A chemokine receptor CCR2 allele delays HIV-1 disease progression and is associated with a CCR5 promoter mutation.
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.
Kostrikis
L G
LG
The Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York 10016, USA.
Huang
Y
Y
Moore
J P
JP
Wolinsky
S M
SM
Zhang
L
L
Guo
Y
Y
Deutsch
L
L
Phair
J
J
Neumann
A U
AU
Ho
D D
DD
D000483:Alleles; D018791:CD4 Lymphocyte Count; D015331:Cohort Studies; D018450:Disease Progression; D005838:Genotype; D015658:HIV Infections / Q000235:genetics*; D006679:HIV Seropositivity; D015528:HIV Seroprevalence; D015497:HIV-1; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D011379:Prognosis; D011401:Promoter Regions, Genetic; D054390:Receptors, CCR2; D019713:Receptors, CCR5 / Q000235:genetics*; D019707:Receptors, Chemokine / Q000235:genetics*
C515334:CCR2 protein, human; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine