A chemokine receptor CCR2 allele delays HIV-1 disease progression and is associated with a CCR5 promoter mutation

Abstract

Viral and host factors influence the rate of HIV-1 disease progression. For HIV-1 to fuse, a CD4+ cell must express a co-receptor that the virus can use. The chemokine receptors CCR5 and CXCR4 are used by R5 and X4 viruses, respectively. Most new infections involve transmission of R5 viruses, but variants can arise later that also use CXCR4 (R5-X4 or X4 viruses). This is associated with an increased rate of CD4+ T-cell loss and poor prognosis. The ability of host cells to support HIV-1 entry also influences progression. The absence of CCR5 in approximately 1% of the Caucasian population, due to homozygosity for a 32-nucleotide deletion in the coding region (delta32-CCR5 allele), very strongly protects against HIV-1 transmission. Heterozygosity for the delta32-CCR5 allele delays progression typically by 2 years. A recent study showed that a conservative substitution (V64I) in the coding region of CCR2 also has a significant impact on disease progression, but not on HIV-1 transmission. This was unexpected, since CCR2 is rarely used as a co-receptor in vitro and the V64I change is in a transmembrane region. Because a subsequent study did not confirm this effect on progression to disease, we analyzed CCR2-V64I using subjects in the Chicago MACS. We show that CCR2-V64I is indeed protective against disease progression and go on to show that the CCR2-V64I allele is in complete linkage disequilibrium with a point mutation in the CCR5 regulatory region.

Evidence for recent selection of the CCR5-Δ32 deletion from differences in its frequency between Ashkenazi and Sephardi Jews

“…In order to verify if differences between Ashkenazi and Sephardi Jews exist also in other CC-chemokine receptor genes we have analysed in our cohort the frequency of the CCR2-64I mutation (see Table 2), which is associated with slower progression to AIDS in a number of retrospective analyses. [12][13] We have found no significant difference in the frequency of the CCR2-64I allele between the Ashkenazi (9.2%, n = 142) and the Sephardi (13.4%, n = 67, P Ͼ 0.2). Although these results are only for a subset of our cohort, note that the difference in CCR5-⌬32 is already significant in that subset.…”

“…We studied Israeli Jewish blood donors of known ancestry in order to expand on that initial observation and look for differences in the distribution of the CCR5-⌬32 allele and genotypes between Ashkenazi and Sephardi Jews. As a control we study the frequency of the CCR2-64I [12][13][14] which was also associated with slower HIV disease progression, as function of the two origin groups. In addition, we discuss a number of possible mechanisms to explain the differences in genetic frequencies between Ashkenazi and Sephardi, considering that both groups originated from the same ancestry about a 1000 years ago.…”

Genetic aspects in sarcoidosis

“…C-C chemokine receptor 2 (CCR2) is a receptor for MCP-1, other related chemokines, and human immunodeficiency virus (HIV)-1 infection. A polymorphism in the gene has been described in which the variant 64Val±±>lle is associated with delayed progression to acquired immunodeficiency syndrome (AIDS) [103]. The same polymorphism was found to be less frequent in 100 Japanese patients with sarcoidosis than in 122 controls (OR=0.369) [104].…”

Global human genetics of HIV-1 infection and China

“…CCR2-64I is common and found in 10% of Caucasians, 15% of African-Americans, 25% of Asians and 17% of Hispanics [50]. Epidemiologic studies by Smith et al first demonstrated the association of CCR2-64I with delayed HIV-1 disease progression [50], which was confirmed by most subsequent studies [73,98,99], but not by others [82,100,101]. CCR2-64I is not associated with reduced risk for HIV-1 infection [50].…”

“…CCR2-64I is not associated with reduced risk for HIV-1 infection [50]. The mechanism for the association of CCR2-64I with delayed disease progression has not been elucidated despite significant attempts to do so [98,102,103].…”