Impact of natural chemokine receptor polymorphisms on perinatal transmission of human immunodeficiency virus type 1.

Abstract

The rate of progression of human immunodeficiency virus type 1 (HIV-1) disease exhibits an extraordinary variation among individuals. The most commonly transmitted strains of HIV-1 fuse with their target cells after interacting with CD4 and the CC-chemokine receptor 5 (CCR5). CCR5 is the major co-receptor for the most commonly transmitted strains of HIV-1 (Alkhatib, ’96; Choe, ’96; Deng, ’96; Doranz, ’96; Dragic, ’96). Over the past few years, several mutations in CCR5 have been identified as natural genetic polymorphisms that are able to influence the probability of acquiring HIV-1 infection or to affect the rate of disease progression, in infected adults or infants (Buseyne, ’88; Dean, ’96; Huang, ’96; Liu, ’96; Samson, ’96; Michael, ’97; Zimmerman, ’97; Shearer, ’98). A deletion of 32nucleotides in the CCR5 gene (denoted CCR5-D32) results in a truncated protein that is not expressed on the cell surface; individuals homozygous for this deletion have an absolute resistance to infection by CCR5-using HIV-1 variants (Dean, ’96; Liu, ’96; Samson, ’96), whereas heterozygotes for CCR5-D32 do not resist HIV-1 infection, but progress more frequently to acquired immunodeficiency syndrome (AIDS). Another mutation in a closely linked chemokine receptor gene, CCR2, also affects HIV-1 disease progression. This mutation, denoted CCR2-64I, is a G-to-A substitution that results in a replacement of valine with isoleucine at position 64 of the CCR2 protein (Smith, ’97). The homozygous CCR2-64I/64I phenotype has no effect on HIV-1 transmission but is associated with a delayed progression to disease (Smith, ’97; Kostrikis, ’98). Several genetic variations have recently been identified within the CCR5 regulatory region (Mummidi, ’97, ’98; Kostrikis, ’98; Martin, ’98; McDermott, ’98), some of which have been reported recently to affect the rate of disease progression in adults (Martin, ’98; McDermott, ’98; Mummidi, ’98).