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fact
sheet
CCR5 receptor gene and HIV infection
Antonio
Guilherme Fonseca Pacheco,
University of Pittsburgh
print version
Published
April, 2002
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CCR5
Gene |
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The gene for
CCR5 is located on chromosome 3 in the p21.3-p24 region. CCR5 is a chemokine receptor present in different
cells, especially in macrophages, monocytes, and T cells, where it acts as
a co-receptor for HIV-1 in these cells. Chemokines and their receptors are
believed to be involved in the inflammatory response, mediating
leukocyte movement and activation.
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Prevalence of
Gene Variants |
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At least 23 alleles have been described for the coding region
of this gene, and most of them are very rare. The most common and most
studied is the
32 allele, a 32 base pair (bp) deletion that confers almost absolute
protection from infection with macrophage tropic (M-tropic) viruses in
homozygous individuals and provides an average 2 to 3 year delay in the
progression to AIDS in those heterozygous for the deletion. The allele’s
prevalence varies by ethnicity, being as high as 10%-15% in Caucasians,
~2% in African Americans, and virtually absent in native Africans and East
Asians (3,6).
Several single nucleotide polymorphisms (SNPs) were described in
the promoter region of CCR5, accounting for six different important
haplotypes. Many studies
showed that the 64I allele of another chemokine receptor coding gene, CCR2, is in very strong linkage disequilibrium with one allele of the
promoter region of CCR5 (1), invariably in combination
with CCR5+ (now named haplotype F*2).
These findings led to the modern classification of 9 haplotypes for
CCR5 (A, B, C, D, E, F*1, F*2, G*1, and G*2; the latter corresponding to
the CCR5
32 allele) that actually encompass its open reading frame, the promoter
region, and the CCR2 gene (3,8).
Gonzales et al. have recently published world-wide distributions of these
haplotypes, showing great variation in their frequencies (3). |
Disease
Burden |
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Ninety percent of the infections caused by HIV 1 involve the
so-called M-tropic (or R5-tropic) strains. In addition to the CD4 receptor
present in macrophages, monocytes, and T cells, these strains also need
the presence of a CCR5 receptor on the cell surface to infect. The 32 bp
deletion causes the resultant protein to be truncated and inactive, and
individuals homozygous for the
32 allele present undetectable concentrations of the receptor, while
heterozygous individuals have 20%-30% of the wild type concentrations (5,6).
The result is that homozygous individuals exposed to M-tropic
strains are protected from infection, while infected heterozygous
individuals present a slower progression to both AIDS and death. In a
cohort of 2,996 people, Marmor et al. showed only one seroconversion among
39 CCR5
32/
32 participants, but this was a T-tropic strain that uses the CXCR4
receptor instead of the CCR5 receptor.
In the same study, the risk ratio (RR) for seroconversion was 0.30
(95% Confidence Interval: 0.08-0.96) in the CCR5
32/+ group compared with the
CCR5+/+
group when controlled for unprotected receptive anal sex (4).
In another study that combined five different cohorts totaling
3,003 patients, Smith et al. showed that seropositive heterozygous
individuals had a prolonged survival time to AIDS (Relative Hazard (RH) =
0.68, p = 0.002) and to death (RH = 0.67, p = 0.02) (7).
In a recent study by Tang et al., some features of the nine
CCR5
haplotypes were studied, and the haplotype
G*2, especially the
genotype A/G*2, was more frequent in individuals highly exposed to HIV and
persistently seronegative (OR = 0.54, 95% CI: 0.32-0.89) (8). Viral load during the first 42 months of infection was lower
in G*2 carriers, especially among those with genotypes A/G*2 and F*2/G*2).
Progression to AIDS was also delayed for
G*2 carriers.
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Interactions |
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Several factors interact in HIV 1 transmission
since the infection depends on variables related to susceptibility,
transmissibility, and host response to infection. Several other genes may
play a role in the susceptibility of the cells to HIV infection.
The role of gene expression of CCR5 chemokine ligands in HIV
infection has been the subject of intense research, since the suppression
of these ligands, secondary to CD8+ cell depletion in
HIV-positive patients, has been demonstrated to lead, at least in part, to
accelerated viral replication. Although
there is strong evidence of potent inhibition of HIV replication in vitro,
studying RANTES, MIP-1a
and MIP-1b
expressions in HIV positive cohorts has shown conflicting results (2).
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Laboratory
Tests
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Several different methods have been used for CCR5
genotyping, but the most common methods are DNA-PCR, followed by
restriction fragment length polymorphism (RFLP) or sequencing.
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Population
Testing |
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To date, no recommendation on population testing
has been issued. Since the major factor in HIV infection is exposure to
the virus, protective measures against the exposure continue to be
recommended as public health policy.
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References |
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Carrington,
M., et al., Genetics of HIV-1 infection: chemokine receptor CCR5
polymorphism and its consequences.
Hum
Mol Genet, 1999. 8(10): p. 1939-45.
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Gallo,
R.C., A. Garzino-Demo, and A.L. DeVico, HIV
infection and pathogenesis: what about chemokines? J Clin Immunol, 1999.
19(5): p. 293-9.
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Gonzalez, E., et al., Global survey of genetic variation in CCR5, RANTES, and MIP-1alpha:
impact on the epidemiology of the HIV-1 pandemic. Proc Natl Acad Sci U S
A, 2001. 98(9): p.
5199-204.
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Marmor,
M., et al., Homozygous and
heterozygous CCR5-Delta32 genotypes are associated with resistance to HIV
infection. J Acquir Immune Defic Syndr, 2001. 27(5):
p. 472-81.
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McNicholl,
J.M., et al., Host genes and HIV: the
role of the chemokine receptor gene CCR5 and its allele. Emerg Infect
Dis, 1997. 3(3): p. 261-71.
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O'Brien,
S.J. and J.P. Moore, The effect of
genetic variation in chemokines and their receptors on HIV transmission and
progression to AIDS. Immunol Rev, 2000. 177:
p. 99-111.
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Smith,
M.W., et al., Contrasting genetic
influence of CCR2 and CCR5 variants on HIV-1 infection and disease
progression. Hemophilia Growth and Development Study (HGDS), Multicenter
AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San
Francisco City Cohort (SFCC), ALIVE Study. Science, 1997. 277(5328):
p. 959-65.
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Tang,
J., et al., Distribution of chemokine receptor CCR2 and CCR5 genotypes
and their relative contribution to human immunodeficiency virus type 1
(HIV-1) seroconversion, early HIV-1 RNA concentration in plasma, and later
disease progression. J Virol. 2002 6(2):662-72.
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Web sites |
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UNAIDS
JAMA
HIV/AIDS Resource Center
Johns
Hopkins AIDS Service
Centers
for Disease Control and Prevention, Office of Genomics and Disease Prevention
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