The role of CCR5 and CCR2 polymorphisms in HIV-1 transmission and disease progression

Abstract

Entry of human immunodeficiency virus type 1 (HIV-1) into target cells requires both CD4 (ref. 1, 2) and one of a growing number of G-protein-coupled seven-transmembrane receptors. Viruses predominantly use one, or occasionally both, of the major co-receptors CCR5 or CXCR4, although other receptors, including CCR2B and CCR3, function as minor co-receptors. CCR3 appears critical in central nervous system infection. A 32-base pair inactivating deletion in CCR5 (delta 32) common to Northern European populations has been associated with reduced, but not absolute, HIV-1 transmission risk and delayed disease progression. A more commonly distributed transition causing a valine to isoleucine switch in transmembrane domain I of CCR2B (64I) with unknown functional consequences was recently shown to delay disease progression but not reduce infection risk. Although we confirm the lack of association of CCR2B 64I with transmission, we cannot confirm the association with delayed progression. Although subjects with CCR5 delta 32 defects had significantly reduced median viral load at study entry, providing a plausible explanation for the association with delayed progression, this association was not seen with CCR2B 64I. Further studies are needed to define the role of CCR2B64I in HIV pathogenesis.

CCR5 promoter polymorphism determines macrophage CCR5 density and magnitude of HIV-1 propagation in vitro

“…Other studies have shown correlations between disease progression and the CCR2-64 I/V amino acid substitution and between CCR5 promoter haplotype/haplotype combinations (diplotype) [10,19,[23][24][25][26][27][28]. We were unable to demonstrate any relationship between these diplotypes and the in vitro phenotype; however, these additional analyses may have been limited by the small numbers of individuals in the diplotype in vitro phenotype categories observed in this study.…”

Apoptosis in SIV infection

“…[156][157][158] Individuals homozygous for CCR5D32 are resistant to HIV-1 infection, whereas the disease progresses slowly in individuals who are heterozygous for this mutation. [159][160][161] Other studies have shown that the proportion of T cells expressing CCR5 differs greatly between individuals and increases chronically in HIV-infected individuals during disease progression, 162,163 and others have shown that the cell surface density of CCR5 correlates positively with disease progression. 164,165 It has been also reported that T-cell depletion in peripheral blood during primary infection was related to T cells expressing CCR5.…”

Frequency of the CCRdelta32 allele in Brazilians: a study in colorectal cancer and in HTLV-I infection

“…Although there is no evidence for a strong protective effect in heterozygotes (Dean et al, 1996;Huang et al, 1996;Michael et al, 1997), a modest reduction in HIV incidence has been reported (Samson et al, 1996b). Also, the observation that cohorts of long-term survivors are enriched for CCR5∆32 heterozygotes suggests the existence of some protection against the AIDS progression (Dean et al, 1996;Michael et al, 1997).…”