CCR5 promoter polymorphism and HIV-1 disease progression. Multicenter AIDS Cohort Study (MACS)

Area of Science:

• Genetics and immunology
• HIV-1 pathogenesis research
• Molecular biology of chemokine receptors

Background:

• HIV-1 progression rates vary significantly among infected individuals.
• Inherited alleles CCR5 delta32 and CCR2-641 influence HIV-1 coreceptor function.
• The role of CCR5 promoter polymorphisms in HIV-1 disease progression remains unclear.

Purpose of the Study:

• To investigate the hypothesis that CCR5 promoter polymorphisms affect HIV-1 disease progression.
• To identify specific CCR5 promoter variants influencing the rate of progression to AIDS.

Main Methods:

• Directed heteroduplex analysis was employed to detect CCR5 promoter polymorphisms.
• In vitro assays compared promoter activity using a chloramphenicol acetyltransferase reporter gene.
• In vivo analysis involved genotyping HIV-1 seroconvertors discordant at polymorphic loci.

Main Results:

• A common A/G polymorphism (59029-A/G) was identified in the CCR5 promoter.
• The 59029-G allele exhibited 45% lower promoter activity in vitro compared to 59029-A.
• Individuals with the 59029-G/G genotype progressed to AIDS 3.8 years slower than 59029-A/A homozygotes (p=0.004).

Conclusions:

• CCR5 promoter polymorphisms are significant factors in HIV-1 pathogenesis.
• The CCR5 59029-G/G genotype offers protection against rapid AIDS progression, potentially via reduced CCR5 mRNA.
• The CCR5 promoter 59029 site represents a novel therapeutic target for HIV-1 infection.