Contrasting Genetic Influence of CCR2 and CCR5 Variants on HIV-1 Infection and Disease Progression

Abstract

The critical role of chemokine receptors (CCR5 and CXCR4) in human immunodeficiency virus-type 1 (HIV-1) infection and pathogenesis prompted a search for polymorphisms in other chemokine receptor genes that mediate HIV-1 disease progression. A mutation (CCR2-64I) within the first transmembrane region of the CCR2 chemokine and HIV-1 receptor gene is described that occurred at an allele frequency of 10 to 15 percent among Caucasians and African Americans. Genetic association analysis of five acquired immunodeficiency syndrome (AIDS) cohorts (3003 patients) revealed that although CCR2-64I exerts no influence on the incidence of HIV-1 infection, HIV-1-infected individuals carrying the CCR2-64I allele progressed to AIDS 2 to 4 years later than individuals homozygous for the common allele. Because CCR2-64I occurs invariably on a CCR5-+-bearing chromosomal haplotype, the independent effects of CCR5-Delta32 (which also delays AIDS onset) and CCR2-64I were determined. An estimated 38 to 45 percent of AIDS patients whose disease progresses rapidly (less than 3 years until onset of AIDS symptoms after HIV-1 exposure) can be attributed to their CCR2-+/+ or CCR5-+/+ genotype, whereas the survival of 28 to 29 percent of long-term survivors, who avoid AIDS for 16 years or more, can be explained by a mutant genotype for CCR2 or CCR5.

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].…”

“…Unlike the CCR5-32 allele that inactivated the major HIV-1 coreceptor, CCR2-64I causes a conservative change in a nonexposed portion of a coreceptor of questionable physiologic relevance [68,96,97]. 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].…”

“…Significant studies in the past few years have also demonstrated that innate immunity including genetic polymorphisms in host genes can affect the risk for HIV-1 infection and disease progression (Tab. 1), although the effect of these alleles has been inconsistent [32,[45][46][47][48][49][50][51][52][53][54][55] (reviewed in [56]). Here, we review global and Chinese studies on human genetic polymorphisms and their association with HIV-1 infection.…”

“…individuals that are CCR5-32 homozygotes (people who inherited the CCR5-32 from both parents) are resistant to HIV-1 infection, indicating that genotype CCR5-32 is highly protective against HIV-1 infection [45][46][47][48][49][50]54]. However, this protection is not absolute because rare individuals homozygous for CCR5-32 are infected with HIV-1 strains that may utilize another co-receptor, such as CXCR4 [64][65][66][67][68].…”

“…However, this protection is not absolute because rare individuals homozygous for CCR5-32 are infected with HIV-1 strains that may utilize another co-receptor, such as CXCR4 [64][65][66][67][68]. Furthermore, homozygous CCR5-32 is found only in 1% of the general population of Caucasians, but not in Africans, Asians or other ethnic groups [45][46][47][48][49][50]54], and the majority of highly exposed yet uninfected individuals have two normal CCR5 alleles (called wild-type, or wt). Similarly, we found CCR5-32 homozygotes in 1.0% (7 out of 705) of HIV-1 seronegative individuals and 3.1% (3 out of 97) of ES.…”