of people who appear to have HIV resistance • Identification of other resistance factors is an important key

  11. Rationale • Investigate CX3CR1 chemotactic activity and investigate its possible resistance powers • Search for genetic variants and its effects on regulating HIV

  12. Method • 78 random French Caucasian blood donors were screened for the CX3CR1 coding sequence mutations • 5 single nucleotide polymorphisms (SNP’s) were identified • All were in the transmembrane domains of the receptor

  13. Results • 4 SNP’s were found to be nonsynonymous

  14. Method • Distribution of V2491 and T280M was studied in 565 individuals from 3 HIV cohorts: • Patients with intermediate progression (IMMUNOCO cohort) • Patients with asymptomatic long-term progression (ALT cohort) • Patients with a known date of serocnversion (SEROCO cohort)

  15. Results • Of the 9 possible genotypes, 6 were observed • Frequencies were observed from 50% for the homozygous wild type to 2% for the doubly mutated homozygote

  16. Results • 3 were never detected • G/G at codon 249 followed by C/T at codon 280 • G /G at codon 249 followed by T/T at codon 280 • G/A at codon 249 followed by T/T at codon 280 • The absence suggests SnP’s are tightly linked & the C/T substitiution at the position 280 occored only when theres an A at codon 249

  17. A likelihood ratio test was done for linkage equilibrium • The test confirmed that the SNP’s were in complete linkage disequilibrium • So only 3 haplotypes of CX3CR1 were found in the Caucasian population: • V249 T280 haplotype • I249 T280 haplotype • I249 M280 haplotype • Respective frequencies were 71.4%, 12.3% & 16.2%

  18. TABLE 1

  19. Disease progression • Case analysis showed more people with the I249 M280 haplotype in the IMMUNOCO cohort compart with ALT cohort had higher rate of disease progression • The CCR5 32 allele was more frequent in the ALT cohort • Results suggest the CX3CR1 1249 M280 haplotype adversely affects HIV progression

  20. Table 2

  21. Disease progression • A Kaplan-Meier survival analysis of those from the SEROCO cohort showed faster progression to AIDS for CX3CR1-M280 homozygotes than CX3CR1-T280 homozygotes (fig. 1-A) • Disease progression was similar for heterozygotes and wild-type homozygotes • This suggests that the effect of the CX3CR1-1249 M280 haplotype is recessive • (in contrast, CCR5-32 AND CCR2-64I alleles have dominant effects)

  22. Figure 1-A & 1-B

  23. Figure 1-B • Those who were partially protected by the CCR5-32 allele were excluded from the analysis • When this was done, the acceleration to AIDS or CD4 decline was more pronounced • This is exhibited in figure 1-B

  24. Analysis of CX3CR1 SNP distribution • The CX3CR1 gene is on the chromosome 3p21 • This is in the vicinity of the CCR5 and CCR2 genes • The SNP was analyzed to verify that the effect is ue to CX3CR1 • The CX3CR1 SNP was analyzed in relation to the CCR5-32 and CCR2-641 alleles

  25. Results • Neither CX3CR1 SNPexhibited any linkage disequilibrium with CCR2-641 or CCR5-32 • No linkage disequilibrium was found between CX3CR1 V249I and T289M • Therefore, the CX3CR1-I249 M280 haplotype is independent of any previously defined disease-modifying mutations in CCR5 & CCR2

  26. Comparison of fractalkine binding & primary peripheral blood mononuclear cells (PBMCs) • 2 CX3CR1 SNPs defining the haplotype are in the coding sequence • These could affect the receptor function • To test this fractalkine binding and PBMCs were compared from HIV infected patients • Patients were homozygous for CX3CR1-V249 T280 VS. CX3CR1-1249 M280

  27. Results • Tests showed reduced binding affinity of 125I-labeled fractalkine to cells from CX3CR1-1249 M280 homozygotes vs. wild-type cells • This shows 2 SNPs affect the integrity of the receptor • Total # of binding sites pre cell was reduced in CX3CR1-I249 M280 homozygotes vs. wild-type

  28. Characterization of fractalkine binding parameters • This was done in order to determine the specific effect on the function of each SNP constituting the CX3CR1-I249 M280 haplotype • They were characterized for PBMCs from 2 pateints • Patients were homozygous for haplotype CX3CR1-I249 T280

  29. Results • Receptor expression did not differ enough from the other haplotypes • Fractalkine binding affinity differed fro comparision with CX3CR1-V249 T280 & CX3Cr1-I249 M280 • This data shows that T280M may directly affect ligand recognition • Further research is needed

  30. Conclusion • The results of this experiment show that CX3CR1 is polymorphic in Caucasian population • Variant haplotype CX3CR1I249 M280 is associated with accelerated HIV disease • Reduced receptor expression & fractalkine binding could compromise normal immune responses • This could lead to accelerated progression of HIV & AIDS • Further research is needed

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