322-W.
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Polymorphisms of Host Genes in Exposed Seronegative Individuals: Impact on HIV-1 Transmission
Y. Hwangbo, J. McElrath, H. Liu, J. Lee, H. Zhu, L. Corey, and T. Zhu*
Univ. of Washington Sch. of Med., Seattle
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Background: Polymorphisms in host genes have been shown to affect HIV-1 transmission and disease progression. Our objective was to determine the overall effect of host genes on HIV-1 transmission by characterizing the genetic polymorphisms in CCR1, CCR2, CCR5, and RANTES in exposed seronegative (ES) individuals.
Methods: The cohorts include 58 ES who have had repeated, unprotected sexual contacts with HIV-1-infected partners, 182 HIV-1 negatives, and 175 HIV-1 positives including 17 long-term non-progressors (LTNP). All of the participants are Caucasian. Direct sequencing was used for CCR1, CCR5, and RANTES coding region. PCR or RFLP were used for genotyping CCR5-DELTA32, CCR2-64I, RANTES promoter -403A and -28G. Fisher,s exact test was used for statistic analysis.
Results: No polymorphism except CCR5-DELTA32 was found in the coding regions of CCR1, CCR5, and RANTES. The frequency of CCR5-DELTA32 homozygote in ES is 3.4%, significantly higher than the non-ES HIV-1 negative and HIV-1 positive groups (p = 0.02). The frequency of CCR5-DELTA32 heterozygote in LTNP is 52.9%, significantly higher than in HIV-1 progressors (p = 0.03). These results confirm that CCR5-DELTA32 homozygosity is associated with the resistance to HIV-1 infection and that heterozygosity delays disease progression. The frequencies of CCR2-64I homozygote in ES, HIV-1 negative, HIV-1 positive, and LTNP are 0.0%, 1.6%, 0.0%, and 5.9%, respectively, while for heterozygote are 12.1%, 12.6%, 16.1%, and 0.0%. There was no significant difference in the frequencies of CCR2-64I genotype and allele among these groups. However, 3 CCR2-64I homozygotes were found in HIV-1-negative cohort (1.6%) and 1 in HIV-1-positive cohort (0.6%), suggesting a possible association between CCR2-64I homozygosity and the resistance to HIV-1 infection. The genotype frequencies of RANTES promoter in ES are 67.2% for G1; 1.7% for G2, G5; 0.0% for G3, G6; and 29.4% for G4.
Conclusions: Compared with the published data, we found neither G1 nor G4 to be associated with the altered risk of HIV-1 infection in Caucasians either with CCR5-DELTA32 (p = 0.55) or without CCR5-DELTA32 (p = 0.86). The mechanisms underlying the resistance to HIV-1 infection in ES are likely to be multifarious.
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