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CCR5 promoter polymorphism and HIV-1 disease progression. Multicenter AIDS Cohort Study (MACS).
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- Author(s): McDermott, David H.; Zimmerman, Peter A.; Guignard, Florence; Kleeberger, Cynthia A.; Leitman, Susan F.; McDermott, D H (AUTHOR); Zimmerman, P A (AUTHOR); Guignard, F (AUTHOR); Kleeberger, C A (AUTHOR); Leitman, S F (AUTHOR); Murphy, P M (AUTHOR)
- Source:
Lancet. 9/12/1998, Vol. 352 Issue 9131, p866-870. 5p. 2 Charts, 10 Graphs. - Source:
- Additional Information
- Subject Terms: GENETIC polymorphisms; HIV infections; CHEMOKINES; HIV-positive persons; PATHOLOGY; AIDS; ALLELES; CELL receptors; COMPARATIVE studies; DNA; DOCUMENTATION; GENES; HIV; LONGITUDINAL method; RESEARCH methodology; MEDICAL cooperation; NUCLEOTIDES; POLYMERASE chain reaction; RESEARCH; EVALUATION research; DISEASE progression
- Abstract:
Background: The rate of progression to AIDS varies among individuals infected with HIV-1. Factors responsible include two inherited human alleles, CCR5 delta32 and CCR2-641, which alter the protein-coding regions for the HIV-1 coreceptors/chemokine receptors CCR5 and CCR2b. We tested the hypothesis that polymorphisms of the CCR5 promoter might affect the rate of progression of HIV-1 infected people to AIDS.Methods: We used directed heteroduplex analysis to identify polymorphism in the CCR5 promoter. Promoter-variants were compared in vitro with a chloramphenicol acetyltransferase reporter gene, and in vivo by genotyping HIV-1 seroconvertors discordant at polymorphous loci.Findings: An A/G polymorphism was identified at basepair 59029 (Genbank U95626) in the CCR5 promoter. Both promoter alleles were common (43-68% allelic frequency for 59029-A depending on race). When in-vitro promoter activity was measured, 59029-G had 45% lower activity than 59029-A (p=0.05). In a cohort of HIV-1 seroconvertors lacking both CCR5 delta32 and CCR2-641, 59029-G/G individuals progressed to AIDS on average 3.8 years more slowly than 59029-A/A individuals (p=0.004). 59029-G/A discordance did not correlate with discordant rates of infection.Interpretation: Our results are consistent with the hypothesis that CCR5 is important in HIV-1 pathogenesis. CCR5 59029-G/G appears to be protective relative to CCR5 59029-A/A, and about twice as protective relative to CCR5 delta32 or CCR2-641. This effect may be the result of reduced CCR5 mRNA production. These results identify the first site in the CCR5 promoter that may be a useful target for treatment of HIV-1 infection. [ABSTRACT FROM AUTHOR] - Abstract: Copyright of Lancet is the property of Lancet and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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